{"gene":"KRT19","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2016,"finding":"KRT19 directly interacts with the β-catenin/RAC1 complex in breast cancer cells, enhancing nuclear translocation of β-catenin, which drives NUMB expression and thereby suppresses NOTCH signaling; knockdown of KRT19 reduces nuclear β-catenin, lowers NUMB, and activates NOTCH-mediated cancer stem cell properties.","method":"Co-immunoprecipitation, knockdown/overexpression with phenotypic readouts (proliferation, migration, invasion, sphere formation), nuclear fractionation, reporter assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple orthogonal functional assays, mechanistic pathway placement validated in patient-derived CSLCs","pmids":["27345400"],"is_preprint":false},{"year":2019,"finding":"In colon cancer cells KRT19 interacts with β-catenin alone (not with RAC1), enabling LEF/TCF transcription factor binding to LEF1 and TCF7 promoters and activating Wnt/Notch signaling, whereas in breast cancer KRT19 interacts with the β-catenin/RAC1 complex and suppresses Notch via NUMB upregulation — demonstrating tissue-context-dependent differential protein interactions.","method":"Co-immunoprecipitation, ChIP assay, knockdown with cell proliferation/invasion assays, promoter-binding analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP in two cancer types, single lab","pmids":["30650643"],"is_preprint":false},{"year":2019,"finding":"CK19 physically interacts with CFTR at the apical plasma membrane of bronchial epithelial cells; CK19 overexpression stabilizes both wild-type and VX-809-rescued F508del-CFTR at the plasma membrane by preventing Rab7A-mediated lysosomal degradation, thereby promoting chloride secretion. CK19 expression is reduced ~40% in primary CF bronchial epithelial cells.","method":"Co-immunoprecipitation (CK19–CFTR interaction), overexpression/knockdown with surface biotinylation, Rab7A dominantnegative rescue, Ussing chamber Cl⁻ secretion assay, cell fractionation","journal":"FASEB Journal","confidence":"High","confidence_rationale":"Tier 1–2 — direct protein interaction validated, mechanistic rescue experiment with Rab7A, functional ion-transport readout, multiple orthogonal methods","pmids":["31450978"],"is_preprint":false},{"year":2024,"finding":"A nuclear fraction of KRT19 acts as a transcriptional corepressor: KRT19 binds HDAC1 and RCOR1 (components of the CoREST complex), enhances HDAC1–RCOR1 interaction, increases CoREST deacetylase activity, and represses hepatocyte-specific genes including HNF4A, promoting dedifferentiation and liver tumorigenesis.","method":"Cell fractionation (nuclear KRT19 identification), tandem affinity purification/mass spectrometry (CoREST complex interaction), Co-IP, HDAC activity assay, KRT19 KO with ChIP-seq (HNF4A locus), in vivo multiplexed genome editing of hepatocytes, patient-derived xenograft experiments","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1–2 — mass spectrometry-identified interaction confirmed by Co-IP, enzymatic activity assay, ChIP-seq, in vivo KO; multiple orthogonal methods in one study","pmids":["38557414"],"is_preprint":false},{"year":2021,"finding":"Linc-KILH lncRNA binds KRT19 protein and inhibits phosphorylation of KRT19 at Ser35, causing KRT19 to translocate from cytoplasm to the plasma membrane; this enhanced membrane-localized KRT19 interacts with β-catenin (but not RAC1 in HCC cells) and promotes nuclear β-catenin translocation and Notch1 signaling activation.","method":"RNA-protein pulldown, Co-IP, phosphorylation assay, subcellular fractionation/immunofluorescence, knockdown with proliferation/metastasis assays in vitro and in vivo","journal":"International Journal of Biological Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and fractionation confirm interaction and localization shift; single lab with multiple methods","pmids":["33767587"],"is_preprint":false},{"year":1997,"finding":"In a pancreatic adenocarcinoma cell model, transfection of K8 stabilizes endogenous K19, forming K8/K19 keratin filaments; co-expression of K18 with K8 suppresses cell motility, soft-agar growth, and in vivo tumorigenicity in a K18-dose-dependent manner, whereas K8/K19-expressing cells retain motile and tumorigenic properties.","method":"Stable transfection of K8 and/or K18, Western blot (K19 stabilization), soft-agar colony assay, motility assay, syngeneic tumor injection","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 — reconstitution in cell model with multiple functional readouts; single lab","pmids":["9152022"],"is_preprint":false},{"year":2016,"finding":"miR-26a directly targets the 3′UTR of KRT19 mRNA, suppressing KRT19 protein expression; knockdown of miR-26a increases the side-population (SP) fraction of cholangiocarcinoma cells via KRT19 upregulation, and ectopic miR-26a expression suppresses cell proliferation and tumor growth in vitro and in vivo.","method":"3′UTR luciferase reporter assay (direct miR-26a–KRT19 interaction), gain/loss-of-function assays, SP cell flow cytometry, xenograft model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3′UTR binding validated by reporter assay, functional rescue experiments; single lab","pmids":["27833076"],"is_preprint":false},{"year":2024,"finding":"miR-374b-5p directly targets KRT19, inhibiting activation of the Wnt/β-catenin pathway and suppressing EMT in pancreatic cancer; under hypoxia, HIF1α upregulates KRT19 expression and loss of miR-642a-5p further elevates KRT19, promoting pancreatic cancer progression.","method":"3′UTR luciferase reporter assay (miR-374b-5p–KRT19), overexpression/knockdown with proliferation/migration/invasion assays, Western blot for EMT markers and Wnt components, hypoxia/HIF1α manipulation","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay confirms direct miRNA–KRT19 interaction, pathway effects validated by multiple functional assays; single lab","pmids":["39280598"],"is_preprint":false},{"year":2019,"finding":"BRAFV600E mutation induces KRT19 expression in thyroid cancer cells; KRT19 knockdown inhibits proliferation and migration, and mechanistically KRT19 promotes epithelial-mesenchymal transition (EMT) to drive lymph node metastasis.","method":"BRAFV600E overexpression with KRT19 measurement, KRT19 knockdown with proliferation/migration assays, EMT marker analysis (Western blot/qPCR), TCGA database validation","journal":"Oncology Letters","confidence":"Medium","confidence_rationale":"Tier 2–3 — upstream inducer identified (BRAFV600E) with functional KD phenotype and EMT pathway placement; single lab","pmids":["31289571"],"is_preprint":false},{"year":2018,"finding":"KRT19 modulates cancer stem cell reprogramming in breast cancer by regulating expression of CSC markers (ALDH1, CXCR4, CD133) and the phosphorylation status of Src and GSK3β (Tyr216); overexpression of KRT19 in aggressive CSLCs attenuates CSC properties, while KRT19 knockdown enhances them.","method":"KRT19 knockdown/overexpression, sphere formation assay, drug resistance assay, Western blot for phospho-Src and phospho-GSK3β, CSC marker quantification by flow cytometry","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple orthogonal assays but mechanistic link to kinase phosphorylation is correlative; single lab","pmids":["29747452"],"is_preprint":false},{"year":2003,"finding":"Linc00974 acts as a competing endogenous RNA (ceRNA) for miR-642, indirectly upregulating KRT19 expression; elevated KRT19 activates Notch and TGF-β signaling pathways to promote hepatocellular carcinoma proliferation and metastasis.","method":"miRNA target prediction and validation, ceRNA luciferase assay, KRT19 knockdown, cDNA microarray pathway analysis, xenograft models","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — ceRNA mechanism validated by reporter assay; pathway activation confirmed by microarray and KD phenotype; single lab","pmids":["25476897"],"is_preprint":false},{"year":2020,"finding":"CK19 promotes epithelial ovarian cancer cell proliferation, migration, and invasion by activating the Wnt/β-catenin signaling pathway, as shown by upregulation of β-catenin, TCF7, LEF1, c-MYC, and cyclin D1 upon CK19 overexpression and their downregulation upon knockdown.","method":"CK19 overexpression/knockdown, Transwell invasion/migration assay, CCK-8 proliferation assay, Western blot and RT-PCR for Wnt pathway components","journal":"OncoTargets and Therapy","confidence":"Low","confidence_rationale":"Tier 3 — single lab, KD/OE with pathway marker readout but no direct binding assay between CK19 and Wnt components shown","pmids":["32273715"],"is_preprint":false},{"year":2010,"finding":"KRT19 promoter methylation represses KRT19 gene expression in renal carcinoma cell lines; treatment with the demethylating agent 5-aza-2′-deoxycytidine and the HDAC inhibitor trichostatin A re-activates KRT19 expression with concomitant decrease in promoter methylation, demonstrating epigenetic regulation of KRT19.","method":"Methylation-specific PCR/bisulfite sequencing of promoter, 5-aza-dC + TSA treatment with RT-PCR expression measurement in renal carcinoma cell lines","journal":"DNA and Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct epigenetic manipulation with functional rescue of expression; limited to cell lines","pmids":["20874491"],"is_preprint":false}],"current_model":"KRT19 functions as a multifunctional intermediate filament protein whose mechanistic roles include: (1) scaffolding a β-catenin/RAC1 signaling complex that controls nuclear β-catenin translocation, NUMB expression, and Wnt/NOTCH crosstalk in a tissue-context-dependent manner; (2) stabilizing CFTR at the apical plasma membrane by blocking Rab7A-mediated lysosomal degradation; (3) acting in the nucleus as a transcriptional corepressor that enhances CoREST/HDAC1 deacetylase activity to silence hepatocyte-differentiation genes; and (4) being regulated post-translationally by phosphorylation at Ser35 (modulated by Linc-KILH) and transcriptionally by miRNAs (miR-26a, miR-374b-5p, miR-642a-5p) and upstream oncogenic signals such as BRAFV600E."},"narrative":{"teleology":[{"year":1997,"claim":"The question of whether KRT19 plays a passive structural role or an active functional role in epithelial cells was first addressed: K8 co-expression stabilizes endogenous K19 into filaments, and K8/K19-expressing cells retain motile and tumorigenic properties distinct from K8/K18-expressing cells, establishing that KRT19-containing filaments have functional consequences beyond cytoskeletal support.","evidence":"Stable transfection of K8 ± K18 in pancreatic adenocarcinoma cells with soft-agar colony, motility, and syngeneic tumor assays","pmids":["9152022"],"confidence":"Medium","gaps":["Mechanism by which K19 vs K18 filaments differentially affect motility was not identified","No direct signaling interactors of K19 were mapped"]},{"year":2010,"claim":"Whether KRT19 expression is epigenetically silenced in cancer was resolved: KRT19 promoter CpG methylation represses transcription in renal carcinoma, and demethylation plus HDAC inhibition restores expression, establishing epigenetic regulation as a layer controlling KRT19 levels.","evidence":"Methylation-specific PCR, bisulfite sequencing, 5-aza-dC + TSA treatment in renal carcinoma cell lines","pmids":["20874491"],"confidence":"Medium","gaps":["Upstream signals directing promoter methylation were not identified","Whether methylation-based silencing occurs in non-renal cancers was not tested"]},{"year":2014,"claim":"The mechanism by which lncRNAs regulate KRT19 abundance was established: Linc00974 acts as a ceRNA sponging miR-642 to upregulate KRT19, which in turn activates Notch and TGF-β signaling to promote hepatocellular carcinoma progression.","evidence":"ceRNA luciferase assay, KRT19 knockdown, cDNA microarray pathway analysis, xenograft models","pmids":["25476897"],"confidence":"Medium","gaps":["Direct binding between KRT19 protein and Notch/TGF-β pathway components was not demonstrated","ceRNA stoichiometry in physiological conditions was not assessed"]},{"year":2016,"claim":"The central signaling mechanism of KRT19 was defined: KRT19 directly scaffolds a β-catenin/RAC1 complex, promoting nuclear β-catenin translocation and NUMB-mediated Notch suppression in breast cancer cells, thereby linking an intermediate filament protein to Wnt/Notch crosstalk.","evidence":"Reciprocal Co-IP, nuclear fractionation, reporter assays, knockdown/overexpression with proliferation, migration, invasion, and sphere formation readouts in patient-derived CSLCs","pmids":["27345400"],"confidence":"High","gaps":["Structural basis of KRT19–β-catenin–RAC1 ternary complex was not resolved","Whether the interaction occurs outside breast cancer lineages was untested at this point"]},{"year":2016,"claim":"Post-transcriptional regulation of KRT19 by miRNA was established: miR-26a directly binds the KRT19 3′UTR to suppress protein expression, with functional consequences on the side-population fraction and tumor growth in cholangiocarcinoma.","evidence":"3′UTR luciferase reporter assay, gain/loss-of-function assays, SP flow cytometry, xenograft model","pmids":["27833076"],"confidence":"Medium","gaps":["Whether miR-26a regulation of KRT19 operates in non-biliary epithelia was not examined","Other miRNA targets contributing to the phenotype were not excluded"]},{"year":2018,"claim":"The downstream signaling consequences of KRT19 in cancer stem cells were extended: KRT19 modulates Src and GSK3β phosphorylation and CSC marker expression (ALDH1, CXCR4, CD133) in breast cancer, connecting its scaffold function to kinase-level signaling.","evidence":"KRT19 knockdown/overexpression, sphere formation, drug resistance assay, Western blot for phospho-Src and phospho-GSK3β","pmids":["29747452"],"confidence":"Medium","gaps":["Direct binding of KRT19 to Src or GSK3β was not tested—kinase effects remain correlative","Mechanism linking β-catenin scaffold to Src phosphorylation was not delineated"]},{"year":2019,"claim":"Tissue-context dependence of KRT19 signaling was established: in colon cancer KRT19 interacts with β-catenin alone (not RAC1), enabling LEF/TCF promoter binding and activating—rather than suppressing—Notch, contrasting with the β-catenin/RAC1/NUMB axis in breast cancer.","evidence":"Co-IP, ChIP assay at LEF1/TCF7 promoters, knockdown with proliferation/invasion readouts in colon vs breast cancer cells","pmids":["30650643"],"confidence":"Medium","gaps":["Determinants specifying whether RAC1 is included in the complex remain unknown","Whether context-dependent effects reflect stoichiometric differences or distinct post-translational modifications was not resolved"]},{"year":2019,"claim":"A non-signaling, membrane-stabilization function of KRT19 was discovered: KRT19 physically interacts with CFTR at the apical membrane and prevents Rab7A-mediated lysosomal trafficking, stabilizing both wild-type and pharmacologically rescued F508del-CFTR and sustaining chloride secretion.","evidence":"Co-IP of CK19–CFTR, surface biotinylation, Rab7A dominant-negative rescue, Ussing chamber Cl⁻ secretion in primary bronchial epithelial cells","pmids":["31450978"],"confidence":"High","gaps":["Binding interface between KRT19 and CFTR was not mapped","Whether reduced CK19 in CF epithelia is a cause or consequence of disease pathology was not fully resolved"]},{"year":2019,"claim":"An upstream oncogenic inducer of KRT19 was identified: BRAFV600E drives KRT19 expression in thyroid cancer, and KRT19 promotes EMT-mediated metastasis.","evidence":"BRAFV600E overexpression, KRT19 knockdown with proliferation/migration assays, EMT marker Western blot","pmids":["31289571"],"confidence":"Medium","gaps":["Direct transcriptional mechanism by which BRAFV600E upregulates KRT19 promoter was not mapped","EMT effects were correlative without direct β-catenin interaction data in thyroid cells"]},{"year":2021,"claim":"Post-translational control of KRT19 localization was delineated: the lncRNA Linc-KILH binds KRT19 and inhibits Ser35 phosphorylation, redirecting KRT19 from cytoplasm to plasma membrane where it engages β-catenin (without RAC1) to activate Notch1 in hepatocellular carcinoma.","evidence":"RNA-protein pulldown, phosphorylation assay, subcellular fractionation, immunofluorescence, Co-IP, in vivo metastasis assays","pmids":["33767587"],"confidence":"Medium","gaps":["Kinase responsible for Ser35 phosphorylation was not identified","Structural basis for lncRNA-mediated phosphorylation inhibition is unknown"]},{"year":2024,"claim":"A nuclear function of KRT19 was discovered: nuclear KRT19 binds HDAC1 and RCOR1, enhances CoREST deacetylase activity, and represses hepatocyte-differentiation genes including HNF4A, establishing KRT19 as a transcriptional corepressor that promotes liver dedifferentiation and tumorigenesis.","evidence":"Tandem affinity purification/mass spectrometry, Co-IP, HDAC activity assay, ChIP-seq at HNF4A locus, in vivo multiplexed genome editing, patient-derived xenograft experiments","pmids":["38557414"],"confidence":"High","gaps":["Whether nuclear KRT19 retains filament structure or exists as soluble monomers/oligomers is unknown","Genome-wide target spectrum of KRT19-CoREST beyond HNF4A was not comprehensively defined"]},{"year":2024,"claim":"Additional miRNA regulators of KRT19 were identified: miR-374b-5p directly targets KRT19 to inhibit Wnt/β-catenin and EMT in pancreatic cancer, while HIF1α-driven hypoxia and loss of miR-642a-5p converge to upregulate KRT19.","evidence":"3′UTR luciferase reporter assay, overexpression/knockdown with proliferation/migration/invasion assays, hypoxia/HIF1α manipulation","pmids":["39280598"],"confidence":"Medium","gaps":["Relative contributions of miR-374b-5p vs miR-642a-5p to KRT19 regulation under physiological conditions were not quantified","Whether HIF1α directly binds the KRT19 promoter was not demonstrated"]},{"year":null,"claim":"Major unresolved questions include: the structural basis of KRT19's interactions with β-catenin, CFTR, and the CoREST complex; the determinants specifying tissue-context-dependent partner selection (RAC1 inclusion vs exclusion); the identity of the Ser35 kinase; and whether the nuclear corepressor function and membrane scaffold function operate simultaneously or are mutually exclusive pools in the same cell.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural or cryo-EM data for any KRT19 signaling complex","Mechanism sorting KRT19 between cytoplasmic filaments, plasma membrane, and nuclear pools is undefined","In vivo genetic models (knockout mice) have not clearly separated structural from signaling functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4,7,9,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,12]}],"complexes":["CoREST complex (HDAC1/RCOR1)"],"partners":["CTNNB1","RAC1","CFTR","HDAC1","RCOR1","KRT8"],"other_free_text":[]},"mechanistic_narrative":"KRT19 is a type I intermediate filament keratin that, beyond its structural role, functions as a signaling scaffold and transcriptional corepressor across multiple epithelial cell contexts. KRT19 directly binds β-catenin—alone or in a β-catenin/RAC1 complex depending on tissue type—to promote nuclear β-catenin translocation and modulate Wnt and Notch pathway crosstalk; in breast cancer this suppresses Notch via NUMB upregulation, whereas in colon cancer and hepatocellular carcinoma it activates LEF/TCF-driven transcription and Notch signaling [PMID:27345400, PMID:30650643, PMID:33767587]. In bronchial epithelial cells, KRT19 stabilizes CFTR at the apical plasma membrane by blocking Rab7A-mediated lysosomal degradation, thereby sustaining chloride secretion [PMID:31450978]. A nuclear pool of KRT19 interacts with HDAC1 and RCOR1 to enhance CoREST deacetylase activity and repress hepatocyte-differentiation genes such as HNF4A, promoting liver dedifferentiation and tumorigenesis [PMID:38557414]. KRT19 expression is regulated epigenetically by promoter methylation, post-translationally by Ser35 phosphorylation modulated by the lncRNA Linc-KILH, and post-transcriptionally by miRNAs including miR-26a and miR-374b-5p [PMID:20874491, PMID:33767587, PMID:27833076, PMID:39280598]."},"prefetch_data":{"uniprot":{"accession":"P08727","full_name":"Keratin, type I cytoskeletal 19","aliases":["Cytokeratin-19","CK-19","Keratin-19","K19"],"length_aa":400,"mass_kda":44.1,"function":"Involved in the organization of myofibers. Together with KRT8, helps to link the contractile apparatus to dystrophin at the costameres of striated muscle","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P08727/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT19","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT19","total_profiled":1310},"omim":[{"mim_id":"620053","title":"LONG INTERGENIC NONCODING RNA 974; LINC00974","url":"https://www.omim.org/entry/620053"},{"mim_id":"614384","title":"MICRO RNA 492; MIR492","url":"https://www.omim.org/entry/614384"},{"mim_id":"601047","title":"CAVEOLIN 1; CAV1","url":"https://www.omim.org/entry/601047"},{"mim_id":"178500","title":"INTERSTITIAL LUNG DISEASE 2; ILD2","url":"https://www.omim.org/entry/178500"},{"mim_id":"148070","title":"KERATIN 18, TYPE I; KRT18","url":"https://www.omim.org/entry/148070"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Intermediate filaments","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":857.0},{"tissue":"intestine","ntpm":737.0},{"tissue":"salivary gland","ntpm":772.3},{"tissue":"urinary bladder","ntpm":729.8}],"url":"https://www.proteinatlas.org/search/KRT19"},"hgnc":{"alias_symbol":["K19","CK19","K1CS","MGC15366"],"prev_symbol":[]},"alphafold":{"accession":"P08727","domains":[{"cath_id":"-","chopping":"144-229_252-390","consensus_level":"medium","plddt":93.9203,"start":144,"end":390}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08727","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08727-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08727-F1-predicted_aligned_error_v6.png","plddt_mean":79.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRT19","jax_strain_url":"https://www.jax.org/strain/search?query=KRT19"},"sequence":{"accession":"P08727","fasta_url":"https://rest.uniprot.org/uniprotkb/P08727.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08727/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08727"}},"corpus_meta":[{"pmid":"2464285","id":"PMC_2464285","title":"Suprabasal 40 kd keratin (K19) expression as an immunohistologic marker of premalignancy in oral epithelium.","date":"1989","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/2464285","citation_count":201,"is_preprint":false},{"pmid":"26046762","id":"PMC_26046762","title":"Krt19(+)/Lgr5(-) Cells Are Radioresistant Cancer-Initiating Stem Cells in the Colon and Intestine.","date":"2015","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/26046762","citation_count":172,"is_preprint":false},{"pmid":"25476897","id":"PMC_25476897","title":"A novel biomarker Linc00974 interacting with KRT19 promotes proliferation and metastasis in hepatocellular carcinoma.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/25476897","citation_count":168,"is_preprint":false},{"pmid":"18543299","id":"PMC_18543299","title":"A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs.","date":"2008","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/18543299","citation_count":163,"is_preprint":false},{"pmid":"18324628","id":"PMC_18324628","title":"Intra-operative rapid diagnostic method based on CK19 mRNA expression for the detection of lymph node metastases in breast cancer.","date":"2008","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18324628","citation_count":135,"is_preprint":false},{"pmid":"27345400","id":"PMC_27345400","title":"KRT19 directly interacts with β-catenin/RAC1 complex to regulate NUMB-dependent NOTCH signaling pathway and breast cancer properties.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27345400","citation_count":110,"is_preprint":false},{"pmid":"8874391","id":"PMC_8874391","title":"Detection of micrometastases in colorectal cancer patients by K19 and K20 reverse-transcription polymerase chain reaction.","date":"1996","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8874391","citation_count":102,"is_preprint":false},{"pmid":"10762743","id":"PMC_10762743","title":"Molecular detection of cancer cells in bone marrow and peripheral blood of patients with operable breast cancer. Comparison of CK19, MUC1 and CEA using RT-PCR.","date":"2000","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/10762743","citation_count":92,"is_preprint":false},{"pmid":"11269941","id":"PMC_11269941","title":"The human hair follicle contains two distinct K19 positive compartments in the outer root sheath: a unifying hypothesis for stem cell reservoir?","date":"2000","source":"Differentiation; research in biological diversity","url":"https://pubmed.ncbi.nlm.nih.gov/11269941","citation_count":86,"is_preprint":false},{"pmid":"16762018","id":"PMC_16762018","title":"Immunohistological evaluation of Ki-67, p63, CK19 and p53 expression in oral epithelial dysplasias.","date":"2006","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16762018","citation_count":85,"is_preprint":false},{"pmid":"22888980","id":"PMC_22888980","title":"Expression of CK-19, galectin-3 and HBME-1 in the differentiation of thyroid lesions: systematic review and diagnostic meta-analysis.","date":"2012","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22888980","citation_count":82,"is_preprint":false},{"pmid":"16080916","id":"PMC_16080916","title":"Melanocytes in the corneal limbus interact with K19-positive basal epithelial cells.","date":"2005","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/16080916","citation_count":80,"is_preprint":false},{"pmid":"32742454","id":"PMC_32742454","title":"CK19-positive Hepatocellular Carcinoma is a Characteristic Subtype.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32742454","citation_count":79,"is_preprint":false},{"pmid":"1384338","id":"PMC_1384338","title":"Markers for dysplasia of the upper aerodigestive tract. 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Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/34973373","citation_count":11,"is_preprint":false},{"pmid":"9152022","id":"PMC_9152022","title":"Contrasting effects of K8 and K18 on stabilizing K19 expression, cell motility and tumorigenicity in the BSp73 adenocarcinoma.","date":"1997","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/9152022","citation_count":11,"is_preprint":false},{"pmid":"30021014","id":"PMC_30021014","title":"Analysis of KRT1, KRT10, KRT19, TP53 and MMP9 expression in pediatric and adult cholesteatoma.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30021014","citation_count":11,"is_preprint":false},{"pmid":"38557414","id":"PMC_38557414","title":"Nuclear KRT19 is a transcriptional corepressor promoting histone deacetylation and liver tumorigenesis.","date":"2024","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/38557414","citation_count":10,"is_preprint":false},{"pmid":"20874491","id":"PMC_20874491","title":"Functional and epigenetic characterization of the KRT19 gene in renal cell neoplasms.","date":"2010","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20874491","citation_count":10,"is_preprint":false},{"pmid":"20723431","id":"PMC_20723431","title":"[Nuclear accumulation of CXCR4 and overexpressions of VEGF-C and CK19 are associated with a higher risk of lymph node metastasis in hepatocellular carcinoma].","date":"2010","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/20723431","citation_count":10,"is_preprint":false},{"pmid":"27386436","id":"PMC_27386436","title":"A Pilot Study of CK19, CK20 and GCC mRNA in the Peripheral Blood as a Colorectal Cancer Biomarker Panel.","date":"2016","source":"International journal of molecular and cellular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27386436","citation_count":10,"is_preprint":false},{"pmid":"15716612","id":"PMC_15716612","title":"RET/PTC and CK19 expression in papillary thyroid carcinoma and its clinicopathologic correlation.","date":"2005","source":"Journal of Korean medical science","url":"https://pubmed.ncbi.nlm.nih.gov/15716612","citation_count":10,"is_preprint":false},{"pmid":"33964951","id":"PMC_33964951","title":"HBME1 and CK19 expression in non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) vs other follicular patterned thyroid lesions.","date":"2021","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33964951","citation_count":9,"is_preprint":false},{"pmid":"16080517","id":"PMC_16080517","title":"Radioimmunotherapy and apoptotic induction on CK19-overexpressing human cervical carcinoma cells with Re-188-mAbCx-99.","date":"2005","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16080517","citation_count":9,"is_preprint":false},{"pmid":"26323510","id":"PMC_26323510","title":"Immunotherapy for Lewis lung carcinoma utilizing dendritic cells infected with CK19 gene recombinant adenoviral vectors.","date":"2015","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/26323510","citation_count":9,"is_preprint":false},{"pmid":"32273715","id":"PMC_32273715","title":"CK19 Promotes Ovarian Cancer Development by Impacting on Wnt/β-Catenin Pathway.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32273715","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55091,"output_tokens":3463,"usd":0.108609},"stage2":{"model":"claude-opus-4-6","input_tokens":6941,"output_tokens":3566,"usd":0.185782},"total_usd":0.294391,"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\": 2016,\n      \"finding\": \"KRT19 directly interacts with the β-catenin/RAC1 complex in breast cancer cells, enhancing nuclear translocation of β-catenin, which drives NUMB expression and thereby suppresses NOTCH signaling; knockdown of KRT19 reduces nuclear β-catenin, lowers NUMB, and activates NOTCH-mediated cancer stem cell properties.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression with phenotypic readouts (proliferation, migration, invasion, sphere formation), nuclear fractionation, reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple orthogonal functional assays, mechanistic pathway placement validated in patient-derived CSLCs\",\n      \"pmids\": [\"27345400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In colon cancer cells KRT19 interacts with β-catenin alone (not with RAC1), enabling LEF/TCF transcription factor binding to LEF1 and TCF7 promoters and activating Wnt/Notch signaling, whereas in breast cancer KRT19 interacts with the β-catenin/RAC1 complex and suppresses Notch via NUMB upregulation — demonstrating tissue-context-dependent differential protein interactions.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, knockdown with cell proliferation/invasion assays, promoter-binding analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP in two cancer types, single lab\",\n      \"pmids\": [\"30650643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CK19 physically interacts with CFTR at the apical plasma membrane of bronchial epithelial cells; CK19 overexpression stabilizes both wild-type and VX-809-rescued F508del-CFTR at the plasma membrane by preventing Rab7A-mediated lysosomal degradation, thereby promoting chloride secretion. CK19 expression is reduced ~40% in primary CF bronchial epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation (CK19–CFTR interaction), overexpression/knockdown with surface biotinylation, Rab7A dominantnegative rescue, Ussing chamber Cl⁻ secretion assay, cell fractionation\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct protein interaction validated, mechanistic rescue experiment with Rab7A, functional ion-transport readout, multiple orthogonal methods\",\n      \"pmids\": [\"31450978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A nuclear fraction of KRT19 acts as a transcriptional corepressor: KRT19 binds HDAC1 and RCOR1 (components of the CoREST complex), enhances HDAC1–RCOR1 interaction, increases CoREST deacetylase activity, and represses hepatocyte-specific genes including HNF4A, promoting dedifferentiation and liver tumorigenesis.\",\n      \"method\": \"Cell fractionation (nuclear KRT19 identification), tandem affinity purification/mass spectrometry (CoREST complex interaction), Co-IP, HDAC activity assay, KRT19 KO with ChIP-seq (HNF4A locus), in vivo multiplexed genome editing of hepatocytes, patient-derived xenograft experiments\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mass spectrometry-identified interaction confirmed by Co-IP, enzymatic activity assay, ChIP-seq, in vivo KO; multiple orthogonal methods in one study\",\n      \"pmids\": [\"38557414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Linc-KILH lncRNA binds KRT19 protein and inhibits phosphorylation of KRT19 at Ser35, causing KRT19 to translocate from cytoplasm to the plasma membrane; this enhanced membrane-localized KRT19 interacts with β-catenin (but not RAC1 in HCC cells) and promotes nuclear β-catenin translocation and Notch1 signaling activation.\",\n      \"method\": \"RNA-protein pulldown, Co-IP, phosphorylation assay, subcellular fractionation/immunofluorescence, knockdown with proliferation/metastasis assays in vitro and in vivo\",\n      \"journal\": \"International Journal of Biological Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and fractionation confirm interaction and localization shift; single lab with multiple methods\",\n      \"pmids\": [\"33767587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"In a pancreatic adenocarcinoma cell model, transfection of K8 stabilizes endogenous K19, forming K8/K19 keratin filaments; co-expression of K18 with K8 suppresses cell motility, soft-agar growth, and in vivo tumorigenicity in a K18-dose-dependent manner, whereas K8/K19-expressing cells retain motile and tumorigenic properties.\",\n      \"method\": \"Stable transfection of K8 and/or K18, Western blot (K19 stabilization), soft-agar colony assay, motility assay, syngeneic tumor injection\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reconstitution in cell model with multiple functional readouts; single lab\",\n      \"pmids\": [\"9152022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-26a directly targets the 3′UTR of KRT19 mRNA, suppressing KRT19 protein expression; knockdown of miR-26a increases the side-population (SP) fraction of cholangiocarcinoma cells via KRT19 upregulation, and ectopic miR-26a expression suppresses cell proliferation and tumor growth in vitro and in vivo.\",\n      \"method\": \"3′UTR luciferase reporter assay (direct miR-26a–KRT19 interaction), gain/loss-of-function assays, SP cell flow cytometry, xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3′UTR binding validated by reporter assay, functional rescue experiments; single lab\",\n      \"pmids\": [\"27833076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-374b-5p directly targets KRT19, inhibiting activation of the Wnt/β-catenin pathway and suppressing EMT in pancreatic cancer; under hypoxia, HIF1α upregulates KRT19 expression and loss of miR-642a-5p further elevates KRT19, promoting pancreatic cancer progression.\",\n      \"method\": \"3′UTR luciferase reporter assay (miR-374b-5p–KRT19), overexpression/knockdown with proliferation/migration/invasion assays, Western blot for EMT markers and Wnt components, hypoxia/HIF1α manipulation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay confirms direct miRNA–KRT19 interaction, pathway effects validated by multiple functional assays; single lab\",\n      \"pmids\": [\"39280598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BRAFV600E mutation induces KRT19 expression in thyroid cancer cells; KRT19 knockdown inhibits proliferation and migration, and mechanistically KRT19 promotes epithelial-mesenchymal transition (EMT) to drive lymph node metastasis.\",\n      \"method\": \"BRAFV600E overexpression with KRT19 measurement, KRT19 knockdown with proliferation/migration assays, EMT marker analysis (Western blot/qPCR), TCGA database validation\",\n      \"journal\": \"Oncology Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — upstream inducer identified (BRAFV600E) with functional KD phenotype and EMT pathway placement; single lab\",\n      \"pmids\": [\"31289571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KRT19 modulates cancer stem cell reprogramming in breast cancer by regulating expression of CSC markers (ALDH1, CXCR4, CD133) and the phosphorylation status of Src and GSK3β (Tyr216); overexpression of KRT19 in aggressive CSLCs attenuates CSC properties, while KRT19 knockdown enhances them.\",\n      \"method\": \"KRT19 knockdown/overexpression, sphere formation assay, drug resistance assay, Western blot for phospho-Src and phospho-GSK3β, CSC marker quantification by flow cytometry\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple orthogonal assays but mechanistic link to kinase phosphorylation is correlative; single lab\",\n      \"pmids\": [\"29747452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Linc00974 acts as a competing endogenous RNA (ceRNA) for miR-642, indirectly upregulating KRT19 expression; elevated KRT19 activates Notch and TGF-β signaling pathways to promote hepatocellular carcinoma proliferation and metastasis.\",\n      \"method\": \"miRNA target prediction and validation, ceRNA luciferase assay, KRT19 knockdown, cDNA microarray pathway analysis, xenograft models\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ceRNA mechanism validated by reporter assay; pathway activation confirmed by microarray and KD phenotype; single lab\",\n      \"pmids\": [\"25476897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CK19 promotes epithelial ovarian cancer cell proliferation, migration, and invasion by activating the Wnt/β-catenin signaling pathway, as shown by upregulation of β-catenin, TCF7, LEF1, c-MYC, and cyclin D1 upon CK19 overexpression and their downregulation upon knockdown.\",\n      \"method\": \"CK19 overexpression/knockdown, Transwell invasion/migration assay, CCK-8 proliferation assay, Western blot and RT-PCR for Wnt pathway components\",\n      \"journal\": \"OncoTargets and Therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, KD/OE with pathway marker readout but no direct binding assay between CK19 and Wnt components shown\",\n      \"pmids\": [\"32273715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KRT19 promoter methylation represses KRT19 gene expression in renal carcinoma cell lines; treatment with the demethylating agent 5-aza-2′-deoxycytidine and the HDAC inhibitor trichostatin A re-activates KRT19 expression with concomitant decrease in promoter methylation, demonstrating epigenetic regulation of KRT19.\",\n      \"method\": \"Methylation-specific PCR/bisulfite sequencing of promoter, 5-aza-dC + TSA treatment with RT-PCR expression measurement in renal carcinoma cell lines\",\n      \"journal\": \"DNA and Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct epigenetic manipulation with functional rescue of expression; limited to cell lines\",\n      \"pmids\": [\"20874491\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT19 functions as a multifunctional intermediate filament protein whose mechanistic roles include: (1) scaffolding a β-catenin/RAC1 signaling complex that controls nuclear β-catenin translocation, NUMB expression, and Wnt/NOTCH crosstalk in a tissue-context-dependent manner; (2) stabilizing CFTR at the apical plasma membrane by blocking Rab7A-mediated lysosomal degradation; (3) acting in the nucleus as a transcriptional corepressor that enhances CoREST/HDAC1 deacetylase activity to silence hepatocyte-differentiation genes; and (4) being regulated post-translationally by phosphorylation at Ser35 (modulated by Linc-KILH) and transcriptionally by miRNAs (miR-26a, miR-374b-5p, miR-642a-5p) and upstream oncogenic signals such as BRAFV600E.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KRT19 is a type I intermediate filament keratin that, beyond its structural role, functions as a signaling scaffold and transcriptional corepressor across multiple epithelial cell contexts. KRT19 directly binds β-catenin—alone or in a β-catenin/RAC1 complex depending on tissue type—to promote nuclear β-catenin translocation and modulate Wnt and Notch pathway crosstalk; in breast cancer this suppresses Notch via NUMB upregulation, whereas in colon cancer and hepatocellular carcinoma it activates LEF/TCF-driven transcription and Notch signaling [PMID:27345400, PMID:30650643, PMID:33767587]. In bronchial epithelial cells, KRT19 stabilizes CFTR at the apical plasma membrane by blocking Rab7A-mediated lysosomal degradation, thereby sustaining chloride secretion [PMID:31450978]. A nuclear pool of KRT19 interacts with HDAC1 and RCOR1 to enhance CoREST deacetylase activity and repress hepatocyte-differentiation genes such as HNF4A, promoting liver dedifferentiation and tumorigenesis [PMID:38557414]. KRT19 expression is regulated epigenetically by promoter methylation, post-translationally by Ser35 phosphorylation modulated by the lncRNA Linc-KILH, and post-transcriptionally by miRNAs including miR-26a and miR-374b-5p [PMID:20874491, PMID:33767587, PMID:27833076, PMID:39280598].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"The question of whether KRT19 plays a passive structural role or an active functional role in epithelial cells was first addressed: K8 co-expression stabilizes endogenous K19 into filaments, and K8/K19-expressing cells retain motile and tumorigenic properties distinct from K8/K18-expressing cells, establishing that KRT19-containing filaments have functional consequences beyond cytoskeletal support.\",\n      \"evidence\": \"Stable transfection of K8 ± K18 in pancreatic adenocarcinoma cells with soft-agar colony, motility, and syngeneic tumor assays\",\n      \"pmids\": [\"9152022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which K19 vs K18 filaments differentially affect motility was not identified\", \"No direct signaling interactors of K19 were mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Whether KRT19 expression is epigenetically silenced in cancer was resolved: KRT19 promoter CpG methylation represses transcription in renal carcinoma, and demethylation plus HDAC inhibition restores expression, establishing epigenetic regulation as a layer controlling KRT19 levels.\",\n      \"evidence\": \"Methylation-specific PCR, bisulfite sequencing, 5-aza-dC + TSA treatment in renal carcinoma cell lines\",\n      \"pmids\": [\"20874491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signals directing promoter methylation were not identified\", \"Whether methylation-based silencing occurs in non-renal cancers was not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The mechanism by which lncRNAs regulate KRT19 abundance was established: Linc00974 acts as a ceRNA sponging miR-642 to upregulate KRT19, which in turn activates Notch and TGF-β signaling to promote hepatocellular carcinoma progression.\",\n      \"evidence\": \"ceRNA luciferase assay, KRT19 knockdown, cDNA microarray pathway analysis, xenograft models\",\n      \"pmids\": [\"25476897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding between KRT19 protein and Notch/TGF-β pathway components was not demonstrated\", \"ceRNA stoichiometry in physiological conditions was not assessed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The central signaling mechanism of KRT19 was defined: KRT19 directly scaffolds a β-catenin/RAC1 complex, promoting nuclear β-catenin translocation and NUMB-mediated Notch suppression in breast cancer cells, thereby linking an intermediate filament protein to Wnt/Notch crosstalk.\",\n      \"evidence\": \"Reciprocal Co-IP, nuclear fractionation, reporter assays, knockdown/overexpression with proliferation, migration, invasion, and sphere formation readouts in patient-derived CSLCs\",\n      \"pmids\": [\"27345400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of KRT19–β-catenin–RAC1 ternary complex was not resolved\", \"Whether the interaction occurs outside breast cancer lineages was untested at this point\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Post-transcriptional regulation of KRT19 by miRNA was established: miR-26a directly binds the KRT19 3′UTR to suppress protein expression, with functional consequences on the side-population fraction and tumor growth in cholangiocarcinoma.\",\n      \"evidence\": \"3′UTR luciferase reporter assay, gain/loss-of-function assays, SP flow cytometry, xenograft model\",\n      \"pmids\": [\"27833076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether miR-26a regulation of KRT19 operates in non-biliary epithelia was not examined\", \"Other miRNA targets contributing to the phenotype were not excluded\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The downstream signaling consequences of KRT19 in cancer stem cells were extended: KRT19 modulates Src and GSK3β phosphorylation and CSC marker expression (ALDH1, CXCR4, CD133) in breast cancer, connecting its scaffold function to kinase-level signaling.\",\n      \"evidence\": \"KRT19 knockdown/overexpression, sphere formation, drug resistance assay, Western blot for phospho-Src and phospho-GSK3β\",\n      \"pmids\": [\"29747452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of KRT19 to Src or GSK3β was not tested—kinase effects remain correlative\", \"Mechanism linking β-catenin scaffold to Src phosphorylation was not delineated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Tissue-context dependence of KRT19 signaling was established: in colon cancer KRT19 interacts with β-catenin alone (not RAC1), enabling LEF/TCF promoter binding and activating—rather than suppressing—Notch, contrasting with the β-catenin/RAC1/NUMB axis in breast cancer.\",\n      \"evidence\": \"Co-IP, ChIP assay at LEF1/TCF7 promoters, knockdown with proliferation/invasion readouts in colon vs breast cancer cells\",\n      \"pmids\": [\"30650643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants specifying whether RAC1 is included in the complex remain unknown\", \"Whether context-dependent effects reflect stoichiometric differences or distinct post-translational modifications was not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A non-signaling, membrane-stabilization function of KRT19 was discovered: KRT19 physically interacts with CFTR at the apical membrane and prevents Rab7A-mediated lysosomal trafficking, stabilizing both wild-type and pharmacologically rescued F508del-CFTR and sustaining chloride secretion.\",\n      \"evidence\": \"Co-IP of CK19–CFTR, surface biotinylation, Rab7A dominant-negative rescue, Ussing chamber Cl⁻ secretion in primary bronchial epithelial cells\",\n      \"pmids\": [\"31450978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface between KRT19 and CFTR was not mapped\", \"Whether reduced CK19 in CF epithelia is a cause or consequence of disease pathology was not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"An upstream oncogenic inducer of KRT19 was identified: BRAFV600E drives KRT19 expression in thyroid cancer, and KRT19 promotes EMT-mediated metastasis.\",\n      \"evidence\": \"BRAFV600E overexpression, KRT19 knockdown with proliferation/migration assays, EMT marker Western blot\",\n      \"pmids\": [\"31289571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional mechanism by which BRAFV600E upregulates KRT19 promoter was not mapped\", \"EMT effects were correlative without direct β-catenin interaction data in thyroid cells\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Post-translational control of KRT19 localization was delineated: the lncRNA Linc-KILH binds KRT19 and inhibits Ser35 phosphorylation, redirecting KRT19 from cytoplasm to plasma membrane where it engages β-catenin (without RAC1) to activate Notch1 in hepatocellular carcinoma.\",\n      \"evidence\": \"RNA-protein pulldown, phosphorylation assay, subcellular fractionation, immunofluorescence, Co-IP, in vivo metastasis assays\",\n      \"pmids\": [\"33767587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for Ser35 phosphorylation was not identified\", \"Structural basis for lncRNA-mediated phosphorylation inhibition is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A nuclear function of KRT19 was discovered: nuclear KRT19 binds HDAC1 and RCOR1, enhances CoREST deacetylase activity, and represses hepatocyte-differentiation genes including HNF4A, establishing KRT19 as a transcriptional corepressor that promotes liver dedifferentiation and tumorigenesis.\",\n      \"evidence\": \"Tandem affinity purification/mass spectrometry, Co-IP, HDAC activity assay, ChIP-seq at HNF4A locus, in vivo multiplexed genome editing, patient-derived xenograft experiments\",\n      \"pmids\": [\"38557414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nuclear KRT19 retains filament structure or exists as soluble monomers/oligomers is unknown\", \"Genome-wide target spectrum of KRT19-CoREST beyond HNF4A was not comprehensively defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Additional miRNA regulators of KRT19 were identified: miR-374b-5p directly targets KRT19 to inhibit Wnt/β-catenin and EMT in pancreatic cancer, while HIF1α-driven hypoxia and loss of miR-642a-5p converge to upregulate KRT19.\",\n      \"evidence\": \"3′UTR luciferase reporter assay, overexpression/knockdown with proliferation/migration/invasion assays, hypoxia/HIF1α manipulation\",\n      \"pmids\": [\"39280598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of miR-374b-5p vs miR-642a-5p to KRT19 regulation under physiological conditions were not quantified\", \"Whether HIF1α directly binds the KRT19 promoter was not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include: the structural basis of KRT19's interactions with β-catenin, CFTR, and the CoREST complex; the determinants specifying tissue-context-dependent partner selection (RAC1 inclusion vs exclusion); the identity of the Ser35 kinase; and whether the nuclear corepressor function and membrane scaffold function operate simultaneously or are mutually exclusive pools in the same cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural or cryo-EM data for any KRT19 signaling complex\", \"Mechanism sorting KRT19 between cytoplasmic filaments, plasma membrane, and nuclear pools is undefined\", \"In vivo genetic models (knockout mice) have not clearly separated structural from signaling functions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4, 7, 9, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 12]}\n    ],\n    \"complexes\": [\n      \"CoREST complex (HDAC1/RCOR1)\"\n    ],\n    \"partners\": [\n      \"CTNNB1\",\n      \"RAC1\",\n      \"CFTR\",\n      \"HDAC1\",\n      \"RCOR1\",\n      \"KRT8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}