{"gene":"KRT19","run_date":"2026-06-10T02:59:49","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 promotes NUMB expression; NUMB in turn suppresses NOTCH signaling. Knockdown of KRT19 reduces nuclear β-catenin, lowers NUMB expression, and activates NOTCH signaling, increasing cancer stem cell properties.","method":"Co-immunoprecipitation, knockdown (siRNA/shRNA), nuclear fractionation, reporter assays, patient-derived cancer stem cell-like cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and nuclear fractionation with functional KD phenotype, single lab, multiple orthogonal methods","pmids":["27345400"],"is_preprint":false},{"year":2019,"finding":"In colon cancer cells, KRT19 interacts with β-catenin but NOT with RAC1, allowing LEF/TCF transcription factors to bind LEF1 and TCF7 promoter regions and activate Wnt/Notch signaling. This contrasts with breast cancer where KRT19 interacts with the β-catenin/RAC1 complex. KRT19 knockdown in colon cancer suppresses cancer properties by downregulating Wnt/Notch signaling without altering NUMB transcription.","method":"Co-immunoprecipitation, ChIP assay, knockdown, cell proliferation/invasion assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating differential binding partners in breast vs colon cancer, single lab, multiple orthogonal methods","pmids":["30650643"],"is_preprint":false},{"year":2018,"finding":"KRT19 regulates cancer stem cell reprogramming by modulating expression of cancer stem cell markers (ALDH1, CXCR4, CD133) and phosphorylation of Src and GSK3β (Tyr216). Overexpression of KRT19 in highly aggressive cancer stem cell-like cells attenuates cancer stem cell properties.","method":"KRT19 overexpression and knockdown, Western blot for phosphorylation status, sphere formation assay, flow cytometry","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single set of methods without direct binding/structural validation of KRT19-Src/GSK3β interaction","pmids":["29747452"],"is_preprint":false},{"year":2019,"finding":"CK19 stabilizes CFTR at the apical plasma membrane of bronchial epithelial cells by preventing Rab7A-mediated lysosomal degradation. CK19 overexpression increased Cl⁻ secretion across human bronchial epithelial cells, and CK19 expression was ~40% reduced in F508del CF patient-derived cells. CK19 also positively regulated MRP4 expression at the plasma membrane.","method":"Co-immunoprecipitation (identifying CK19 as CFTR-interacting protein), CK19 overexpression, endocytosis/lysosomal degradation assays, Rab7A functional studies, Ussing chamber Cl⁻ secretion measurements","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — identified binding partner by pulldown, functional reconstitution with Cl⁻ secretion assay, mechanistic dissection of Rab7A-mediated degradation pathway, multiple orthogonal methods in one study","pmids":["31450978"],"is_preprint":false},{"year":2024,"finding":"KRT19 has a previously unrecognized nuclear fraction and acts as a transcriptional corepressor by interacting with HDAC1 and RCOR1 (components of the CoREST complex), enhancing CoREST complex formation and increasing deacetylase activity. KRT19 promotes CoREST-mediated histone deacetylation at hepatocyte-specific gene loci (including HNF4A), causing dedifferentiation and liver tumorigenesis. FOXP4 was identified as a direct transcriptional activator of KRT19 in liver cancer.","method":"Cell fractionation (nuclear KRT19), tandem affinity purification/mass spectrometry (identifying HDAC1 and RCOR1 as interactors), in vivo multiplexed genome editing, ChIP-seq, HDAC activity assay, KRT19 knockout","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — tandem affinity purification identifying CoREST complex components, ChIP-seq, in vivo genome editing, HDAC activity assays, and multiple orthogonal methods establishing novel nuclear function","pmids":["38557414"],"is_preprint":false},{"year":2021,"finding":"Linc-KILH (lncRNA) interacts with KRT19 protein and inhibits phosphorylation of KRT19 at Ser35, thereby enhancing translocation of KRT19 from cytoplasm to membrane in KRT19-positive HCC cells. This promotes interaction between β-catenin and KRT19 in the cytoplasm, enhancing nuclear translocation of β-catenin and activation of Notch1 signaling, promoting HCC proliferation and metastasis.","method":"RNA immunoprecipitation, co-immunoprecipitation, phosphorylation site mutation (Ser35), cell fractionation, in vitro and in vivo functional assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site identified and mutated, co-IP for β-catenin/KRT19 interaction, cell fractionation for localization, single lab","pmids":["33767587"],"is_preprint":false},{"year":2016,"finding":"miR-26a directly binds the 3'UTR of KRT19 mRNA and suppresses KRT19 expression. Knockdown of miR-26a increases the side-population (stem-like) cell fraction by promoting KRT19 expression in cholangiocarcinoma cells.","method":"3'UTR luciferase reporter assay, miR-26a overexpression/knockdown, SP cell flow cytometry, in vitro and in vivo tumor growth assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR binding validated by reporter assay, functional loss/gain experiments, single lab","pmids":["27833076"],"is_preprint":false},{"year":1997,"finding":"Expression of K8 in a vimentin-expressing pancreatic adenocarcinoma cell line stabilizes endogenous K19, forming K8/K19 keratin filaments. K18 expression alone (without K8) yielded unstable K18 protein and suppressed tumor motility and tumorigenicity, while K8/K19-expressing cells retained motility and tumorigenic ability.","method":"Transfection of K8 and/or K18 into keratin-null adenocarcinoma cells, Western blot for protein stability, soft agar growth, in vivo tumor formation in syngeneic animals, motility assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution with defined constructs, in vivo tumorigenicity, single lab with multiple orthogonal assays","pmids":["9152022"],"is_preprint":false},{"year":2019,"finding":"BRAFV600E overexpression in thyroid cancer cell lines induces KRT19 expression. KRT19 knockdown inhibits proliferation and migration of thyroid cancer cells. KRT19 promotes epithelial-mesenchymal transition (EMT) in thyroid cancer, and KRT19 expression correlates with lymph node metastasis.","method":"BRAFV600E overexpression construct, KRT19 knockdown, cell proliferation/migration assays, EMT marker Western blot","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional KD with proliferation/migration readouts; upstream regulation by BRAFV600E shown by overexpression only","pmids":["31289571"],"is_preprint":false},{"year":2017,"finding":"In lacrimal gland morphogenesis, Krt19 specifically labels the presumptive ductal domain and luminal cell layer (distinct from Krt14-labeled basal cells). Inhibition of Notch signaling prevents ductal identity and leads to ectopic terminal end buds, placing Notch signaling upstream of the Krt19-positive ductal cell identity.","method":"Genetic fate mapping (Krt14-Cre), Fucci reporter, immunofluorescence, pharmacologic Notch inhibition, histology","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic fate mapping combined with Notch inhibition establishes pathway epistasis for ductal identity, single lab","pmids":["29033846"],"is_preprint":false},{"year":1995,"finding":"In rat gonadal development, K19 and K18 gene expression is regulated at the transcriptional level. K19 mRNA is expressed in undifferentiated gonads and ovarian somatic cells, while K18 mRNA appears at the onset of testicular differentiation (day 13.5) as Sertoli cells differentiate; K19 mRNA then disappears. This switch in K19/K18 transcriptional activity is one of the earliest events of testicular differentiation after SRY expression.","method":"Northern blot, RT-PCR, in situ hybridization with species-specific riboprobes, temporal analysis across embryonic days","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple RNA detection methods (Northern blot, RT-PCR, in situ hybridization) establishing transcriptional regulation, single lab","pmids":["8541209"],"is_preprint":false},{"year":2021,"finding":"AMD3100/Plerixafor was proposed to overcome immune inhibition mediated by a CXCL12-KRT19 coating on pancreatic and colorectal cancer cells that stimulates CXCR4 on immune cells to suppress the intratumoral immune reaction. (Note: this paper discusses a mechanistic hypothesis based on clinical Phase 1 study observations; direct experimental validation of the KRT19-CXCL12 coating mechanism is limited in the abstract.)","method":"Clinical Phase 1 study interpretation; mechanistic discussion without direct in vitro/in vivo binding experiments described in abstract","journal":"British journal of cancer","confidence":"Low","confidence_rationale":"Tier 4 / Weak — mechanistic claim is proposed/discussed based on clinical observations; no direct binding or functional experiment described in the abstract","pmids":["33772153"],"is_preprint":false},{"year":2010,"finding":"KRT19 promoter methylation can silence KRT19 expression in renal carcinoma cell lines; treatment with 5-aza-2'-deoxycytidine (DNA demethylase) and trichostatin A (HDAC inhibitor) re-expressed KRT19 and decreased promoter methylation in three cell lines. However, in primary renal tumors, KRT19 promoter methylation was infrequent (20.5%), suggesting other genetic mechanisms regulate KRT19 in vivo.","method":"Methylation-specific PCR, treatment with 5-aza-2'-deoxycytidine + trichostatin A, RT-PCR expression analysis in cell lines and 112 primary tumors","journal":"DNA and cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epigenetic regulation shown in cell lines by drug treatment only; not validated in primary tumors, single lab","pmids":["20874491"],"is_preprint":false},{"year":2024,"finding":"KRT19 promotes pancreatic cancer cell proliferation, migration, and invasion. miR-642a-5p directly targets KRT19 and suppresses Wnt/β-catenin pathway activation and EMT. Under hypoxic conditions, HIF1α positively correlates with KRT19 and promotes its expression; loss of miR-642a-5p under hypoxia upregulates KRT19.","method":"KRT19 overexpression/knockdown, miR-642a-5p target validation (luciferase reporter implied), Wnt/β-catenin pathway assays, hypoxia experiments, HIF1α correlation","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays with KRT19 overexpression/KD; miRNA targeting and HIF1α regulation supported but methodology depth unclear from abstract alone, single lab","pmids":["39280598"],"is_preprint":false},{"year":2020,"finding":"CK19 overexpression in ovarian cancer cells promotes invasion, proliferation, and migration, and activates the Wnt/β-catenin signaling pathway, upregulating β-catenin, TCF7, LEF1, c-MYC, and cyclin D1.","method":"CK19 overexpression and 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 / Weak — single lab, functional overexpression/KD with pathway marker readouts but no direct binding experiment","pmids":["32273715"],"is_preprint":false}],"current_model":"KRT19 is a type I intermediate filament cytoskeletal protein that also operates as a signaling scaffold: it interacts with the β-catenin/RAC1 complex (in a cell-type-dependent manner) to regulate nuclear β-catenin translocation and downstream Wnt/NOTCH/NUMB signaling; it localizes to a previously unrecognized nuclear fraction where it acts as a transcriptional corepressor by enhancing assembly and deacetylase activity of the CoREST (HDAC1/RCOR1) complex to silence hepatocyte-specific differentiation genes; it stabilizes CFTR at the apical plasma membrane by blocking Rab7A-mediated lysosomal degradation; its expression is regulated at the transcriptional level (including by BRAFV600E, HIF1α, and FOXP4) and post-translationally by phosphorylation at Ser35 (modulated by lncRNA Linc-KILH); and in keratin filament assembly, K8 co-expression is required to stabilize K19 protein."},"narrative":{"mechanistic_narrative":"KRT19 is a type I intermediate filament cytoskeletal protein whose protein stability depends on co-expression of its type II partner K8, with which it forms K8/K19 keratin filaments [PMID:9152022]. Beyond its structural role, KRT19 functions as a context-dependent signaling scaffold for the Wnt/β-catenin–Notch axis: it binds β-catenin and, in breast cancer, the β-catenin/RAC1 complex to drive nuclear β-catenin translocation and NUMB expression that restrains NOTCH signaling [PMID:27345400], whereas in colon cancer it engages β-catenin independently of RAC1 to permit LEF/TCF-driven Wnt/Notch activation [PMID:30650643]. This scaffolding activity is gated by phosphorylation at Ser35, which controls cytoplasmic-versus-membrane partitioning of KRT19 and its β-catenin engagement [PMID:33767587]. KRT19 also has a nuclear pool in which it acts as a transcriptional corepressor, binding HDAC1 and RCOR1 to enhance assembly and deacetylase activity of the CoREST complex and silence hepatocyte-specific genes including HNF4A, driving dedifferentiation and liver tumorigenesis [PMID:38557414]. At the apical plasma membrane it stabilizes CFTR by blocking Rab7A-mediated lysosomal degradation, increasing chloride secretion in bronchial epithelium [PMID:31450978]. KRT19 expression is set transcriptionally — by FOXP4 in liver cancer [PMID:38557414] — and during development KRT19 marks ductal/luminal epithelial identity downstream of Notch signaling in lacrimal gland morphogenesis [PMID:29033846].","teleology":[{"year":1995,"claim":"Established that KRT19 expression is transcriptionally controlled and developmentally dynamic, marking undifferentiated gonadal and ovarian somatic cells before being switched off as testicular differentiation begins.","evidence":"Northern blot, RT-PCR, and in situ hybridization across rat embryonic gonadal development","pmids":["8541209"],"confidence":"Medium","gaps":["Does not identify the transcription factors driving the K19/K18 switch","No protein-level or functional readout"]},{"year":1997,"claim":"Resolved a key determinant of KRT19 stability, showing that K8 co-expression is required to stabilize K19 protein into K8/K19 filaments and that keratin pairing influences tumor cell motility and tumorigenicity.","evidence":"Transfection of K8/K18 into keratin-null pancreatic adenocarcinoma cells with stability, motility, and in vivo tumorigenicity assays","pmids":["9152022"],"confidence":"Medium","gaps":["Does not define the structural basis of K8-dependent K19 stabilization","Mechanism linking filament composition to motility unresolved"]},{"year":2016,"claim":"Defined KRT19 as a signaling scaffold by showing it binds the β-catenin/RAC1 complex to drive nuclear β-catenin, NUMB induction, and NOTCH suppression, restraining cancer stem cell properties.","evidence":"Reciprocal Co-IP, nuclear fractionation, knockdown, and reporter assays in breast cancer cells","pmids":["27345400"],"confidence":"Medium","gaps":["Direct binding interface not mapped","Single cell-type context"]},{"year":2016,"claim":"Identified a post-transcriptional brake on KRT19, showing miR-26a directly represses KRT19 mRNA to limit the stem-like cell fraction in cholangiocarcinoma.","evidence":"3'UTR luciferase reporter, miR-26a gain/loss, side-population flow cytometry, and in vivo tumor assays","pmids":["27833076"],"confidence":"Medium","gaps":["Downstream effectors of KRT19 in stemness not dissected here"]},{"year":2019,"claim":"Showed KRT19's β-catenin scaffolding is context-dependent: in colon cancer it binds β-catenin without RAC1, enabling LEF/TCF-driven Wnt/Notch activation rather than NUMB-mediated suppression.","evidence":"Co-IP, ChIP, knockdown, and proliferation/invasion assays in colon cancer cells","pmids":["30650643"],"confidence":"Medium","gaps":["Molecular basis of cell-type-specific RAC1 inclusion/exclusion unknown"]},{"year":2019,"claim":"Uncovered a membrane-stabilizing function distinct from signaling, showing CK19 protects CFTR from Rab7A-mediated lysosomal degradation to sustain apical chloride secretion.","evidence":"Co-IP, overexpression, endocytosis/degradation assays, Rab7A functional studies, and Ussing chamber Cl- measurements in bronchial epithelium","pmids":["31450978"],"confidence":"High","gaps":["Structural basis of CK19-CFTR interaction not defined","Whether the same mechanism applies to MRP4 directly not established"]},{"year":2021,"claim":"Established Ser35 phosphorylation as a switch governing KRT19 subcellular partitioning, with Linc-KILH inhibiting Ser35 phosphorylation to promote membrane localization and β-catenin engagement.","evidence":"RNA-IP, Co-IP, Ser35 phosphosite mutation, and fractionation in KRT19-positive HCC cells","pmids":["33767587"],"confidence":"Medium","gaps":["Identity of the Ser35 kinase not determined","Quantitative link between phospho-state and β-catenin output unresolved"]},{"year":2024,"claim":"Revealed a nuclear corepressor function for KRT19, showing it binds HDAC1/RCOR1 to enhance CoREST complex assembly and deacetylase activity, silencing hepatocyte genes (HNF4A) and driving dedifferentiation; FOXP4 was identified as a direct KRT19 transcriptional activator.","evidence":"Nuclear fractionation, tandem affinity purification/MS, ChIP-seq, HDAC activity assays, in vivo multiplexed genome editing, and KRT19 knockout in liver cancer models","pmids":["38557414"],"confidence":"High","gaps":["Structural mechanism of CoREST enhancement by KRT19 not defined","Whether nuclear import is regulated by the same Ser35 switch unclear"]},{"year":null,"claim":"How a single intermediate filament protein partitions between cytoskeletal, plasma membrane, and nuclear corepressor roles — and what determines which function dominates in a given cell — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking Ser35 phosphorylation to all subcellular pools","Kinase(s) and import machinery for nuclear KRT19 unknown","Structural details of KRT19 protein-protein interfaces uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[3]}],"complexes":["CoREST (HDAC1/RCOR1) complex","K8/K19 keratin intermediate filament"],"partners":["CTNNB1","RAC1","HDAC1","RCOR1","CFTR","KRT8","RAB7A"],"other_free_text":[]}},"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":175,"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":169,"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":164,"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":113,"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; 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Knockdown of KRT19 reduces nuclear β-catenin, lowers NUMB expression, and activates NOTCH signaling, increasing cancer stem cell properties.\",\n      \"method\": \"Co-immunoprecipitation, knockdown (siRNA/shRNA), nuclear fractionation, reporter assays, patient-derived cancer stem cell-like cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and nuclear fractionation with functional KD phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27345400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In colon cancer cells, KRT19 interacts with β-catenin but NOT with RAC1, allowing LEF/TCF transcription factors to bind LEF1 and TCF7 promoter regions and activate Wnt/Notch signaling. This contrasts with breast cancer where KRT19 interacts with the β-catenin/RAC1 complex. KRT19 knockdown in colon cancer suppresses cancer properties by downregulating Wnt/Notch signaling without altering NUMB transcription.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, knockdown, cell proliferation/invasion assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating differential binding partners in breast vs colon cancer, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30650643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KRT19 regulates cancer stem cell reprogramming by modulating expression of cancer stem cell markers (ALDH1, CXCR4, CD133) and phosphorylation of Src and GSK3β (Tyr216). Overexpression of KRT19 in highly aggressive cancer stem cell-like cells attenuates cancer stem cell properties.\",\n      \"method\": \"KRT19 overexpression and knockdown, Western blot for phosphorylation status, sphere formation assay, flow cytometry\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single set of methods without direct binding/structural validation of KRT19-Src/GSK3β interaction\",\n      \"pmids\": [\"29747452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CK19 stabilizes CFTR at the apical plasma membrane of bronchial epithelial cells by preventing Rab7A-mediated lysosomal degradation. CK19 overexpression increased Cl⁻ secretion across human bronchial epithelial cells, and CK19 expression was ~40% reduced in F508del CF patient-derived cells. CK19 also positively regulated MRP4 expression at the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation (identifying CK19 as CFTR-interacting protein), CK19 overexpression, endocytosis/lysosomal degradation assays, Rab7A functional studies, Ussing chamber Cl⁻ secretion measurements\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identified binding partner by pulldown, functional reconstitution with Cl⁻ secretion assay, mechanistic dissection of Rab7A-mediated degradation pathway, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31450978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KRT19 has a previously unrecognized nuclear fraction and acts as a transcriptional corepressor by interacting with HDAC1 and RCOR1 (components of the CoREST complex), enhancing CoREST complex formation and increasing deacetylase activity. KRT19 promotes CoREST-mediated histone deacetylation at hepatocyte-specific gene loci (including HNF4A), causing dedifferentiation and liver tumorigenesis. FOXP4 was identified as a direct transcriptional activator of KRT19 in liver cancer.\",\n      \"method\": \"Cell fractionation (nuclear KRT19), tandem affinity purification/mass spectrometry (identifying HDAC1 and RCOR1 as interactors), in vivo multiplexed genome editing, ChIP-seq, HDAC activity assay, KRT19 knockout\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — tandem affinity purification identifying CoREST complex components, ChIP-seq, in vivo genome editing, HDAC activity assays, and multiple orthogonal methods establishing novel nuclear function\",\n      \"pmids\": [\"38557414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Linc-KILH (lncRNA) interacts with KRT19 protein and inhibits phosphorylation of KRT19 at Ser35, thereby enhancing translocation of KRT19 from cytoplasm to membrane in KRT19-positive HCC cells. This promotes interaction between β-catenin and KRT19 in the cytoplasm, enhancing nuclear translocation of β-catenin and activation of Notch1 signaling, promoting HCC proliferation and metastasis.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, phosphorylation site mutation (Ser35), cell fractionation, in vitro and in vivo functional assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site identified and mutated, co-IP for β-catenin/KRT19 interaction, cell fractionation for localization, single lab\",\n      \"pmids\": [\"33767587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-26a directly binds the 3'UTR of KRT19 mRNA and suppresses KRT19 expression. Knockdown of miR-26a increases the side-population (stem-like) cell fraction by promoting KRT19 expression in cholangiocarcinoma cells.\",\n      \"method\": \"3'UTR luciferase reporter assay, miR-26a overexpression/knockdown, SP cell flow cytometry, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR binding validated by reporter assay, functional loss/gain experiments, single lab\",\n      \"pmids\": [\"27833076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Expression of K8 in a vimentin-expressing pancreatic adenocarcinoma cell line stabilizes endogenous K19, forming K8/K19 keratin filaments. K18 expression alone (without K8) yielded unstable K18 protein and suppressed tumor motility and tumorigenicity, while K8/K19-expressing cells retained motility and tumorigenic ability.\",\n      \"method\": \"Transfection of K8 and/or K18 into keratin-null adenocarcinoma cells, Western blot for protein stability, soft agar growth, in vivo tumor formation in syngeneic animals, motility assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution with defined constructs, in vivo tumorigenicity, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"9152022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BRAFV600E overexpression in thyroid cancer cell lines induces KRT19 expression. KRT19 knockdown inhibits proliferation and migration of thyroid cancer cells. KRT19 promotes epithelial-mesenchymal transition (EMT) in thyroid cancer, and KRT19 expression correlates with lymph node metastasis.\",\n      \"method\": \"BRAFV600E overexpression construct, KRT19 knockdown, cell proliferation/migration assays, EMT marker Western blot\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional KD with proliferation/migration readouts; upstream regulation by BRAFV600E shown by overexpression only\",\n      \"pmids\": [\"31289571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In lacrimal gland morphogenesis, Krt19 specifically labels the presumptive ductal domain and luminal cell layer (distinct from Krt14-labeled basal cells). Inhibition of Notch signaling prevents ductal identity and leads to ectopic terminal end buds, placing Notch signaling upstream of the Krt19-positive ductal cell identity.\",\n      \"method\": \"Genetic fate mapping (Krt14-Cre), Fucci reporter, immunofluorescence, pharmacologic Notch inhibition, histology\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic fate mapping combined with Notch inhibition establishes pathway epistasis for ductal identity, single lab\",\n      \"pmids\": [\"29033846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"In rat gonadal development, K19 and K18 gene expression is regulated at the transcriptional level. K19 mRNA is expressed in undifferentiated gonads and ovarian somatic cells, while K18 mRNA appears at the onset of testicular differentiation (day 13.5) as Sertoli cells differentiate; K19 mRNA then disappears. This switch in K19/K18 transcriptional activity is one of the earliest events of testicular differentiation after SRY expression.\",\n      \"method\": \"Northern blot, RT-PCR, in situ hybridization with species-specific riboprobes, temporal analysis across embryonic days\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple RNA detection methods (Northern blot, RT-PCR, in situ hybridization) establishing transcriptional regulation, single lab\",\n      \"pmids\": [\"8541209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AMD3100/Plerixafor was proposed to overcome immune inhibition mediated by a CXCL12-KRT19 coating on pancreatic and colorectal cancer cells that stimulates CXCR4 on immune cells to suppress the intratumoral immune reaction. (Note: this paper discusses a mechanistic hypothesis based on clinical Phase 1 study observations; direct experimental validation of the KRT19-CXCL12 coating mechanism is limited in the abstract.)\",\n      \"method\": \"Clinical Phase 1 study interpretation; mechanistic discussion without direct in vitro/in vivo binding experiments described in abstract\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — mechanistic claim is proposed/discussed based on clinical observations; no direct binding or functional experiment described in the abstract\",\n      \"pmids\": [\"33772153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KRT19 promoter methylation can silence KRT19 expression in renal carcinoma cell lines; treatment with 5-aza-2'-deoxycytidine (DNA demethylase) and trichostatin A (HDAC inhibitor) re-expressed KRT19 and decreased promoter methylation in three cell lines. However, in primary renal tumors, KRT19 promoter methylation was infrequent (20.5%), suggesting other genetic mechanisms regulate KRT19 in vivo.\",\n      \"method\": \"Methylation-specific PCR, treatment with 5-aza-2'-deoxycytidine + trichostatin A, RT-PCR expression analysis in cell lines and 112 primary tumors\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epigenetic regulation shown in cell lines by drug treatment only; not validated in primary tumors, single lab\",\n      \"pmids\": [\"20874491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KRT19 promotes pancreatic cancer cell proliferation, migration, and invasion. miR-642a-5p directly targets KRT19 and suppresses Wnt/β-catenin pathway activation and EMT. Under hypoxic conditions, HIF1α positively correlates with KRT19 and promotes its expression; loss of miR-642a-5p under hypoxia upregulates KRT19.\",\n      \"method\": \"KRT19 overexpression/knockdown, miR-642a-5p target validation (luciferase reporter implied), Wnt/β-catenin pathway assays, hypoxia experiments, HIF1α correlation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays with KRT19 overexpression/KD; miRNA targeting and HIF1α regulation supported but methodology depth unclear from abstract alone, single lab\",\n      \"pmids\": [\"39280598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CK19 overexpression in ovarian cancer cells promotes invasion, proliferation, and migration, and activates the Wnt/β-catenin signaling pathway, upregulating β-catenin, TCF7, LEF1, c-MYC, and cyclin D1.\",\n      \"method\": \"CK19 overexpression and 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 / Weak — single lab, functional overexpression/KD with pathway marker readouts but no direct binding experiment\",\n      \"pmids\": [\"32273715\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT19 is a type I intermediate filament cytoskeletal protein that also operates as a signaling scaffold: it interacts with the β-catenin/RAC1 complex (in a cell-type-dependent manner) to regulate nuclear β-catenin translocation and downstream Wnt/NOTCH/NUMB signaling; it localizes to a previously unrecognized nuclear fraction where it acts as a transcriptional corepressor by enhancing assembly and deacetylase activity of the CoREST (HDAC1/RCOR1) complex to silence hepatocyte-specific differentiation genes; it stabilizes CFTR at the apical plasma membrane by blocking Rab7A-mediated lysosomal degradation; its expression is regulated at the transcriptional level (including by BRAFV600E, HIF1α, and FOXP4) and post-translationally by phosphorylation at Ser35 (modulated by lncRNA Linc-KILH); and in keratin filament assembly, K8 co-expression is required to stabilize K19 protein.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KRT19 is a type I intermediate filament cytoskeletal protein whose protein stability depends on co-expression of its type II partner K8, with which it forms K8/K19 keratin filaments [#7]. Beyond its structural role, KRT19 functions as a context-dependent signaling scaffold for the Wnt/β-catenin–Notch axis: it binds β-catenin and, in breast cancer, the β-catenin/RAC1 complex to drive nuclear β-catenin translocation and NUMB expression that restrains NOTCH signaling [#0], whereas in colon cancer it engages β-catenin independently of RAC1 to permit LEF/TCF-driven Wnt/Notch activation [#1]. This scaffolding activity is gated by phosphorylation at Ser35, which controls cytoplasmic-versus-membrane partitioning of KRT19 and its β-catenin engagement [#5]. KRT19 also has a nuclear pool in which it acts as a transcriptional corepressor, binding HDAC1 and RCOR1 to enhance assembly and deacetylase activity of the CoREST complex and silence hepatocyte-specific genes including HNF4A, driving dedifferentiation and liver tumorigenesis [#4]. At the apical plasma membrane it stabilizes CFTR by blocking Rab7A-mediated lysosomal degradation, increasing chloride secretion in bronchial epithelium [#3]. KRT19 expression is set transcriptionally — by FOXP4 in liver cancer [#4] — and during development KRT19 marks ductal/luminal epithelial identity downstream of Notch signaling in lacrimal gland morphogenesis [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that KRT19 expression is transcriptionally controlled and developmentally dynamic, marking undifferentiated gonadal and ovarian somatic cells before being switched off as testicular differentiation begins.\",\n      \"evidence\": \"Northern blot, RT-PCR, and in situ hybridization across rat embryonic gonadal development\",\n      \"pmids\": [\"8541209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the transcription factors driving the K19/K18 switch\", \"No protein-level or functional readout\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolved a key determinant of KRT19 stability, showing that K8 co-expression is required to stabilize K19 protein into K8/K19 filaments and that keratin pairing influences tumor cell motility and tumorigenicity.\",\n      \"evidence\": \"Transfection of K8/K18 into keratin-null pancreatic adenocarcinoma cells with stability, motility, and in vivo tumorigenicity assays\",\n      \"pmids\": [\"9152022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the structural basis of K8-dependent K19 stabilization\", \"Mechanism linking filament composition to motility unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined KRT19 as a signaling scaffold by showing it binds the β-catenin/RAC1 complex to drive nuclear β-catenin, NUMB induction, and NOTCH suppression, restraining cancer stem cell properties.\",\n      \"evidence\": \"Reciprocal Co-IP, nuclear fractionation, knockdown, and reporter assays in breast cancer cells\",\n      \"pmids\": [\"27345400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface not mapped\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a post-transcriptional brake on KRT19, showing miR-26a directly represses KRT19 mRNA to limit the stem-like cell fraction in cholangiocarcinoma.\",\n      \"evidence\": \"3'UTR luciferase reporter, miR-26a gain/loss, side-population flow cytometry, and in vivo tumor assays\",\n      \"pmids\": [\"27833076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of KRT19 in stemness not dissected here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed KRT19's β-catenin scaffolding is context-dependent: in colon cancer it binds β-catenin without RAC1, enabling LEF/TCF-driven Wnt/Notch activation rather than NUMB-mediated suppression.\",\n      \"evidence\": \"Co-IP, ChIP, knockdown, and proliferation/invasion assays in colon cancer cells\",\n      \"pmids\": [\"30650643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of cell-type-specific RAC1 inclusion/exclusion unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Uncovered a membrane-stabilizing function distinct from signaling, showing CK19 protects CFTR from Rab7A-mediated lysosomal degradation to sustain apical chloride secretion.\",\n      \"evidence\": \"Co-IP, overexpression, endocytosis/degradation assays, Rab7A functional studies, and Ussing chamber Cl- measurements in bronchial epithelium\",\n      \"pmids\": [\"31450978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CK19-CFTR interaction not defined\", \"Whether the same mechanism applies to MRP4 directly not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established Ser35 phosphorylation as a switch governing KRT19 subcellular partitioning, with Linc-KILH inhibiting Ser35 phosphorylation to promote membrane localization and β-catenin engagement.\",\n      \"evidence\": \"RNA-IP, Co-IP, Ser35 phosphosite mutation, and fractionation in KRT19-positive HCC cells\",\n      \"pmids\": [\"33767587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the Ser35 kinase not determined\", \"Quantitative link between phospho-state and β-catenin output unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a nuclear corepressor function for KRT19, showing it binds HDAC1/RCOR1 to enhance CoREST complex assembly and deacetylase activity, silencing hepatocyte genes (HNF4A) and driving dedifferentiation; FOXP4 was identified as a direct KRT19 transcriptional activator.\",\n      \"evidence\": \"Nuclear fractionation, tandem affinity purification/MS, ChIP-seq, HDAC activity assays, in vivo multiplexed genome editing, and KRT19 knockout in liver cancer models\",\n      \"pmids\": [\"38557414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of CoREST enhancement by KRT19 not defined\", \"Whether nuclear import is regulated by the same Ser35 switch unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single intermediate filament protein partitions between cytoskeletal, plasma membrane, and nuclear corepressor roles — and what determines which function dominates in a given cell — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking Ser35 phosphorylation to all subcellular pools\", \"Kinase(s) and import machinery for nuclear KRT19 unknown\", \"Structural details of KRT19 protein-protein interfaces uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"CoREST (HDAC1/RCOR1) complex\", \"K8/K19 keratin intermediate filament\"],\n    \"partners\": [\"CTNNB1\", \"RAC1\", \"HDAC1\", \"RCOR1\", \"CFTR\", \"KRT8\", \"RAB7A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}