{"gene":"KRT14","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2006,"finding":"Heterozygous nonsense or frameshift mutations in the E1/V1-encoding region (nonhelical head domain) of KRT14 cause Naegeli-Franceschetti-Jadassohn syndrome (NFJS) and dermatopathia pigmentosa reticularis (DPR), distinct from rod-domain mutations that cause EBS. Ultrastructural examination showed increased apoptotic activity in the basal cell layer, suggesting the N-terminal domain of KRT14 protects against apoptosis.","method":"Linkage analysis (LOD score 8.3), direct sequencing of KRT14 in 5 families, ultrastructural examination of patient skin biopsies, immunofluorescence","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across 5 independent families with multiple orthogonal methods (linkage, sequencing, ultrastructure)","pmids":["16960809"],"is_preprint":false},{"year":2007,"finding":"NFJS-causing KRT14 mutations result in haploinsufficiency for K14 protein. Decreased KRT14 expression in HaCaT keratinocytes increases susceptibility to TNF-alpha-induced apoptosis, establishing a mechanistic link between K14 loss and enhanced pro-apoptotic signaling in basal keratinocytes.","method":"siRNA knockdown of KRT14 in HaCaT cells, apoptosis assay with TNF-alpha stimulation, doxycycline rescue experiment","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined apoptotic phenotype and rescue, single lab, two methods","pmids":["18049449"],"is_preprint":false},{"year":2011,"finding":"Mutations in the helix boundary motifs (helix initiation and termination motifs) of the KRT14 rod domain are associated with the most severe EBS phenotype (Dowling-Meara), establishing a genotype-phenotype correlation based on structural disruption of keratin intermediate filament assembly.","method":"Direct sequencing of KRT14 coding sequence and cDNA in 76 EBS probands; immunofluorescence microscopy with anti-K14/K5 antibodies on skin biopsies","journal":"The British journal of dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — large cohort (76 probands), replicated genotype-phenotype correlation across multiple independent studies","pmids":["21375516"],"is_preprint":false},{"year":2011,"finding":"Two different amino acid substitutions at KRT14 position Ala413 produce different clinical outcomes: p.Ala413Pro (proline) causes pathogenic structural distortion of the keratin filament and keratin clumping in transfected cells, while p.Ala413Thr (threonine) does not disrupt filament structure and is a benign polymorphism. This demonstrates that the nature of the amino acid change, not just its position, determines pathogenicity.","method":"In silico structural modeling, in vitro transfection of HaCaT cells with mutant KRT14 cDNA constructs, quantification of keratin-clumped cells","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transfection assay with structural modeling, single lab, two orthogonal methods","pmids":["21593775"],"is_preprint":false},{"year":2014,"finding":"The EIATYR/KLLEGE motif at the C-terminal end of KRT14's 2B helix (around residues 413-418) is critical for maintaining structural stability of the KRT14:KRT5 heterodimer. Molecular dynamics simulations show that p.Leu418Gln disrupts intermolecular π-stacking between KRT14:Tyr415 and KRT5:Tyr470.","method":"Sanger sequencing, molecular dynamics simulations of KRT14:KRT5 heterodimer structure","journal":"Experimental dermatology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no in vitro functional validation of the interaction","pmids":["24981776"],"is_preprint":false},{"year":2016,"finding":"KRT14 expression marks a minor subpopulation of bladder basal cells that possesses self-renewal capacity and gives rise to all cell types of the urothelium during natural and injury-induced regeneration. These KRT14+ cells also represent cells of origin of urothelial cancer.","method":"Genetic lineage tracing in mice using KRT14-Cre, injury-induced regeneration assays, urothelial cancer initiation experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic fate mapping with defined cellular phenotype, multiple experimental conditions (homeostasis, injury, tumorigenesis)","pmids":["27320313"],"is_preprint":false},{"year":2016,"finding":"KRT14 regulates osteoblast matrix mineralization. siRNA knockdown of Krt14 in rat primary osteoblasts reduces ColI and osteocalcin gene expression, decreases soluble osteocalcin and collagen levels, and attenuates mineralization induced by kaempferol via the AMPK/mTOR pathway.","method":"siRNA knockdown of Krt14, gene expression analysis, AMPK/mTOR inhibitor experiments, AFM ultrastructural analysis","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotypic readout and pathway inhibitor experiments, single lab","pmids":["26956522"],"is_preprint":false},{"year":2017,"finding":"Inhibition of retinoic acid (RA) signaling upregulates Krt5 and Krt14 expression in isolated salivary gland epithelium explants independently of stem cell markers, demonstrating that RA signaling directly represses basal keratin expression in developing salivary epithelium.","method":"Isolated embryonic mouse salivary gland epithelium explant culture with RA signaling inhibitors, gene expression analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isolated tissue explant with direct chemical perturbation, single lab, direct functional consequence demonstrated","pmids":["27884045"],"is_preprint":false},{"year":2019,"finding":"A sub-population of ovarian cancer spheroid cells expressing KRT14 functions as 'leader cells' that mediate mesothelial clearance and invasion. Loss of KRT14 completely abrogates invasive capacity without affecting cell viability or proliferation, indicating an invasion-specific role.","method":"In vitro invasion model with imaging mass spectrometry, KRT14 siRNA/knockout loss-of-function, viability and proliferation assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with specific invasion phenotype, single lab, multiple readouts","pmids":["31443478"],"is_preprint":false},{"year":2022,"finding":"EZH2-mediated H3K27me3 promotes KRT14 transcription (not repression) in TNBC cells by attenuating binding of the transcriptional repressor SP1 to the KRT14 promoter. KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis.","method":"EZH2 knockdown, H3K27me3 inhibitor (EPZ6438) treatment, SP1 chromatin immunoprecipitation at KRT14 promoter, KRT14 knockdown migration/invasion assays, in vivo peritoneal metastasis mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal ChIP, loss-of-function at multiple levels (EZH2 KD, H3K27me3 inhibition, KRT14 KD), in vitro and in vivo validation, mechanistic pathway defined","pmids":["36446780"],"is_preprint":false},{"year":2022,"finding":"Krt14 binds the tumor suppressor stratifin (Sfn/14-3-3σ) in airway basal cells. Krt14 knockout reduces Sfn protein abundance and increases expression of ΔNp63α (an oncogene promoting basal cell identity), whereas Krt14 knockout basal cells fail to differentiate into club and ciliated cells but show enhanced clonogenicity.","method":"CRISPR knockout of Krt14 and Krt15 in primary mouse airway basal cells, co-immunoprecipitation/binding assay for Krt14-Sfn interaction, in vitro differentiation assays, in vivo label-retaining cell assay","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with defined differentiation phenotype and protein binding assay, single lab","pmids":["36512409"],"is_preprint":false},{"year":2010,"finding":"AAV-mediated gene targeting of KRT14 in human keratinocytes can precisely disrupt the mutant allele. EBS patient keratinocytes with corrected KRT14 mutations generate histologically normal skin grafts after transplantation to athymic mice, demonstrating that mutant KRT14 with dominant-negative activity is the cause of the weak epidermal phenotype.","method":"AAV gene targeting vector with promoter trap design, transplantation of corrected keratinocytes to athymic mice, histological analysis of skin grafts","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — precise gene correction with in vivo functional rescue, single lab","pmids":["20571545"],"is_preprint":false},{"year":2017,"finding":"CRISPR/Cas9 double-nicking strategy targeting KRT14 intron 7 with HDR achieves >30% correction efficiency of the causative hotspot mutation in exon 6 in EBS keratinocytes. Corrected cells show absence of disease-associated K14 aggregates in the cytoplasm, confirming that the mutant KRT14 protein forms cytoplasmic aggregates that disrupt intermediate filament polymerization.","method":"CRISPR/Cas9 D10A nickase pair, homology-directed repair with minicircle donor, immunofluorescence for K14 aggregates, NGS off-target analysis","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional correction with phenotypic readout (aggregate disappearance), single lab, orthogonal validation","pmids":["28888469"],"is_preprint":false},{"year":2025,"finding":"KRT14 directly interacts with the translation initiation factor eIF4H through its N-terminal Head domain. This interaction modulates eIF4H association with the eIF4F complex and selectively promotes translation of ACOX2 mRNA via its 5' UTR, driving lipid metabolic reprogramming and cisplatin resistance in bladder cancer.","method":"Co-immunoprecipitation, molecular interaction assays, domain mapping (N-terminal Head domain), ACOX2 mRNA translation assays, xenograft mouse models, patient-derived tissue analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by Co-IP with domain mapping, functional translation assay, in vivo validation, single lab","pmids":["41444318"],"is_preprint":false},{"year":2025,"finding":"KRT14 directly interacts with IGF2BP1 via residues D226/E227 within the nuclear export signal of KRT14, which are recognized by residues K294/E295 in the KH2 domain of IGF2BP1. This interaction facilitates IGF2BP1-mediated cytoplasmic trafficking and auto-stabilization of IGF2BP1 mRNA, amplifying pro-invasive gene expression in basal muscle-invasive bladder cancer.","method":"Co-immunoprecipitation, domain mapping, residue-level mutational analysis, mRNA stability assays, BMIBC mouse models, clinical cohort analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction with domain-level mapping and residue identification, functional mRNA stability assay, in vivo validation, single lab","pmids":["42261838"],"is_preprint":false},{"year":2025,"finding":"lncRNA ABCE1-5 directly binds KRT14 mRNA sequences (demonstrated by RNA pulldown-mass spectrometry and RNA immunoprecipitation), destabilizing KRT14 mRNA. Decreased ABCE1-5 increases KRT14 expression, which activates mTOR/AKT phosphorylation; KRT14 knockdown reverses mTOR activation caused by ABCE1-5 silencing, placing KRT14 upstream of mTOR/AKT signaling in pulmonary fibrosis.","method":"RNA pulldown-mass spectrometry, RNA immunoprecipitation, loss- and gain-of-function experiments in vitro and in vivo (AAV6 intratracheal injection in bleomycin mouse model), KRT14 siRNA epistasis experiment","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-protein interaction confirmed by RPD-MS and RIP, epistasis by KRT14 KD rescue, in vivo validation, single lab","pmids":["40111939"],"is_preprint":false},{"year":2022,"finding":"ATG5 deficiency specifically in KRT14+ salivary gland progenitor cells induces pyroptosis (cleaved gasdermin D elevation in KRT14+ cells), leading to functional impairment of salivary glands. Pyroptosis inhibitor treatment rescues the reduced saliva flow rate, placing KRT14+ cell autophagy upstream of gasdermin D-mediated pyroptosis in gland homeostasis.","method":"Conditional knockout (Atg5flox/flox; Krt14-Cre), immunofluorescence, TUNEL, western blot for cleaved gasdermin D and cleaved caspase 3, pyroptosis inhibitor rescue, saliva function measurement","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO with defined pyroptotic phenotype and pharmacological rescue, single lab","pmids":["36342387"],"is_preprint":false}],"current_model":"KRT14 encodes a type I intermediate filament keratin that heterodimerizes with KRT5 to form the structural cytoskeleton of basal epithelial cells; mutations in its conserved rod-domain helix boundary motifs disrupt filament assembly and cause epidermolysis bullosa simplex, while truncating mutations in its N-terminal head domain cause haploinsufficiency and NFJS/DPR partly through increased susceptibility to TNF-alpha-induced apoptosis. Beyond its structural role, KRT14 regulates airway basal cell differentiation by binding the tumor suppressor stratifin, drives cisplatin resistance in bladder cancer through a direct interaction with eIF4H that promotes ACOX2 mRNA translation, and promotes invasive cancer progression in bladder cancer via stabilization of IGF2BP1, collectively revealing that KRT14 functions both as a cytoskeletal scaffold and as a signaling scaffold that controls translational and apoptotic pathways in epithelial cells."},"narrative":{"mechanistic_narrative":"KRT14 encodes a type I intermediate filament keratin that heterodimerizes with KRT5 to form the structural cytoskeleton of basal epithelial cells, and it marks self-renewing basal progenitor populations that regenerate epithelia and serve as cells of origin for cancer [PMID:27320313]. Filament assembly depends on conserved rod-domain motifs: mutations in the helix initiation/termination motifs produce the most severe epidermolysis bullosa simplex phenotype [PMID:21375516], and pathogenicity is determined by the specific substitution, with C-terminal 2B-helix residues stabilizing the KRT14:KRT5 heterodimer [PMID:21593775]. Mutant KRT14 acts in a dominant-negative manner by forming cytoplasmic aggregates that disrupt intermediate filament polymerization, as shown by gene correction restoring normal filament organization and skin architecture [PMID:20571545, PMID:28888469]. Distinct truncating mutations in the nonhelical N-terminal head domain cause Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis through haploinsufficiency, with reduced K14 increasing susceptibility to TNF-alpha-induced apoptosis in basal keratinocytes [PMID:16960809, PMID:18049449]. Beyond its cytoskeletal role, KRT14 functions as a signaling scaffold: it binds stratifin to control airway basal cell differentiation [PMID:36512409], drives cisplatin resistance in bladder cancer by interacting with eIF4H through its head domain to selectively promote ACOX2 mRNA translation [PMID:41444318], and promotes invasive bladder cancer by stabilizing IGF2BP1 via a defined nuclear-export-signal interaction [PMID:42261838]. Its expression is set by chromatin and RNA-level regulators including EZH2/SP1 in triple-negative breast cancer [PMID:36446780] and a destabilizing lncRNA upstream of mTOR/AKT signaling in pulmonary fibrosis [PMID:40111939].","teleology":[{"year":2006,"claim":"Established that head-domain truncating mutations define a disease class distinct from rod-domain EBS and revealed an anti-apoptotic function for the KRT14 N-terminus.","evidence":"Linkage and sequencing across 5 NFJS/DPR families with ultrastructural analysis of basal keratinocytes","pmids":["16960809"],"confidence":"High","gaps":["Did not define the molecular mechanism linking head-domain loss to apoptosis","No direct biochemical readout of the protective activity"]},{"year":2007,"claim":"Showed NFJS mutations act through haploinsufficiency and mechanistically tied K14 loss to enhanced pro-apoptotic signaling.","evidence":"siRNA knockdown in HaCaT keratinocytes with TNF-alpha apoptosis assay and doxycycline rescue","pmids":["18049449"],"confidence":"Medium","gaps":["Single cell line, single lab","Apoptotic effector pathway downstream of TNF-alpha not resolved"]},{"year":2010,"claim":"Demonstrated that mutant KRT14 exerts dominant-negative activity by correcting the mutant allele and restoring normal skin.","evidence":"AAV gene targeting in EBS patient keratinocytes and grafting onto athymic mice","pmids":["20571545"],"confidence":"Medium","gaps":["Single lab","Correction efficiency and durability in vivo not fully characterized"]},{"year":2011,"claim":"Defined a genotype-phenotype correlation in which helix boundary motif mutations produce the most severe EBS, and showed substitution identity—not just position—dictates pathogenicity.","evidence":"Sequencing of 76 EBS probands and transfection-based filament assays distinguishing p.Ala413Pro from benign p.Ala413Thr","pmids":["21375516","21593775"],"confidence":"High","gaps":["Quantitative assembly defects not measured biochemically","Mechanism by which proline distorts the helix not directly visualized"]},{"year":2014,"claim":"Proposed an atomistic basis for heterodimer stability via π-stacking between KRT14 and KRT5 tyrosines.","evidence":"Sanger sequencing and molecular dynamics simulations of the KRT14:KRT5 2B helix","pmids":["24981776"],"confidence":"Low","gaps":["Computational prediction only, no in vitro validation of the interaction","Functional consequence on filament assembly not tested experimentally"]},{"year":2016,"claim":"Identified KRT14 as a marker of self-renewing basal progenitors that regenerate urothelium and seed urothelial cancer, extending KRT14 from structural marker to functional stem-cell lineage label.","evidence":"Genetic lineage tracing with KRT14-Cre in mouse homeostasis, injury, and tumor initiation models","pmids":["27320313"],"confidence":"High","gaps":["Whether KRT14 protein actively drives stemness versus merely marking it is unresolved"]},{"year":2016,"claim":"Linked KRT14 to osteoblast matrix mineralization via the AMPK/mTOR pathway.","evidence":"siRNA knockdown in rat primary osteoblasts with pathway inhibitors and AFM ultrastructure","pmids":["26956522"],"confidence":"Medium","gaps":["Single lab","Direct molecular connection between KRT14 and AMPK/mTOR not defined"]},{"year":2017,"claim":"Placed basal keratin expression under retinoic acid control during salivary epithelial development.","evidence":"Isolated embryonic mouse salivary epithelium explants treated with RA signaling inhibitors","pmids":["27884045"],"confidence":"Medium","gaps":["Transcriptional mediators between RA signaling and the Krt5/Krt14 promoters not identified"]},{"year":2019,"claim":"Defined an invasion-specific role for KRT14+ leader cells distinct from proliferation in ovarian cancer.","evidence":"In vitro mesothelial clearance/invasion model with KRT14 loss-of-function and viability/proliferation controls","pmids":["31443478"],"confidence":"Medium","gaps":["Molecular effectors of invasion downstream of KRT14 not identified","In vivo metastasis not tested in this study"]},{"year":2022,"claim":"Resolved transcriptional and protein-interaction control of KRT14 across tissues: EZH2/SP1 chromatin regulation drives KRT14 in TNBC metastasis, and KRT14-stratifin binding governs airway basal cell differentiation.","evidence":"EZH2 knockdown, H3K27me3 inhibition and SP1 ChIP in TNBC; CRISPR KO and Co-IP in primary airway basal cells","pmids":["36446780","36512409"],"confidence":"High","gaps":["Whether stratifin binding is direct or filament-mediated not fully dissected","How KRT14 loss elevates ΔNp63α mechanistically unresolved"]},{"year":2022,"claim":"Used KRT14+ cells to define a progenitor compartment whose autophagy restrains gasdermin D-mediated pyroptosis in salivary gland homeostasis.","evidence":"Atg5 conditional knockout under Krt14-Cre with pyroptosis markers and pharmacological rescue","pmids":["36342387"],"confidence":"Medium","gaps":["KRT14 protein function not directly implicated; KRT14-Cre used as a cell-type driver","Mechanism linking ATG5 loss to gasdermin D activation not defined"]},{"year":2025,"claim":"Established KRT14 as a signaling scaffold in bladder cancer through two defined direct interactions: head-domain binding to eIF4H driving ACOX2 translation and cisplatin resistance, and a nuclear-export-signal interaction with IGF2BP1 driving invasion.","evidence":"Co-IP with domain and residue-level mapping, translation and mRNA stability assays, xenograft/BMIBC mouse models and patient tissue","pmids":["41444318","42261838"],"confidence":"Medium","gaps":["Both interactions from single labs without reciprocal independent confirmation","How a cytoskeletal keratin engages translation machinery structurally remains unclear"]},{"year":2025,"claim":"Positioned KRT14 downstream of a destabilizing lncRNA and upstream of mTOR/AKT signaling in pulmonary fibrosis.","evidence":"RNA pulldown-MS and RIP for lncRNA ABCE1-5 binding to KRT14 mRNA, with KRT14 knockdown epistasis and AAV6 in vivo bleomycin model","pmids":["40111939"],"confidence":"Medium","gaps":["Single lab","Mechanism by which KRT14 activates mTOR/AKT phosphorylation not defined"]},{"year":null,"claim":"How a single keratin reconciles its cytoskeletal scaffolding function with diverse signaling roles—translation control, RNA-binding-protein stabilization, and apoptosis regulation—remains mechanistically unintegrated.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model linking filament assembly to non-structural partner binding","Independent confirmation of the eIF4H and IGF2BP1 interactions outside originating labs is lacking","Whether signaling functions require assembled filaments or soluble KRT14 is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,3,11,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,13,14]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,3,4]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12,13]}],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,13,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,7,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,16]}],"complexes":[],"partners":["KRT5","SFN","EIF4H","IGF2BP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02533","full_name":"Keratin, type I cytoskeletal 14","aliases":["Cytokeratin-14","CK-14","Keratin-14","K14"],"length_aa":472,"mass_kda":51.6,"function":"The nonhelical tail domain is involved in promoting KRT5-KRT14 filaments to self-organize into large bundles and enhances the mechanical properties involved in resilience of keratin intermediate filaments in vitro","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P02533/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT14","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT14","total_profiled":1310},"omim":[{"mim_id":"620150","title":"EPIDERMOLYTIC HYPERKERATOSIS 2A, AUTOSOMAL DOMINANT; EHK2A","url":"https://www.omim.org/entry/620150"},{"mim_id":"619594","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 2C, LOCALIZED; EBS2C","url":"https://www.omim.org/entry/619594"},{"mim_id":"619588","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 2B, GENERALIZED INTERMEDIATE; EBS2B","url":"https://www.omim.org/entry/619588"},{"mim_id":"619555","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 2A, GENERALIZED SEVERE; EBS2A","url":"https://www.omim.org/entry/619555"},{"mim_id":"617294","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH OR WITHOUT CARDIOMYOPATHY; EBS6","url":"https://www.omim.org/entry/617294"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Intermediate filaments","reliability":"Enhanced"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":6581.3}],"url":"https://www.proteinatlas.org/search/KRT14"},"hgnc":{"alias_symbol":[],"prev_symbol":["EBS3","EBS4"]},"alphafold":{"accession":"P02533","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P02533","model_url":"https://alphafold.ebi.ac.uk/files/AF-P02533-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P02533-F1-predicted_aligned_error_v6.png","plddt_mean":73.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRT14","jax_strain_url":"https://www.jax.org/strain/search?query=KRT14"},"sequence":{"accession":"P02533","fasta_url":"https://rest.uniprot.org/uniprotkb/P02533.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P02533/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P02533"}},"corpus_meta":[{"pmid":"27320313","id":"PMC_27320313","title":"KRT14 marks a subpopulation of bladder basal cells with pivotal role in regeneration and tumorigenesis.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27320313","citation_count":140,"is_preprint":false},{"pmid":"36446780","id":"PMC_36446780","title":"EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36446780","citation_count":110,"is_preprint":false},{"pmid":"21375516","id":"PMC_21375516","title":"Mutations in KRT5 and KRT14 cause epidermolysis bullosa simplex in 75% of the patients.","date":"2011","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/21375516","citation_count":86,"is_preprint":false},{"pmid":"16960809","id":"PMC_16960809","title":"Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14.","date":"2006","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16960809","citation_count":83,"is_preprint":false},{"pmid":"28888469","id":"PMC_28888469","title":"Cut and Paste: Efficient Homology-Directed Repair of a Dominant Negative KRT14 Mutation via CRISPR/Cas9 Nickases.","date":"2017","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/28888469","citation_count":71,"is_preprint":false},{"pmid":"31443478","id":"PMC_31443478","title":"Keratin-14 (KRT14) Positive Leader Cells Mediate Mesothelial Clearance and Invasion by Ovarian Cancer Cells.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31443478","citation_count":49,"is_preprint":false},{"pmid":"16786515","id":"PMC_16786515","title":"Novel and recurrent mutations in keratin KRT5 and KRT14 genes in epidermolysis bullosa simplex: implications for disease phenotype and keratin filament assembly.","date":"2006","source":"Human 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the keratin 14 gene (KRT14).","date":"1998","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/9804355","citation_count":37,"is_preprint":false},{"pmid":"27884045","id":"PMC_27884045","title":"Retinoic acid signaling regulates Krt5 and Krt14 independently of stem cell markers in submandibular salivary gland epithelium.","date":"2017","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/27884045","citation_count":35,"is_preprint":false},{"pmid":"20571545","id":"PMC_20571545","title":"Efficient KRT14 targeting and functional characterization of transplanted human keratinocytes for the treatment of epidermolysis bullosa simplex.","date":"2010","source":"Molecular therapy : the journal of the American Society of Gene 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Ultrastructural examination showed increased apoptotic activity in the basal cell layer, suggesting the N-terminal domain of KRT14 protects against apoptosis.\",\n      \"method\": \"Linkage analysis (LOD score 8.3), direct sequencing of KRT14 in 5 families, ultrastructural examination of patient skin biopsies, immunofluorescence\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across 5 independent families with multiple orthogonal methods (linkage, sequencing, ultrastructure)\",\n      \"pmids\": [\"16960809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NFJS-causing KRT14 mutations result in haploinsufficiency for K14 protein. Decreased KRT14 expression in HaCaT keratinocytes increases susceptibility to TNF-alpha-induced apoptosis, establishing a mechanistic link between K14 loss and enhanced pro-apoptotic signaling in basal keratinocytes.\",\n      \"method\": \"siRNA knockdown of KRT14 in HaCaT cells, apoptosis assay with TNF-alpha stimulation, doxycycline rescue experiment\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined apoptotic phenotype and rescue, single lab, two methods\",\n      \"pmids\": [\"18049449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mutations in the helix boundary motifs (helix initiation and termination motifs) of the KRT14 rod domain are associated with the most severe EBS phenotype (Dowling-Meara), establishing a genotype-phenotype correlation based on structural disruption of keratin intermediate filament assembly.\",\n      \"method\": \"Direct sequencing of KRT14 coding sequence and cDNA in 76 EBS probands; immunofluorescence microscopy with anti-K14/K5 antibodies on skin biopsies\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large cohort (76 probands), replicated genotype-phenotype correlation across multiple independent studies\",\n      \"pmids\": [\"21375516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Two different amino acid substitutions at KRT14 position Ala413 produce different clinical outcomes: p.Ala413Pro (proline) causes pathogenic structural distortion of the keratin filament and keratin clumping in transfected cells, while p.Ala413Thr (threonine) does not disrupt filament structure and is a benign polymorphism. This demonstrates that the nature of the amino acid change, not just its position, determines pathogenicity.\",\n      \"method\": \"In silico structural modeling, in vitro transfection of HaCaT cells with mutant KRT14 cDNA constructs, quantification of keratin-clumped cells\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transfection assay with structural modeling, single lab, two orthogonal methods\",\n      \"pmids\": [\"21593775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The EIATYR/KLLEGE motif at the C-terminal end of KRT14's 2B helix (around residues 413-418) is critical for maintaining structural stability of the KRT14:KRT5 heterodimer. Molecular dynamics simulations show that p.Leu418Gln disrupts intermolecular π-stacking between KRT14:Tyr415 and KRT5:Tyr470.\",\n      \"method\": \"Sanger sequencing, molecular dynamics simulations of KRT14:KRT5 heterodimer structure\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no in vitro functional validation of the interaction\",\n      \"pmids\": [\"24981776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KRT14 expression marks a minor subpopulation of bladder basal cells that possesses self-renewal capacity and gives rise to all cell types of the urothelium during natural and injury-induced regeneration. These KRT14+ cells also represent cells of origin of urothelial cancer.\",\n      \"method\": \"Genetic lineage tracing in mice using KRT14-Cre, injury-induced regeneration assays, urothelial cancer initiation experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic fate mapping with defined cellular phenotype, multiple experimental conditions (homeostasis, injury, tumorigenesis)\",\n      \"pmids\": [\"27320313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KRT14 regulates osteoblast matrix mineralization. siRNA knockdown of Krt14 in rat primary osteoblasts reduces ColI and osteocalcin gene expression, decreases soluble osteocalcin and collagen levels, and attenuates mineralization induced by kaempferol via the AMPK/mTOR pathway.\",\n      \"method\": \"siRNA knockdown of Krt14, gene expression analysis, AMPK/mTOR inhibitor experiments, AFM ultrastructural analysis\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotypic readout and pathway inhibitor experiments, single lab\",\n      \"pmids\": [\"26956522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Inhibition of retinoic acid (RA) signaling upregulates Krt5 and Krt14 expression in isolated salivary gland epithelium explants independently of stem cell markers, demonstrating that RA signaling directly represses basal keratin expression in developing salivary epithelium.\",\n      \"method\": \"Isolated embryonic mouse salivary gland epithelium explant culture with RA signaling inhibitors, gene expression analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isolated tissue explant with direct chemical perturbation, single lab, direct functional consequence demonstrated\",\n      \"pmids\": [\"27884045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A sub-population of ovarian cancer spheroid cells expressing KRT14 functions as 'leader cells' that mediate mesothelial clearance and invasion. Loss of KRT14 completely abrogates invasive capacity without affecting cell viability or proliferation, indicating an invasion-specific role.\",\n      \"method\": \"In vitro invasion model with imaging mass spectrometry, KRT14 siRNA/knockout loss-of-function, viability and proliferation assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with specific invasion phenotype, single lab, multiple readouts\",\n      \"pmids\": [\"31443478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EZH2-mediated H3K27me3 promotes KRT14 transcription (not repression) in TNBC cells by attenuating binding of the transcriptional repressor SP1 to the KRT14 promoter. KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis.\",\n      \"method\": \"EZH2 knockdown, H3K27me3 inhibitor (EPZ6438) treatment, SP1 chromatin immunoprecipitation at KRT14 promoter, KRT14 knockdown migration/invasion assays, in vivo peritoneal metastasis mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal ChIP, loss-of-function at multiple levels (EZH2 KD, H3K27me3 inhibition, KRT14 KD), in vitro and in vivo validation, mechanistic pathway defined\",\n      \"pmids\": [\"36446780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Krt14 binds the tumor suppressor stratifin (Sfn/14-3-3σ) in airway basal cells. Krt14 knockout reduces Sfn protein abundance and increases expression of ΔNp63α (an oncogene promoting basal cell identity), whereas Krt14 knockout basal cells fail to differentiate into club and ciliated cells but show enhanced clonogenicity.\",\n      \"method\": \"CRISPR knockout of Krt14 and Krt15 in primary mouse airway basal cells, co-immunoprecipitation/binding assay for Krt14-Sfn interaction, in vitro differentiation assays, in vivo label-retaining cell assay\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with defined differentiation phenotype and protein binding assay, single lab\",\n      \"pmids\": [\"36512409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AAV-mediated gene targeting of KRT14 in human keratinocytes can precisely disrupt the mutant allele. EBS patient keratinocytes with corrected KRT14 mutations generate histologically normal skin grafts after transplantation to athymic mice, demonstrating that mutant KRT14 with dominant-negative activity is the cause of the weak epidermal phenotype.\",\n      \"method\": \"AAV gene targeting vector with promoter trap design, transplantation of corrected keratinocytes to athymic mice, histological analysis of skin grafts\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — precise gene correction with in vivo functional rescue, single lab\",\n      \"pmids\": [\"20571545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRISPR/Cas9 double-nicking strategy targeting KRT14 intron 7 with HDR achieves >30% correction efficiency of the causative hotspot mutation in exon 6 in EBS keratinocytes. Corrected cells show absence of disease-associated K14 aggregates in the cytoplasm, confirming that the mutant KRT14 protein forms cytoplasmic aggregates that disrupt intermediate filament polymerization.\",\n      \"method\": \"CRISPR/Cas9 D10A nickase pair, homology-directed repair with minicircle donor, immunofluorescence for K14 aggregates, NGS off-target analysis\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional correction with phenotypic readout (aggregate disappearance), single lab, orthogonal validation\",\n      \"pmids\": [\"28888469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KRT14 directly interacts with the translation initiation factor eIF4H through its N-terminal Head domain. This interaction modulates eIF4H association with the eIF4F complex and selectively promotes translation of ACOX2 mRNA via its 5' UTR, driving lipid metabolic reprogramming and cisplatin resistance in bladder cancer.\",\n      \"method\": \"Co-immunoprecipitation, molecular interaction assays, domain mapping (N-terminal Head domain), ACOX2 mRNA translation assays, xenograft mouse models, patient-derived tissue analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by Co-IP with domain mapping, functional translation assay, in vivo validation, single lab\",\n      \"pmids\": [\"41444318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KRT14 directly interacts with IGF2BP1 via residues D226/E227 within the nuclear export signal of KRT14, which are recognized by residues K294/E295 in the KH2 domain of IGF2BP1. This interaction facilitates IGF2BP1-mediated cytoplasmic trafficking and auto-stabilization of IGF2BP1 mRNA, amplifying pro-invasive gene expression in basal muscle-invasive bladder cancer.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, residue-level mutational analysis, mRNA stability assays, BMIBC mouse models, clinical cohort analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction with domain-level mapping and residue identification, functional mRNA stability assay, in vivo validation, single lab\",\n      \"pmids\": [\"42261838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"lncRNA ABCE1-5 directly binds KRT14 mRNA sequences (demonstrated by RNA pulldown-mass spectrometry and RNA immunoprecipitation), destabilizing KRT14 mRNA. Decreased ABCE1-5 increases KRT14 expression, which activates mTOR/AKT phosphorylation; KRT14 knockdown reverses mTOR activation caused by ABCE1-5 silencing, placing KRT14 upstream of mTOR/AKT signaling in pulmonary fibrosis.\",\n      \"method\": \"RNA pulldown-mass spectrometry, RNA immunoprecipitation, loss- and gain-of-function experiments in vitro and in vivo (AAV6 intratracheal injection in bleomycin mouse model), KRT14 siRNA epistasis experiment\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-protein interaction confirmed by RPD-MS and RIP, epistasis by KRT14 KD rescue, in vivo validation, single lab\",\n      \"pmids\": [\"40111939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATG5 deficiency specifically in KRT14+ salivary gland progenitor cells induces pyroptosis (cleaved gasdermin D elevation in KRT14+ cells), leading to functional impairment of salivary glands. Pyroptosis inhibitor treatment rescues the reduced saliva flow rate, placing KRT14+ cell autophagy upstream of gasdermin D-mediated pyroptosis in gland homeostasis.\",\n      \"method\": \"Conditional knockout (Atg5flox/flox; Krt14-Cre), immunofluorescence, TUNEL, western blot for cleaved gasdermin D and cleaved caspase 3, pyroptosis inhibitor rescue, saliva function measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO with defined pyroptotic phenotype and pharmacological rescue, single lab\",\n      \"pmids\": [\"36342387\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT14 encodes a type I intermediate filament keratin that heterodimerizes with KRT5 to form the structural cytoskeleton of basal epithelial cells; mutations in its conserved rod-domain helix boundary motifs disrupt filament assembly and cause epidermolysis bullosa simplex, while truncating mutations in its N-terminal head domain cause haploinsufficiency and NFJS/DPR partly through increased susceptibility to TNF-alpha-induced apoptosis. Beyond its structural role, KRT14 regulates airway basal cell differentiation by binding the tumor suppressor stratifin, drives cisplatin resistance in bladder cancer through a direct interaction with eIF4H that promotes ACOX2 mRNA translation, and promotes invasive cancer progression in bladder cancer via stabilization of IGF2BP1, collectively revealing that KRT14 functions both as a cytoskeletal scaffold and as a signaling scaffold that controls translational and apoptotic pathways in epithelial cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KRT14 encodes a type I intermediate filament keratin that heterodimerizes with KRT5 to form the structural cytoskeleton of basal epithelial cells, and it marks self-renewing basal progenitor populations that regenerate epithelia and serve as cells of origin for cancer [#5]. Filament assembly depends on conserved rod-domain motifs: mutations in the helix initiation/termination motifs produce the most severe epidermolysis bullosa simplex phenotype [#2], and pathogenicity is determined by the specific substitution, with C-terminal 2B-helix residues stabilizing the KRT14:KRT5 heterodimer [#3]. Mutant KRT14 acts in a dominant-negative manner by forming cytoplasmic aggregates that disrupt intermediate filament polymerization, as shown by gene correction restoring normal filament organization and skin architecture [#11, #12]. Distinct truncating mutations in the nonhelical N-terminal head domain cause Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis through haploinsufficiency, with reduced K14 increasing susceptibility to TNF-alpha-induced apoptosis in basal keratinocytes [#0, #1]. Beyond its cytoskeletal role, KRT14 functions as a signaling scaffold: it binds stratifin to control airway basal cell differentiation [#10], drives cisplatin resistance in bladder cancer by interacting with eIF4H through its head domain to selectively promote ACOX2 mRNA translation [#13], and promotes invasive bladder cancer by stabilizing IGF2BP1 via a defined nuclear-export-signal interaction [#14]. Its expression is set by chromatin and RNA-level regulators including EZH2/SP1 in triple-negative breast cancer [#9] and a destabilizing lncRNA upstream of mTOR/AKT signaling in pulmonary fibrosis [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that head-domain truncating mutations define a disease class distinct from rod-domain EBS and revealed an anti-apoptotic function for the KRT14 N-terminus.\",\n      \"evidence\": \"Linkage and sequencing across 5 NFJS/DPR families with ultrastructural analysis of basal keratinocytes\",\n      \"pmids\": [\"16960809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular mechanism linking head-domain loss to apoptosis\", \"No direct biochemical readout of the protective activity\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed NFJS mutations act through haploinsufficiency and mechanistically tied K14 loss to enhanced pro-apoptotic signaling.\",\n      \"evidence\": \"siRNA knockdown in HaCaT keratinocytes with TNF-alpha apoptosis assay and doxycycline rescue\",\n      \"pmids\": [\"18049449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line, single lab\", \"Apoptotic effector pathway downstream of TNF-alpha not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that mutant KRT14 exerts dominant-negative activity by correcting the mutant allele and restoring normal skin.\",\n      \"evidence\": \"AAV gene targeting in EBS patient keratinocytes and grafting onto athymic mice\",\n      \"pmids\": [\"20571545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Correction efficiency and durability in vivo not fully characterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a genotype-phenotype correlation in which helix boundary motif mutations produce the most severe EBS, and showed substitution identity—not just position—dictates pathogenicity.\",\n      \"evidence\": \"Sequencing of 76 EBS probands and transfection-based filament assays distinguishing p.Ala413Pro from benign p.Ala413Thr\",\n      \"pmids\": [\"21375516\", \"21593775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative assembly defects not measured biochemically\", \"Mechanism by which proline distorts the helix not directly visualized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Proposed an atomistic basis for heterodimer stability via π-stacking between KRT14 and KRT5 tyrosines.\",\n      \"evidence\": \"Sanger sequencing and molecular dynamics simulations of the KRT14:KRT5 2B helix\",\n      \"pmids\": [\"24981776\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction only, no in vitro validation of the interaction\", \"Functional consequence on filament assembly not tested experimentally\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified KRT14 as a marker of self-renewing basal progenitors that regenerate urothelium and seed urothelial cancer, extending KRT14 from structural marker to functional stem-cell lineage label.\",\n      \"evidence\": \"Genetic lineage tracing with KRT14-Cre in mouse homeostasis, injury, and tumor initiation models\",\n      \"pmids\": [\"27320313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KRT14 protein actively drives stemness versus merely marking it is unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked KRT14 to osteoblast matrix mineralization via the AMPK/mTOR pathway.\",\n      \"evidence\": \"siRNA knockdown in rat primary osteoblasts with pathway inhibitors and AFM ultrastructure\",\n      \"pmids\": [\"26956522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct molecular connection between KRT14 and AMPK/mTOR not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed basal keratin expression under retinoic acid control during salivary epithelial development.\",\n      \"evidence\": \"Isolated embryonic mouse salivary epithelium explants treated with RA signaling inhibitors\",\n      \"pmids\": [\"27884045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional mediators between RA signaling and the Krt5/Krt14 promoters not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined an invasion-specific role for KRT14+ leader cells distinct from proliferation in ovarian cancer.\",\n      \"evidence\": \"In vitro mesothelial clearance/invasion model with KRT14 loss-of-function and viability/proliferation controls\",\n      \"pmids\": [\"31443478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors of invasion downstream of KRT14 not identified\", \"In vivo metastasis not tested in this study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved transcriptional and protein-interaction control of KRT14 across tissues: EZH2/SP1 chromatin regulation drives KRT14 in TNBC metastasis, and KRT14-stratifin binding governs airway basal cell differentiation.\",\n      \"evidence\": \"EZH2 knockdown, H3K27me3 inhibition and SP1 ChIP in TNBC; CRISPR KO and Co-IP in primary airway basal cells\",\n      \"pmids\": [\"36446780\", \"36512409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether stratifin binding is direct or filament-mediated not fully dissected\", \"How KRT14 loss elevates ΔNp63α mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Used KRT14+ cells to define a progenitor compartment whose autophagy restrains gasdermin D-mediated pyroptosis in salivary gland homeostasis.\",\n      \"evidence\": \"Atg5 conditional knockout under Krt14-Cre with pyroptosis markers and pharmacological rescue\",\n      \"pmids\": [\"36342387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KRT14 protein function not directly implicated; KRT14-Cre used as a cell-type driver\", \"Mechanism linking ATG5 loss to gasdermin D activation not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established KRT14 as a signaling scaffold in bladder cancer through two defined direct interactions: head-domain binding to eIF4H driving ACOX2 translation and cisplatin resistance, and a nuclear-export-signal interaction with IGF2BP1 driving invasion.\",\n      \"evidence\": \"Co-IP with domain and residue-level mapping, translation and mRNA stability assays, xenograft/BMIBC mouse models and patient tissue\",\n      \"pmids\": [\"41444318\", \"42261838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both interactions from single labs without reciprocal independent confirmation\", \"How a cytoskeletal keratin engages translation machinery structurally remains unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned KRT14 downstream of a destabilizing lncRNA and upstream of mTOR/AKT signaling in pulmonary fibrosis.\",\n      \"evidence\": \"RNA pulldown-MS and RIP for lncRNA ABCE1-5 binding to KRT14 mRNA, with KRT14 knockdown epistasis and AAV6 in vivo bleomycin model\",\n      \"pmids\": [\"40111939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism by which KRT14 activates mTOR/AKT phosphorylation not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single keratin reconciles its cytoskeletal scaffolding function with diverse signaling roles—translation control, RNA-binding-protein stabilization, and apoptosis regulation—remains mechanistically unintegrated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model linking filament assembly to non-structural partner binding\", \"Independent confirmation of the eIF4H and IGF2BP1 interactions outside originating labs is lacking\", \"Whether signaling functions require assembled filaments or soluble KRT14 is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3, 11, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 13, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 13, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 7, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KRT5\", \"SFN\", \"EIF4H\", \"IGF2BP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}