{"gene":"KRT14","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2007,"finding":"KRT14 haploinsufficiency (caused by nonsense/frameshift mutations in the E1/V1 N-terminal domain) results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis; knockdown of KRT14 in HaCaT cells increased apoptotic activity, and doxycycline (a negative regulator of TNF-alpha pro-apoptotic signaling) rescued this phenotype, establishing that the N-terminal domain of KRT14 confers protection against pro-apoptotic signals.","method":"siRNA knockdown of KRT14 in HaCaT cells, TNF-alpha apoptosis assay, immunofluorescence of patient skin biopsies","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular phenotype with mechanistic pathway placement in single lab study","pmids":["18049449"],"is_preprint":false},{"year":2006,"finding":"Heterozygous nonsense or frameshift mutations in the N-terminal nonhelical head (E1/V1) domain of KRT14 cause NFJS/DPR ectodermal dysplasias (distinct from rod-domain mutations that cause EBS), demonstrating that different functional domains of KRT14 underlie distinct disease mechanisms; ultrastructural analysis of patient skin showed increased apoptotic activity in KRT14-expressing basal cells.","method":"Genetic linkage analysis, mutation sequencing across 5 families, ultrastructural examination of patient skin biopsies","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — replicated across 5 families with orthogonal structural and genetic evidence","pmids":["16960809"],"is_preprint":false},{"year":2011,"finding":"Mutations in the helix boundary motifs (especially the helix initiation motif) of KRT14 cause the most severe EBS phenotype (Dowling-Meara), establishing structure-function correlation for the rod domain in keratin intermediate filament assembly and mechanical integrity of basal keratinocytes.","method":"Genomic DNA and cDNA sequencing of KRT5/KRT14 in 76 EBS probands, immunofluorescence microscopy with anti-K5/K14 antibodies on patient skin biopsies","journal":"The British journal of dermatology","confidence":"High","confidence_rationale":"Tier 2 — large cohort with orthogonal protein and genetic analysis, replicated genotype-phenotype pattern","pmids":["21375516"],"is_preprint":false},{"year":2011,"finding":"Two different amino acid substitutions at KRT14 position Ala413 (p.Ala413Pro vs p.Ala413Thr) produce distinct structural distortions and different phenotypic severity in EBS; in silico modeling showed proline substitution causes deleterious structural effects, and in vitro transfection into HaCaT cells showed significantly more keratin clumping with p.Ala413Pro than with p.Ala413Thr or wild-type, demonstrating that structural distortion caused by specific amino acid properties determines pathogenicity.","method":"In silico protein structural modeling, in vitro transfection of mutant KRT14 cDNA into HaCaT cells, immunofluorescence assessment of keratin clumping","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro functional assay with structural modeling, single lab","pmids":["21593775"],"is_preprint":false},{"year":2014,"finding":"A p.Leu418Gln mutation in KRT14 disrupts intermolecular π-stacking between KRT14:Tyr415 and KRT5:Tyr470 at the KRT14:KRT5 heterodimer interface (EIATYR/KLLEGE motif), and may affect a putative phosphorylation site at KRT14:Thr414, establishing that the 2B helix C-terminal region is critical for KRT5-KRT14 heterodimer stability.","method":"Molecular dynamics simulation of KRT14 p.Leu418Gln mutation, genetic analysis of EBS family","journal":"Experimental dermatology","confidence":"Low","confidence_rationale":"Tier 4 — computational prediction with genetic validation but no in vitro reconstitution","pmids":["24981776"],"is_preprint":false},{"year":2010,"finding":"AAV-mediated gene targeting of KRT14 in human keratinocytes can precisely correct or disrupt mutant alleles; keratinocytes with correction of the dominant-negative KRT14 mutation produced histologically normal skin grafts after transplantation to athymic mice, demonstrating that dominant-negative KRT14 protein disrupts intermediate filament polymerization in basal keratinocytes, causing epidermal fragility.","method":"AAV gene targeting with promoter trap design, transplantation to athymic mice, histological analysis of skin grafts","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo functional rescue with defined molecular mechanism","pmids":["20571545"],"is_preprint":false},{"year":2017,"finding":"CRISPR/Cas9 nickase-mediated homology-directed repair of a dominant-negative KRT14 hotspot mutation (exon 6) in EBS keratinocytes achieved >30% recombination efficiency and phenotypic correction, demonstrated by absence of disease-associated K14 cytoplasmic aggregates by immunofluorescence, confirming that mutant KRT14 causes keratin aggregate formation in basal keratinocytes.","method":"CRISPR/Cas9 D10A nickase double-nicking HDR, immunofluorescence for K14 aggregates, next-generation sequencing for off-target analysis","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional correction with molecular readout, single lab","pmids":["28888469"],"is_preprint":false},{"year":2023,"finding":"Krt14-KO airway basal cells failed to differentiate into club and ciliated cells but had enhanced clonogenicity; Krt14, but not Krt15, directly bound the tumor suppressor stratifin (Sfn), and Krt14 disruption reduced Sfn protein abundance while increasing ΔNp63α expression during differentiation, establishing that Krt14 regulates basal cell differentiation through a Krt14-Sfn-ΔNp63α axis.","method":"CRISPR-KO of Krt14 in primary mouse airway basal cells, in vitro differentiation assays, co-immunoprecipitation (Krt14-Sfn binding), western blot for Sfn and ΔNp63α, in vivo injury model with label-retaining cell analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — CRISPR-KO with defined phenotype, protein-protein interaction confirmed, in vitro and in vivo, multiple orthogonal methods","pmids":["36512409"],"is_preprint":false},{"year":2016,"finding":"KRT14 marks a minor subpopulation of urothelial basal cells with self-renewal capacity that gives rise to all cell types of the urothelium during natural and injury-induced regeneration; KRT14+ basal cells also represent cells of origin for urothelial cancer, establishing KRT14 as a functional marker of urothelial progenitors.","method":"Genetic lineage tracing of KRT14+ cells in mouse urothelium (Krt14-Cre fate mapping), injury-induced regeneration models, tumor initiation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — in vivo lineage tracing with defined regenerative and tumorigenic phenotypes","pmids":["27320313"],"is_preprint":false},{"year":2019,"finding":"A subpopulation of KRT14-expressing ovarian cancer cells functions as 'leader cells' mediating mesothelial clearance and invasion; KRT14 loss completely abrogated invasive capacity without affecting cell viability or proliferation, demonstrating an invasion-specific role for KRT14.","method":"In vitro invasion model with imaging mass spectrometry, KRT14 knockdown in ovarian cancer spheroids, mesothelial clearance and invasion assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific invasion phenotype, single lab","pmids":["31443478"],"is_preprint":false},{"year":2022,"finding":"EZH2 catalytic function (H3K27me3) promotes KRT14 transcription in TNBC by attenuating binding of the repressor SP1 to the KRT14 promoter; KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis, demonstrating that H3K27me3-mediated SP1 displacement activates KRT14 expression to drive TNBC metastasis.","method":"ChIP-seq for H3K27me3 and SP1, KRT14 knockdown in TNBC cells, in vitro migration/invasion assays, in vivo peritoneal metastasis mouse models, EZH2 inhibitor (EPZ6438) treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including ChIP, in vitro and in vivo functional assays, mechanistic pathway defined","pmids":["36446780"],"is_preprint":false},{"year":2016,"finding":"KRT14 promotes osteoblast mineralization by organizing osteoblast-derived ECM; Krt14 siRNA knockdown in rat primary osteoblasts reduced ColI and OCN expression and soluble osteocalcin/collagen levels, and inhibited kaempferol-induced mTOR activation, placing KRT14 upstream of the mTOR signaling pathway in osteoblast mineralization.","method":"Krt14 siRNA knockdown in rat primary osteoblasts, mineralization assay, AFM ultrastructural analysis, qRT-PCR for ColI/OCN, AMPK/mTOR inhibitor treatment","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple molecular readouts, single lab","pmids":["26956522"],"is_preprint":false},{"year":2025,"finding":"KRT14 directly interacts with translation initiation factor eIF4H through its N-terminal Head domain; this interaction modulates eIF4H association with the eIF4F complex to selectively promote translation of ACOX2 mRNA via its 5' UTR, thereby driving lipid metabolic reprogramming and cisplatin resistance in bladder cancer.","method":"Co-immunoprecipitation, GST pulldown, domain-mapping mutagenesis (N-terminal Head domain), polysome profiling/translation assays, ACOX2 5'UTR reporter, xenograft mouse models, patient-derived tissue analysis","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 — direct protein-protein interaction mapped to specific domain, translational mechanism established with multiple orthogonal methods in single rigorous study","pmids":["41444318"],"is_preprint":false},{"year":2025,"finding":"lncRNA ABCE1-5 directly binds KRT14 mRNA sequences (demonstrated by RNA pulldown-mass spectrometry and RNA immunoprecipitation) and destabilizes KRT14 mRNA, reducing KRT14 protein levels; decreased ABCE1-5 leads to KRT14 upregulation that activates mTOR/AKT phosphorylation to promote pulmonary fibrosis.","method":"RNA pulldown-mass spectrometry, RNA immunoprecipitation, KRT14 knockdown, overexpression in vitro and in vivo (AAV6), bleomycin mouse model","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-protein interaction confirmed by two orthogonal methods with in vivo functional validation, single lab","pmids":["40111939"],"is_preprint":false},{"year":2008,"finding":"Complete absence of KRT14 protein (homozygous truncation mutation Y204X) in recessive EBS leads to compensatory expression of K6 and K16 in the basal layer (normally expressed in hyperproliferative skin), suggesting an alternative keratin pairing with K5 in the absence of K14, revealing the functional requirement for KRT14 in basal keratinocyte intermediate filament network integrity.","method":"Immunofluorescence mapping with monoclonal antibodies against K14, K6, K16 on patient skin biopsies, electron microscopy, genomic DNA mutation analysis","journal":"Clinical and experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein localization with functional consequence demonstrated, single case with orthogonal methods","pmids":["18713255"],"is_preprint":false},{"year":2017,"finding":"Retinoic acid (RA) signaling directly in salivary gland epithelium (demonstrated by isolated epithelium explant cultures) represses Krt5 and Krt14 expression; inhibition of RA signaling upregulates Krt14 and Krt5 independently of stem cell marker Kit regulation, establishing RA as a direct upstream regulator of basal keratin expression in developing epithelium.","method":"Isolated salivary gland epithelium explant cultures, RA signaling inhibition, qRT-PCR for Krt14/Krt5/Kit expression","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — direct tissue manipulation with functional molecular readout, single lab","pmids":["27884045"],"is_preprint":false}],"current_model":"KRT14 encodes a type I intermediate filament keratin that forms obligate heterodimers with KRT5 in basal epithelial cells; its rod domain is essential for keratin filament assembly and mechanical integrity (mutations here cause EBS), its N-terminal head domain protects keratinocytes from TNF-alpha-induced apoptosis and is required for dermatoglyphic/sweat gland development, it interacts with stratifin (Sfn) to regulate airway basal cell differentiation through a ΔNp63α axis, and in cancer contexts KRT14 drives invasion and chemoresistance through a novel interaction with eIF4H that selectively promotes ACOX2 mRNA translation, while its transcription is regulated by EZH2-mediated H3K27me3 displacement of the SP1 repressor and post-transcriptionally by lncRNA ABCE1-5-mediated mRNA destabilization."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing that different KRT14 domains cause distinct diseases resolved a long-standing question of how a single keratin gene could underlie both skin fragility and ectodermal dysplasia: N-terminal head domain truncations cause NFJS/DPR through increased basal cell apoptosis, distinct from rod domain mutations causing EBS.","evidence":"Genetic linkage and mutation analysis across 5 families with ultrastructural examination of patient skin","pmids":["16960809"],"confidence":"High","gaps":["Mechanism by which head domain loss increases apoptosis was not defined at the molecular level","No rescue experiment to confirm causality"]},{"year":2007,"claim":"Demonstrating that KRT14 knockdown sensitizes keratinocytes to TNF-α-induced apoptosis provided a mechanistic explanation for the NFJS/DPR phenotype, showing that KRT14 has a signaling-protective function beyond structural support.","evidence":"siRNA knockdown in HaCaT cells with TNF-α apoptosis assay and doxycycline rescue","pmids":["18049449"],"confidence":"Medium","gaps":["Direct molecular target of KRT14 in anti-apoptotic signaling not identified","Only one cell line tested"]},{"year":2008,"claim":"Complete KRT14 loss revealed the functional requirement for KRT14 in basal keratinocyte filament networks and the capacity for compensatory K6/K16 upregulation, establishing that K14 is not absolutely required for cell survival but is essential for normal filament architecture.","evidence":"Immunofluorescence and electron microscopy of homozygous KRT14-null patient skin biopsy","pmids":["18713255"],"confidence":"Medium","gaps":["Single patient case","Functional consequences of K6/K16 compensation not tested"]},{"year":2010,"claim":"Gene correction of dominant-negative KRT14 mutations restored normal skin graft histology, providing direct functional proof that mutant KRT14 protein actively disrupts filament polymerization rather than simply being non-functional.","evidence":"AAV-mediated gene targeting in human keratinocytes with transplantation to athymic mice","pmids":["20571545"],"confidence":"Medium","gaps":["Long-term stability of correction in regenerating epidermis not assessed"]},{"year":2011,"claim":"Systematic genotype-phenotype mapping across 76 EBS probands established that helix initiation motif mutations cause the most severe (Dowling-Meara) phenotype, while specific amino acid substitutions at the same position produce graded severity depending on structural distortion, defining the structure-function rules for KRT14 rod domain assembly.","evidence":"Large cohort KRT5/KRT14 sequencing with immunofluorescence; in silico modeling and in vitro transfection of Ala413 variants in HaCaT cells","pmids":["21375516","21593775"],"confidence":"High","gaps":["No in vitro filament reconstitution to quantify assembly defects biochemically","Correlation between clumping severity and clinical severity not formally tested across large series"]},{"year":2016,"claim":"KRT14 was established as a functional marker of self-renewing urothelial progenitors and cells of origin for urothelial carcinoma, revealing a role beyond structural support as a marker of stem-like basal cell identity.","evidence":"Krt14-Cre genetic lineage tracing in mouse urothelium with injury and tumor models","pmids":["27320313"],"confidence":"High","gaps":["Whether KRT14 is functionally required for progenitor self-renewal or merely a marker was not distinguished"]},{"year":2016,"claim":"Demonstrating that KRT14 promotes osteoblast mineralization upstream of mTOR signaling expanded KRT14's functional repertoire beyond epithelia, though the mechanism linking an intermediate filament to mTOR activation remained unclear.","evidence":"Krt14 siRNA knockdown in rat primary osteoblasts with mineralization assay and mTOR inhibitor treatment","pmids":["26956522"],"confidence":"Medium","gaps":["Direct molecular link between KRT14 and mTOR activation not identified","Relevance to in vivo bone biology not tested"]},{"year":2017,"claim":"Retinoic acid was identified as a direct upstream repressor of Krt14/Krt5 expression in developing salivary epithelium, establishing an extrinsic signaling input that controls basal keratin identity independently of stem cell programs.","evidence":"Isolated salivary gland epithelium explant cultures with RA signaling inhibition and qRT-PCR","pmids":["27884045"],"confidence":"Medium","gaps":["Whether RA acts directly on KRT14 promoter or through intermediate transcription factors not resolved","Single tissue type tested"]},{"year":2019,"claim":"Demonstrating that KRT14 loss abrogates ovarian cancer invasion without affecting proliferation established an invasion-specific, non-structural function for KRT14 in cancer, distinct from its mechanical role in normal epithelia.","evidence":"KRT14 knockdown in ovarian cancer spheroids with mesothelial clearance and invasion assays","pmids":["31443478"],"confidence":"Medium","gaps":["Downstream effectors of KRT14-mediated invasion not identified","Single cancer type in vitro"]},{"year":2022,"claim":"The discovery that EZH2 activates KRT14 transcription by depositing H3K27me3 to displace the repressor SP1 from the KRT14 promoter revealed an unexpected activating role for a canonically repressive histone mark and explained how KRT14 drives TNBC metastasis.","evidence":"ChIP-seq for H3K27me3 and SP1, KRT14 knockdown with in vitro migration/invasion and in vivo peritoneal metastasis models, EZH2 inhibitor treatment","pmids":["36446780"],"confidence":"High","gaps":["Whether H3K27me3-mediated SP1 displacement is a general mechanism or specific to the KRT14 locus","Contribution of other transcription factors at the KRT14 promoter not assessed"]},{"year":2023,"claim":"Identifying Krt14 as a direct binding partner of stratifin that controls ΔNp63α levels during airway basal cell differentiation provided the first mechanistic link between a keratin intermediate filament protein and a transcriptional differentiation program.","evidence":"CRISPR-KO in primary mouse airway basal cells, co-immunoprecipitation, differentiation assays, in vivo injury model","pmids":["36512409"],"confidence":"High","gaps":["How Krt14-Sfn binding stabilizes Sfn protein not determined","Whether this axis operates in other KRT14-expressing epithelia unknown"]},{"year":2025,"claim":"The discovery that KRT14 directly interacts with eIF4H through its N-terminal head domain to selectively promote ACOX2 translation revealed a previously unsuspected non-cytoskeletal function as a translational regulator, providing a mechanistic basis for KRT14-driven chemoresistance.","evidence":"Co-IP, GST pulldown, domain-mapping mutagenesis, polysome profiling, ACOX2 5'UTR reporter, xenograft models","pmids":["41444318"],"confidence":"High","gaps":["Scope of KRT14-eIF4H translational targets beyond ACOX2 not defined","Whether this translational role is active in normal basal cells or only in cancer contexts"]},{"year":2025,"claim":"Identification of lncRNA ABCE1-5 as a direct destabilizer of KRT14 mRNA added a post-transcriptional regulatory layer and linked KRT14 upregulation to mTOR/AKT-driven pulmonary fibrosis.","evidence":"RNA pulldown-mass spectrometry, RNA immunoprecipitation, KRT14 knockdown/overexpression in vitro and in vivo with bleomycin model","pmids":["40111939"],"confidence":"Medium","gaps":["Mechanism of ABCE1-5-mediated mRNA destabilization (e.g., recruitment of decay machinery) not defined","Whether ABCE1-5 regulation of KRT14 operates in epithelial tissues beyond lung"]},{"year":null,"claim":"It remains unknown how KRT14's non-structural functions (translational regulation via eIF4H, differentiation control via Sfn, anti-apoptotic signaling) are coordinated and whether they depend on filament-incorporated versus soluble pools of KRT14 protein.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of KRT14-eIF4H or KRT14-Sfn complexes exists","Whether KRT14's signaling functions require filament assembly or act from the soluble pool is untested","Genome-wide translational targets of the KRT14-eIF4H axis are undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,3,5,6,14]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,12]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,3,5,6,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,11,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,8,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10,12]}],"complexes":["KRT5-KRT14 heterodimer"],"partners":["KRT5","SFN","EIF4H","SP1"],"other_free_text":[]},"mechanistic_narrative":"KRT14 is a type I intermediate filament keratin expressed in basal epithelial cells, where it forms obligate heterodimers with KRT5 to provide mechanical integrity and regulate cell fate decisions including differentiation, apoptosis, and progenitor cell self-renewal. Dominant-negative mutations in the KRT14 rod domain disrupt filament polymerization and cause epidermolysis bullosa simplex (EBS), with helix boundary motif mutations producing the most severe Dowling-Meara phenotype, while haploinsufficient mutations in the N-terminal head domain cause distinct ectodermal dysplasias (NFJS/DPR) through increased susceptibility to TNF-α-induced apoptosis [PMID:21375516, PMID:16960809, PMID:18049449]. Beyond structural roles, KRT14 directly binds stratifin to regulate airway basal cell differentiation through a ΔNp63α axis, marks urothelial progenitor cells with self-renewal capacity, and interacts with translation initiation factor eIF4H via its N-terminal head domain to selectively promote ACOX2 mRNA translation, driving lipid metabolic reprogramming and chemoresistance in bladder cancer [PMID:36512409, PMID:27320313, PMID:41444318]. KRT14 transcription is activated by EZH2-mediated H3K27me3 displacement of the SP1 repressor and post-transcriptionally regulated by lncRNA ABCE1-5-mediated mRNA destabilization, with KRT14 upregulation promoting invasion and metastasis in triple-negative breast cancer and pulmonary fibrosis through mTOR/AKT signaling [PMID:36446780, PMID:40111939]."},"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":139,"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":106,"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":85,"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 mutation","url":"https://pubmed.ncbi.nlm.nih.gov/16786515","citation_count":48,"is_preprint":false},{"pmid":"20199538","id":"PMC_20199538","title":"Identification of novel and known KRT5 and KRT14 mutations in 53 patients with epidermolysis bullosa simplex: correlation between genotype and phenotype.","date":"2010","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/20199538","citation_count":46,"is_preprint":false},{"pmid":"16098032","id":"PMC_16098032","title":"Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis.","date":"2005","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/16098032","citation_count":39,"is_preprint":false},{"pmid":"9804355","id":"PMC_9804355","title":"Severe palmo-plantar hyperkeratosis in Dowling-Meara epidermolysis bullosa simplex caused by a mutation in 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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KRT14 confers protection against pro-apoptotic signals.\",\n      \"method\": \"siRNA knockdown of KRT14 in HaCaT cells, TNF-alpha apoptosis assay, immunofluorescence of patient skin biopsies\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype with mechanistic pathway placement in single lab study\",\n      \"pmids\": [\"18049449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Heterozygous nonsense or frameshift mutations in the N-terminal nonhelical head (E1/V1) domain of KRT14 cause NFJS/DPR ectodermal dysplasias (distinct from rod-domain mutations that cause EBS), demonstrating that different functional domains of KRT14 underlie distinct disease mechanisms; ultrastructural analysis of patient skin showed increased apoptotic activity in KRT14-expressing basal cells.\",\n      \"method\": \"Genetic linkage analysis, mutation sequencing across 5 families, ultrastructural examination of patient skin biopsies\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across 5 families with orthogonal structural and genetic evidence\",\n      \"pmids\": [\"16960809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mutations in the helix boundary motifs (especially the helix initiation motif) of KRT14 cause the most severe EBS phenotype (Dowling-Meara), establishing structure-function correlation for the rod domain in keratin intermediate filament assembly and mechanical integrity of basal keratinocytes.\",\n      \"method\": \"Genomic DNA and cDNA sequencing of KRT5/KRT14 in 76 EBS probands, immunofluorescence microscopy with anti-K5/K14 antibodies on patient skin biopsies\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large cohort with orthogonal protein and genetic analysis, replicated genotype-phenotype pattern\",\n      \"pmids\": [\"21375516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Two different amino acid substitutions at KRT14 position Ala413 (p.Ala413Pro vs p.Ala413Thr) produce distinct structural distortions and different phenotypic severity in EBS; in silico modeling showed proline substitution causes deleterious structural effects, and in vitro transfection into HaCaT cells showed significantly more keratin clumping with p.Ala413Pro than with p.Ala413Thr or wild-type, demonstrating that structural distortion caused by specific amino acid properties determines pathogenicity.\",\n      \"method\": \"In silico protein structural modeling, in vitro transfection of mutant KRT14 cDNA into HaCaT cells, immunofluorescence assessment of keratin clumping\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro functional assay with structural modeling, single lab\",\n      \"pmids\": [\"21593775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A p.Leu418Gln mutation in KRT14 disrupts intermolecular π-stacking between KRT14:Tyr415 and KRT5:Tyr470 at the KRT14:KRT5 heterodimer interface (EIATYR/KLLEGE motif), and may affect a putative phosphorylation site at KRT14:Thr414, establishing that the 2B helix C-terminal region is critical for KRT5-KRT14 heterodimer stability.\",\n      \"method\": \"Molecular dynamics simulation of KRT14 p.Leu418Gln mutation, genetic analysis of EBS family\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction with genetic validation but no in vitro reconstitution\",\n      \"pmids\": [\"24981776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AAV-mediated gene targeting of KRT14 in human keratinocytes can precisely correct or disrupt mutant alleles; keratinocytes with correction of the dominant-negative KRT14 mutation produced histologically normal skin grafts after transplantation to athymic mice, demonstrating that dominant-negative KRT14 protein disrupts intermediate filament polymerization in basal keratinocytes, causing epidermal fragility.\",\n      \"method\": \"AAV gene targeting with promoter trap design, transplantation to athymic mice, histological analysis of skin grafts\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo functional rescue with defined molecular mechanism\",\n      \"pmids\": [\"20571545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRISPR/Cas9 nickase-mediated homology-directed repair of a dominant-negative KRT14 hotspot mutation (exon 6) in EBS keratinocytes achieved >30% recombination efficiency and phenotypic correction, demonstrated by absence of disease-associated K14 cytoplasmic aggregates by immunofluorescence, confirming that mutant KRT14 causes keratin aggregate formation in basal keratinocytes.\",\n      \"method\": \"CRISPR/Cas9 D10A nickase double-nicking HDR, immunofluorescence for K14 aggregates, next-generation sequencing for off-target analysis\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional correction with molecular readout, single lab\",\n      \"pmids\": [\"28888469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Krt14-KO airway basal cells failed to differentiate into club and ciliated cells but had enhanced clonogenicity; Krt14, but not Krt15, directly bound the tumor suppressor stratifin (Sfn), and Krt14 disruption reduced Sfn protein abundance while increasing ΔNp63α expression during differentiation, establishing that Krt14 regulates basal cell differentiation through a Krt14-Sfn-ΔNp63α axis.\",\n      \"method\": \"CRISPR-KO of Krt14 in primary mouse airway basal cells, in vitro differentiation assays, co-immunoprecipitation (Krt14-Sfn binding), western blot for Sfn and ΔNp63α, in vivo injury model with label-retaining cell analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR-KO with defined phenotype, protein-protein interaction confirmed, in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"36512409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KRT14 marks a minor subpopulation of urothelial basal cells with self-renewal capacity that gives rise to all cell types of the urothelium during natural and injury-induced regeneration; KRT14+ basal cells also represent cells of origin for urothelial cancer, establishing KRT14 as a functional marker of urothelial progenitors.\",\n      \"method\": \"Genetic lineage tracing of KRT14+ cells in mouse urothelium (Krt14-Cre fate mapping), injury-induced regeneration models, tumor initiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo lineage tracing with defined regenerative and tumorigenic phenotypes\",\n      \"pmids\": [\"27320313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A subpopulation of KRT14-expressing ovarian cancer cells functions as 'leader cells' mediating mesothelial clearance and invasion; KRT14 loss completely abrogated invasive capacity without affecting cell viability or proliferation, demonstrating an invasion-specific role for KRT14.\",\n      \"method\": \"In vitro invasion model with imaging mass spectrometry, KRT14 knockdown in ovarian cancer spheroids, mesothelial clearance and invasion assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific invasion phenotype, single lab\",\n      \"pmids\": [\"31443478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EZH2 catalytic function (H3K27me3) promotes KRT14 transcription in TNBC by attenuating binding of the repressor SP1 to the KRT14 promoter; KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis, demonstrating that H3K27me3-mediated SP1 displacement activates KRT14 expression to drive TNBC metastasis.\",\n      \"method\": \"ChIP-seq for H3K27me3 and SP1, KRT14 knockdown in TNBC cells, in vitro migration/invasion assays, in vivo peritoneal metastasis mouse models, EZH2 inhibitor (EPZ6438) treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including ChIP, in vitro and in vivo functional assays, mechanistic pathway defined\",\n      \"pmids\": [\"36446780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KRT14 promotes osteoblast mineralization by organizing osteoblast-derived ECM; Krt14 siRNA knockdown in rat primary osteoblasts reduced ColI and OCN expression and soluble osteocalcin/collagen levels, and inhibited kaempferol-induced mTOR activation, placing KRT14 upstream of the mTOR signaling pathway in osteoblast mineralization.\",\n      \"method\": \"Krt14 siRNA knockdown in rat primary osteoblasts, mineralization assay, AFM ultrastructural analysis, qRT-PCR for ColI/OCN, AMPK/mTOR inhibitor treatment\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple molecular readouts, single lab\",\n      \"pmids\": [\"26956522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KRT14 directly interacts with translation initiation factor eIF4H through its N-terminal Head domain; this interaction modulates eIF4H association with the eIF4F complex to selectively promote translation of ACOX2 mRNA via its 5' UTR, thereby driving lipid metabolic reprogramming and cisplatin resistance in bladder cancer.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, domain-mapping mutagenesis (N-terminal Head domain), polysome profiling/translation assays, ACOX2 5'UTR reporter, xenograft mouse models, patient-derived tissue analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct protein-protein interaction mapped to specific domain, translational mechanism established with multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"41444318\"],\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) and destabilizes KRT14 mRNA, reducing KRT14 protein levels; decreased ABCE1-5 leads to KRT14 upregulation that activates mTOR/AKT phosphorylation to promote pulmonary fibrosis.\",\n      \"method\": \"RNA pulldown-mass spectrometry, RNA immunoprecipitation, KRT14 knockdown, overexpression in vitro and in vivo (AAV6), bleomycin mouse model\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-protein interaction confirmed by two orthogonal methods with in vivo functional validation, single lab\",\n      \"pmids\": [\"40111939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Complete absence of KRT14 protein (homozygous truncation mutation Y204X) in recessive EBS leads to compensatory expression of K6 and K16 in the basal layer (normally expressed in hyperproliferative skin), suggesting an alternative keratin pairing with K5 in the absence of K14, revealing the functional requirement for KRT14 in basal keratinocyte intermediate filament network integrity.\",\n      \"method\": \"Immunofluorescence mapping with monoclonal antibodies against K14, K6, K16 on patient skin biopsies, electron microscopy, genomic DNA mutation analysis\",\n      \"journal\": \"Clinical and experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization with functional consequence demonstrated, single case with orthogonal methods\",\n      \"pmids\": [\"18713255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Retinoic acid (RA) signaling directly in salivary gland epithelium (demonstrated by isolated epithelium explant cultures) represses Krt5 and Krt14 expression; inhibition of RA signaling upregulates Krt14 and Krt5 independently of stem cell marker Kit regulation, establishing RA as a direct upstream regulator of basal keratin expression in developing epithelium.\",\n      \"method\": \"Isolated salivary gland epithelium explant cultures, RA signaling inhibition, qRT-PCR for Krt14/Krt5/Kit expression\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct tissue manipulation with functional molecular readout, single lab\",\n      \"pmids\": [\"27884045\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT14 encodes a type I intermediate filament keratin that forms obligate heterodimers with KRT5 in basal epithelial cells; its rod domain is essential for keratin filament assembly and mechanical integrity (mutations here cause EBS), its N-terminal head domain protects keratinocytes from TNF-alpha-induced apoptosis and is required for dermatoglyphic/sweat gland development, it interacts with stratifin (Sfn) to regulate airway basal cell differentiation through a ΔNp63α axis, and in cancer contexts KRT14 drives invasion and chemoresistance through a novel interaction with eIF4H that selectively promotes ACOX2 mRNA translation, while its transcription is regulated by EZH2-mediated H3K27me3 displacement of the SP1 repressor and post-transcriptionally by lncRNA ABCE1-5-mediated mRNA destabilization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KRT14 is a type I intermediate filament keratin expressed in basal epithelial cells, where it forms obligate heterodimers with KRT5 to provide mechanical integrity and regulate cell fate decisions including differentiation, apoptosis, and progenitor cell self-renewal. Dominant-negative mutations in the KRT14 rod domain disrupt filament polymerization and cause epidermolysis bullosa simplex (EBS), with helix boundary motif mutations producing the most severe Dowling-Meara phenotype, while haploinsufficient mutations in the N-terminal head domain cause distinct ectodermal dysplasias (NFJS/DPR) through increased susceptibility to TNF-α-induced apoptosis [PMID:21375516, PMID:16960809, PMID:18049449]. Beyond structural roles, KRT14 directly binds stratifin to regulate airway basal cell differentiation through a ΔNp63α axis, marks urothelial progenitor cells with self-renewal capacity, and interacts with translation initiation factor eIF4H via its N-terminal head domain to selectively promote ACOX2 mRNA translation, driving lipid metabolic reprogramming and chemoresistance in bladder cancer [PMID:36512409, PMID:27320313, PMID:41444318]. KRT14 transcription is activated by EZH2-mediated H3K27me3 displacement of the SP1 repressor and post-transcriptionally regulated by lncRNA ABCE1-5-mediated mRNA destabilization, with KRT14 upregulation promoting invasion and metastasis in triple-negative breast cancer and pulmonary fibrosis through mTOR/AKT signaling [PMID:36446780, PMID:40111939].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that different KRT14 domains cause distinct diseases resolved a long-standing question of how a single keratin gene could underlie both skin fragility and ectodermal dysplasia: N-terminal head domain truncations cause NFJS/DPR through increased basal cell apoptosis, distinct from rod domain mutations causing EBS.\",\n      \"evidence\": \"Genetic linkage and mutation analysis across 5 families with ultrastructural examination of patient skin\",\n      \"pmids\": [\"16960809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which head domain loss increases apoptosis was not defined at the molecular level\", \"No rescue experiment to confirm causality\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that KRT14 knockdown sensitizes keratinocytes to TNF-α-induced apoptosis provided a mechanistic explanation for the NFJS/DPR phenotype, showing that KRT14 has a signaling-protective function beyond structural support.\",\n      \"evidence\": \"siRNA knockdown in HaCaT cells with TNF-α apoptosis assay and doxycycline rescue\",\n      \"pmids\": [\"18049449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of KRT14 in anti-apoptotic signaling not identified\", \"Only one cell line tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Complete KRT14 loss revealed the functional requirement for KRT14 in basal keratinocyte filament networks and the capacity for compensatory K6/K16 upregulation, establishing that K14 is not absolutely required for cell survival but is essential for normal filament architecture.\",\n      \"evidence\": \"Immunofluorescence and electron microscopy of homozygous KRT14-null patient skin biopsy\",\n      \"pmids\": [\"18713255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient case\", \"Functional consequences of K6/K16 compensation not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Gene correction of dominant-negative KRT14 mutations restored normal skin graft histology, providing direct functional proof that mutant KRT14 protein actively disrupts filament polymerization rather than simply being non-functional.\",\n      \"evidence\": \"AAV-mediated gene targeting in human keratinocytes with transplantation to athymic mice\",\n      \"pmids\": [\"20571545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Long-term stability of correction in regenerating epidermis not assessed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Systematic genotype-phenotype mapping across 76 EBS probands established that helix initiation motif mutations cause the most severe (Dowling-Meara) phenotype, while specific amino acid substitutions at the same position produce graded severity depending on structural distortion, defining the structure-function rules for KRT14 rod domain assembly.\",\n      \"evidence\": \"Large cohort KRT5/KRT14 sequencing with immunofluorescence; in silico modeling and in vitro transfection of Ala413 variants in HaCaT cells\",\n      \"pmids\": [\"21375516\", \"21593775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vitro filament reconstitution to quantify assembly defects biochemically\", \"Correlation between clumping severity and clinical severity not formally tested across large series\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"KRT14 was established as a functional marker of self-renewing urothelial progenitors and cells of origin for urothelial carcinoma, revealing a role beyond structural support as a marker of stem-like basal cell identity.\",\n      \"evidence\": \"Krt14-Cre genetic lineage tracing in mouse urothelium with injury and tumor models\",\n      \"pmids\": [\"27320313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KRT14 is functionally required for progenitor self-renewal or merely a marker was not distinguished\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that KRT14 promotes osteoblast mineralization upstream of mTOR signaling expanded KRT14's functional repertoire beyond epithelia, though the mechanism linking an intermediate filament to mTOR activation remained unclear.\",\n      \"evidence\": \"Krt14 siRNA knockdown in rat primary osteoblasts with mineralization assay and mTOR inhibitor treatment\",\n      \"pmids\": [\"26956522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between KRT14 and mTOR activation not identified\", \"Relevance to in vivo bone biology not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Retinoic acid was identified as a direct upstream repressor of Krt14/Krt5 expression in developing salivary epithelium, establishing an extrinsic signaling input that controls basal keratin identity independently of stem cell programs.\",\n      \"evidence\": \"Isolated salivary gland epithelium explant cultures with RA signaling inhibition and qRT-PCR\",\n      \"pmids\": [\"27884045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RA acts directly on KRT14 promoter or through intermediate transcription factors not resolved\", \"Single tissue type tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that KRT14 loss abrogates ovarian cancer invasion without affecting proliferation established an invasion-specific, non-structural function for KRT14 in cancer, distinct from its mechanical role in normal epithelia.\",\n      \"evidence\": \"KRT14 knockdown in ovarian cancer spheroids with mesothelial clearance and invasion assays\",\n      \"pmids\": [\"31443478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of KRT14-mediated invasion not identified\", \"Single cancer type in vitro\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The discovery that EZH2 activates KRT14 transcription by depositing H3K27me3 to displace the repressor SP1 from the KRT14 promoter revealed an unexpected activating role for a canonically repressive histone mark and explained how KRT14 drives TNBC metastasis.\",\n      \"evidence\": \"ChIP-seq for H3K27me3 and SP1, KRT14 knockdown with in vitro migration/invasion and in vivo peritoneal metastasis models, EZH2 inhibitor treatment\",\n      \"pmids\": [\"36446780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H3K27me3-mediated SP1 displacement is a general mechanism or specific to the KRT14 locus\", \"Contribution of other transcription factors at the KRT14 promoter not assessed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying Krt14 as a direct binding partner of stratifin that controls ΔNp63α levels during airway basal cell differentiation provided the first mechanistic link between a keratin intermediate filament protein and a transcriptional differentiation program.\",\n      \"evidence\": \"CRISPR-KO in primary mouse airway basal cells, co-immunoprecipitation, differentiation assays, in vivo injury model\",\n      \"pmids\": [\"36512409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Krt14-Sfn binding stabilizes Sfn protein not determined\", \"Whether this axis operates in other KRT14-expressing epithelia unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The discovery that KRT14 directly interacts with eIF4H through its N-terminal head domain to selectively promote ACOX2 translation revealed a previously unsuspected non-cytoskeletal function as a translational regulator, providing a mechanistic basis for KRT14-driven chemoresistance.\",\n      \"evidence\": \"Co-IP, GST pulldown, domain-mapping mutagenesis, polysome profiling, ACOX2 5'UTR reporter, xenograft models\",\n      \"pmids\": [\"41444318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Scope of KRT14-eIF4H translational targets beyond ACOX2 not defined\", \"Whether this translational role is active in normal basal cells or only in cancer contexts\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of lncRNA ABCE1-5 as a direct destabilizer of KRT14 mRNA added a post-transcriptional regulatory layer and linked KRT14 upregulation to mTOR/AKT-driven pulmonary fibrosis.\",\n      \"evidence\": \"RNA pulldown-mass spectrometry, RNA immunoprecipitation, KRT14 knockdown/overexpression in vitro and in vivo with bleomycin model\",\n      \"pmids\": [\"40111939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ABCE1-5-mediated mRNA destabilization (e.g., recruitment of decay machinery) not defined\", \"Whether ABCE1-5 regulation of KRT14 operates in epithelial tissues beyond lung\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how KRT14's non-structural functions (translational regulation via eIF4H, differentiation control via Sfn, anti-apoptotic signaling) are coordinated and whether they depend on filament-incorporated versus soluble pools of KRT14 protein.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of KRT14-eIF4H or KRT14-Sfn complexes exists\", \"Whether KRT14's signaling functions require filament assembly or act from the soluble pool is untested\", \"Genome-wide translational targets of the KRT14-eIF4H axis are undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3, 5, 6, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 3, 5, 6, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 11, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 8, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10, 12]}\n    ],\n    \"complexes\": [\n      \"KRT5-KRT14 heterodimer\"\n    ],\n    \"partners\": [\n      \"KRT5\",\n      \"SFN\",\n      \"EIF4H\",\n      \"SP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}