{"gene":"KRT5","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1992,"finding":"KRT5 gene was mapped to chromosome 12q near D12S14, and keratin 5 protein was identified as the major type II keratin of basal cells of epidermis and stratified epithelia, forming the primary structural cytoskeletal component together with its type I partner keratin 14.","method":"PCR analysis of somatic cell hybrids and multicolor fluorescence in situ hybridization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic mapping by two orthogonal methods, single lab, establishes chromosomal localization and partner identity","pmids":["1377166"],"is_preprint":false},{"year":1997,"finding":"KRT5 encodes the primary structural component of 10-nm intermediate filaments in mitotic epidermal basal cells; single missense mutations in the highly conserved KLLEGE motif at the end of the central rod domain (e.g., E477K) disrupt the keratin intermediate filament cytoskeleton, causing EBS skin fragility and blistering.","method":"Direct sequencing of KRT5 exons amplified from leukocyte genomic DNA; identification of recurrent missense mutations","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — mutation mapping with functional inference from conserved domain; replicated across many subsequent studies","pmids":["9036937"],"is_preprint":false},{"year":2006,"finding":"Mutations in KRT5 affecting helix boundary motifs of the rod domain disrupt keratin intermediate filament (KIF) formation; mutations at the helix initiation motif of KRT14 and helix boundary motifs of KRT5 are associated with the most severe EBS phenotype (Dowling-Meara), establishing structure-function correlation for keratin filament assembly.","method":"Sequence analysis of entire coding sequences of KRT5 and KRT14 in EBS patients; analysis of implications for protein structure and KIF formation","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — mutation analysis replicated across multiple studies establishing helix boundary motifs as critical for filament assembly","pmids":["16786515"],"is_preprint":false},{"year":2009,"finding":"EBS keratinocytes carrying a KRT5 mutation (V186L) form cytoplasmic keratin filament aggregates in response to heat stress, demonstrating that mutant KRT5 causes keratin cytoskeleton instability under mechanical/thermal stress; the chemical chaperone TMAO reduces aggregate formation, indicating that protein misfolding underlies the cytoskeletal disruption.","method":"Immortalized cell lines from EBS patients (KRT5 V186L mutation); heat stress experiments; assessment of keratin aggregate formation; TMAO treatment","journal":"Journal of dermatological science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cell-based functional assay with KRT5 mutant lines and chemical rescue, single lab","pmids":["19157792"],"is_preprint":false},{"year":2010,"finding":"Different KRT5 missense mutations (I183M, E475G, V186L) produce distinct degrees of cellular fragility under heat stress in primary keratinocytes, establishing genotype-phenotype relationships at the cellular level; TMAO pretreatment dose-dependently reduces keratin aggregate formation and cell loss in all three mutant backgrounds, suggesting protein stabilization as a therapeutic mechanism.","method":"Primary EBS keratinocyte cultures from patients with identified KRT5 mutations; heat stress assays; TMAO treatment; quantification of aggregate-containing cells and cell loss","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay in primary patient-derived cells, multiple mutant alleles compared, single lab","pmids":["20128788"],"is_preprint":false},{"year":2011,"finding":"Mutations in KRT5 and KRT14 affecting highly conserved helix boundary motifs of the rod domains, and the KRT14 helix initiation motif in particular, are associated with the severest EBS (Dowling-Meara) phenotype, reinforcing that these structural motifs are critical for keratin filament assembly and mechanical integrity of basal keratinocytes.","method":"Genomic DNA and cDNA sequencing of KRT5 and KRT14 in 76 EBS probands; immunofluorescence microscopy with K5 and K14 antibodies on skin biopsies","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — largest cohort study with IF validation; replicated genotype-phenotype correlation across multiple independent studies","pmids":["21375516"],"is_preprint":false},{"year":2014,"finding":"Pre-existing p63+/Krt5+ distal airway stem cells (DASCp63/Krt5) undergo proliferative expansion in response to influenza-induced lung damage and assemble into nascent alveoli; selective ablation of DASCp63/Krt5 in vivo prevents lung regeneration, leading to pre-fibrotic lesions and deficient oxygen exchange; single DASCp63/Krt5-derived pedigrees differentiate to type I and II pneumocytes as well as bronchiolar secretory cells after transplantation.","method":"In vivo selective ablation of Krt5+ cells; transplantation of single-cell-derived pedigrees into infected lung; lineage tracing in mouse influenza model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with specific phenotypic readout plus transplantation differentiation assay, replicated in multiple experimental paradigms","pmids":["25383540"],"is_preprint":false},{"year":2014,"finding":"TGFBR3 and JUND form a negative-feedback circuit that regulates KRT5 expression in single basal-like breast epithelial cells during 3D organotypic culture; the circuit depends on ECM engagement, as cell detachment causes rewiring triggered by RPS6 dephosphorylation and maintained by juxtacrine tenascin C, establishing KRT5 as part of a dynamic ECM-dependent gene expression program.","method":"Single-cell gene expression analysis; 3D organotypic culture; genetic perturbation of TGFBR3 and JUND; detachment assays; in vivo intraductal colonization assay","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (single-cell analysis, genetic perturbation, in vivo), single lab","pmids":["24658685"],"is_preprint":false},{"year":2019,"finding":"Biallelic (homozygous) KRT5 null mutations cause complete absence of KRT5 RNA and protein expression (human KRT5 knockout), resulting in perinatal lethal EBS, demonstrating that KRT5 is essential for basal keratinocyte survival; two homozygous KRT5 missense variants disrupt keratin 5 expression detected by immunofluorescence, causing generalized EBS with recessive inheritance.","method":"Whole exome sequencing and NGS panel; expression profiling; immunofluorescence microscopy on skin tissue; ultrastructural analysis","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — complete human knockout with expression and ultrastructural validation, multiple orthogonal methods","pmids":["31302245"],"is_preprint":false},{"year":2019,"finding":"Krt5+/Krt15+ foregut basal progenitor cells give rise to tumors in response to gastric acid stress in a Cyclooxygenase-2 (COX-2)-dependent manner, establishing that KRT5+ basal progenitors are the cell of origin for these tumors and that COX-2 is required downstream of Krt5+ cell activation.","method":"Genetically engineered mouse models; lineage tracing of Krt5+ cells; COX-2 genetic/pharmacological manipulation; tumor formation assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lineage tracing with genetic epistasis in mouse model, single lab","pmids":["31110179"],"is_preprint":false},{"year":2020,"finding":"FoxM1 directly binds to a consensus AP-2 cis element in the KRT5 promoter to regulate KRT5 gene expression; KRT5 knockdown prevents migration (but not proliferation) of ovarian cancer cells, establishing KRT5 as a downstream transcriptional target of FoxM1 required for cell migration.","method":"ChIP-seq; RNA-seq; qPCR; Western blot; wound healing and migration assays in KRT5-knockdown SK-OV-3 cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and RNA-seq with functional KD validation, single lab","pmids":["32659254"],"is_preprint":false},{"year":2020,"finding":"Trp53 mutation in Krt5-expressing basal cells results in more efficient tumorigenesis of muscle-invasive bladder cancer with squamous differentiation compared to Trp53 mutation in Upk2-expressing luminal cells, establishing Krt5+ basal cells as a cell of origin for basal squamous subtype bladder cancer.","method":"Lineage-specific Cre-mediated Trp53 mutation in Krt5+ vs. Upk2+ cells in mouse chemical carcinogenesis model; morphological and genetic tumor characterization","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific genetic manipulation with defined tumor phenotype, single lab","pmids":["32339497"],"is_preprint":false},{"year":2021,"finding":"Human alveolar type 2 cells (hAEC2s) transdifferentiate into KRT5+ basal cells in response to TGF-β1 signaling and anti-BMP signaling from fibrotic mesenchyme; this transdifferentiation proceeds through alveolar-basal intermediate cell states, establishing a causal lineage trajectory from hAEC2 to metaplastic KRT5+ basal cells in human lung fibrosis.","method":"Organoid co-culture of hAEC2s with lung mesenchyme; single-cell RNA sequencing; TGF-β1 and BMP pathway perturbation; trajectory analysis; in vivo transplantation; histologic analysis of IPF lung","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (scRNA-seq, organoid functional assays, in vivo transplantation, patient tissue validation), single lab with comprehensive evidence","pmids":["34969962"],"is_preprint":false},{"year":2021,"finding":"KRT5 mutation causes collapsed keratin intermediate filaments and intraepidermal blisters without altering the interaction between keratin 5 and keratin 14 or the quantitative protein levels; additionally, KRT5 mutation inhibits MAPK signaling and upregulates desmosomal protein DSG1, and EGFR phosphorylation inhibition upregulates DSG1 in vitro, establishing that KRT5 maintains DSG1 expression through MAPK/EGFR signaling.","method":"Biochemical experiments in patient keratinocytes with homozygous KRT5 mutation; immunofluorescence; co-immunoprecipitation of K5 and K14; Western blot for MAPK and DSG1; EGFR inhibitor treatment in vitro","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays including Co-IP and pathway inhibition with functional readout, single lab","pmids":["34912369"],"is_preprint":false},{"year":2023,"finding":"TRIM29 physically interacts with KRT5 (confirmed by co-immunoprecipitation) and promotes ubiquitination-mediated degradation of KRT5; TRIM29 knockdown decreases KRT5 ubiquitination levels and enhances KRT5 protein stability and expression, and KRT5 knockdown neutralizes the anti-proliferative effect of TRIM29 knockdown in colon cancer cells.","method":"Co-immunoprecipitation; cycloheximide chase assay; Western blot; CCK-8, colony formation and EDU assays; KRT5 and TRIM29 knockdown in colon cancer cells","journal":"Open life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional epistasis (KRT5 KD rescues TRIM29 KD phenotype) and protein stability assay, single lab","pmids":["37671092"],"is_preprint":false},{"year":2023,"finding":"KRT5 downregulation in keratinocytes (via CRISPR/Cas9 or shRNA) decreases expression of Notch ligands in keratinocytes and Notch1 intracellular domain in melanocytes, leading to increased TYR and decreased Fascin1 expression in melanocytes; activation of Notch signaling reverses these effects on melanogenesis, establishing that KRT5 in keratinocytes regulates melanin metabolism in melanocytes through a Notch signaling pathway.","method":"CRISPR/Cas9 site-directed mutation and lentivirus-mediated shRNA KRT5 knockdown in keratinocytes; Notch inhibitor and activator treatment of melanocytes; Western blot; immunohistochemistry of DDD patient lesions with KRT5 mutations","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent KO/KD methods with rescue experiment and patient tissue validation, single lab","pmids":["36809573"],"is_preprint":false},{"year":2023,"finding":"KRT5+ basal cell migration within the fibrotic lung is modulated by ECM composition and organisation; SPARC overexpression in IPF fibroblast-derived ECM restricts KRT5+ cell migration in vitro, identifying SPARC as an ECM component that regulates KRT5+ cell behavior in pulmonary fibrosis.","method":"In vitro migration assays on defined ECM; mass spectrometry-based proteomics of ECM from IPF vs. control fibroblasts; SPARC overexpression in fibroblast-derived matrix; KRT5+ cell migratory assays on fibrotic lung collagen","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics with functional in vitro validation using gain-of-function approach, single lab","pmids":["37758700"],"is_preprint":false},{"year":2025,"finding":"p63 regulates the Krt8-to-Krt5 transition during ameloblast cell differentiation in the enamel organ, paralleling its function in skin development; this regulation involves chromatin landscape remodeling by p63 at shared transcription factor binding sites (p63 and AP-2 family members).","method":"Single-cell RNA sequencing from mouse incisors; trajectory reconstruction; comparative transcriptome analysis; comparative motif discovery; chromatin accessibility analyses (ATAC-seq)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, scRNA-seq trajectory and chromatin analyses without direct KRT5 functional perturbation","pmids":["39990386"],"is_preprint":true},{"year":2024,"finding":"Epithelial detachment and cyclical mechanical stretch drive reduction of KRT5 expression in airway epithelial cells, providing a mechanism for the emergence of a KRT5low/KRT17+ transitional basal cell state in IPF fibrotic niches.","method":"Monolayer airway epithelial cell cultures subjected to detachment and cyclical mechanical stretch; keratin expression measurements; spatial transcriptomics and imaging mass cytometry of IPF lung tissue","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, in vitro functional assay is straightforward but single method, single lab","pmids":[],"is_preprint":true}],"current_model":"KRT5 encodes keratin 5, the major type II keratin that partners with keratin 14 (KRT14) to form the primary 10-nm intermediate filament cytoskeleton of basal keratinocytes; mutations in conserved helix boundary rod domain motifs disrupt filament assembly, causing skin fragility (EBS), and complete KRT5 loss is perinatally lethal; in the lung, KRT5+/p63+ basal stem cells serve as injury-responsive progenitors that can regenerate alveolar epithelium, are regulated by TGF-β/BMP signaling from fibrotic mesenchyme (driving transdifferentiation from AEC2s), and their migration is restricted by SPARC-enriched ECM; KRT5 expression is transcriptionally regulated by FoxM1 (via AP-2 cis elements) and retinoic acid signaling, post-translationally regulated by TRIM29-mediated ubiquitination, and KRT5 itself signals through MAPK/EGFR to maintain DSG1 and through Notch ligand expression to regulate melanogenesis in adjacent melanocytes."},"narrative":{"mechanistic_narrative":"KRT5 encodes keratin 5, the major type II keratin of basal cells in epidermis and stratified epithelia, which pairs with its type I partner keratin 14 to form the primary 10-nm intermediate filament cytoskeleton of mitotic basal keratinocytes [PMID:1377166, PMID:9036937]. Filament assembly depends on highly conserved helix boundary motifs of the central rod domain; missense mutations in these motifs (e.g., the KLLEGE motif, E477K) collapse the keratin filament network and cause epidermolysis bullosa simplex (EBS), with helix boundary lesions producing the most severe Dowling-Meara phenotype [PMID:9036937, PMID:16786515, PMID:21375516]. Mutant KRT5 destabilizes the cytoskeleton under mechanical and thermal stress, driving formation of cytoplasmic keratin aggregates through protein misfolding that chemical chaperones such as TMAO can mitigate [PMID:19157792, PMID:20128788]. Complete biallelic KRT5 loss abolishes keratin 5 expression and causes perinatally lethal EBS, establishing KRT5 as essential for basal keratinocyte survival [PMID:31302245]. Beyond its structural role, KRT5 functions in signaling: it maintains the desmosomal protein DSG1 through MAPK/EGFR signaling [PMID:34912369] and, via keratinocyte Notch ligand expression, regulates melanogenesis in adjacent melanocytes [PMID:36809573]. KRT5 expression is controlled transcriptionally by FoxM1 acting through an AP-2 cis element in the promoter [PMID:32659254] and post-translationally by TRIM29-mediated ubiquitination and degradation [PMID:37671092]. Distinct from its epidermal role, KRT5 marks p63+ basal stem/progenitor cells that act as injury-responsive progenitors regenerating lung epithelium after damage [PMID:25383540], that arise by TGF-β/anti-BMP-driven transdifferentiation of alveolar type 2 cells in fibrosis [PMID:34969962], and that serve as a cell of origin for squamous and basal tumors [PMID:31110179, PMID:32339497].","teleology":[{"year":1992,"claim":"Establishing where KRT5 sits in the genome and what it does at the protein level defined keratin 5 as the major type II keratin of basal epithelial cells partnering with keratin 14.","evidence":"PCR of somatic cell hybrids and FISH mapping to chromosome 12q with protein identification","pmids":["1377166"],"confidence":"Medium","gaps":["Did not establish the structural requirements for filament assembly","No functional perturbation of KRT5"]},{"year":1997,"claim":"Linking specific rod-domain mutations to disease showed that conserved helix boundary motifs are essential for keratin filament integrity and that their disruption causes EBS skin fragility.","evidence":"Direct sequencing of KRT5 exons from EBS patient genomic DNA identifying recurrent missense mutations","pmids":["9036937"],"confidence":"Medium","gaps":["Functional consequence inferred from conservation rather than measured directly","Cellular mechanism of filament collapse not yet shown"]},{"year":2006,"claim":"Correlating mutation position with phenotype severity established structure-function rules, with helix boundary motif lesions producing the most severe Dowling-Meara EBS.","evidence":"Full coding sequence analysis of KRT5 and KRT14 in EBS patients with structural inference","pmids":["16786515"],"confidence":"Medium","gaps":["Did not directly test filament assembly biochemically","Genotype-phenotype mechanism inferred from sequence"]},{"year":2011,"claim":"A large cohort with immunofluorescence validation reinforced that helix boundary motifs underlie the severest EBS, anchoring the structure-function model.","evidence":"Genomic and cDNA sequencing of 76 EBS probands plus K5/K14 immunofluorescence on skin biopsies","pmids":["21375516"],"confidence":"Medium","gaps":["Correlative; no in vitro assembly reconstitution","Modifier contributions not addressed"]},{"year":2010,"claim":"Testing patient keratinocytes under stress showed that mutant KRT5 causes allele-specific cellular fragility via protein misfolding, and that chemical chaperones can stabilize the cytoskeleton.","evidence":"Heat stress and TMAO treatment of primary and immortalized EBS keratinocytes carrying defined KRT5 mutations","pmids":["19157792","20128788"],"confidence":"Medium","gaps":["TMAO efficacy shown in vitro only","Misfolding pathway not structurally resolved"]},{"year":2014,"claim":"Identifying KRT5+/p63+ distal airway stem cells as injury-responsive progenitors extended KRT5 biology beyond skin into regenerative lung epithelium.","evidence":"In vivo ablation of Krt5+ cells and single-cell pedigree transplantation in a mouse influenza model","pmids":["25383540"],"confidence":"High","gaps":["Role of KRT5 protein itself versus the cell population not separated","Signals initiating expansion not defined in this study"]},{"year":2019,"claim":"Generating complete human KRT5 knockouts showed that total loss is perinatally lethal, establishing KRT5 as essential for basal keratinocyte survival rather than merely modulatory.","evidence":"Whole exome/NGS sequencing with expression, immunofluorescence and ultrastructural validation in EBS patients","pmids":["31302245"],"confidence":"High","gaps":["Cause of cell death downstream of KRT5 loss not dissected","Compensation by other keratins not characterized"]},{"year":2020,"claim":"Defining FoxM1-driven transcription and KRT5+ cell-of-origin roles in cancer connected KRT5 to migration programs and tumorigenesis.","evidence":"ChIP-seq/RNA-seq with KRT5 knockdown migration assays in ovarian cancer cells; lineage-specific Trp53 mutation in Krt5+ bladder cells","pmids":["32659254","32339497"],"confidence":"Medium","gaps":["Mechanism linking KRT5 to migration not resolved","Whether KRT5 is driver or marker in these tumors unclear"]},{"year":2021,"claim":"Mapping AEC2-to-KRT5+ basal transdifferentiation defined a causal fibrotic lineage trajectory driven by TGF-β and anti-BMP signaling from mesenchyme.","evidence":"hAEC2-mesenchyme organoid co-culture, scRNA-seq trajectory analysis, pathway perturbation and IPF tissue validation","pmids":["34969962"],"confidence":"High","gaps":["Reversibility of the metaplastic state not established","Role of KRT5 protein in the transition itself unknown"]},{"year":2023,"claim":"Demonstrating KRT5 signaling outputs showed that beyond structure it maintains DSG1 via MAPK/EGFR, regulates melanogenesis via Notch in neighboring melanocytes, and is degraded by TRIM29 ubiquitination.","evidence":"Patient keratinocyte biochemistry with Co-IP and EGFR inhibition; CRISPR/shRNA KRT5 knockdown with Notch modulation; TRIM29 Co-IP and CHX chase in colon cancer cells","pmids":["34912369","36809573","37671092"],"confidence":"Medium","gaps":["Each signaling link rests on single-lab assays","Direct versus indirect coupling of KRT5 to MAPK/Notch not resolved"]},{"year":2023,"claim":"Identifying SPARC as an ECM regulator of KRT5+ cell migration linked the fibrotic matrix microenvironment to aberrant basal cell behavior.","evidence":"Mass spectrometry of IPF versus control fibroblast ECM with SPARC gain-of-function migration assays","pmids":["37758700"],"confidence":"Medium","gaps":["SPARC receptor on KRT5+ cells unidentified","In vivo relevance shown only in vitro"]},{"year":null,"claim":"How mechanical stress and chromatin regulation toggle KRT5 expression to generate transitional basal cell states remains incompletely defined.","evidence":"Preprint scRNA-seq/ATAC-seq of p63-driven Krt8-to-Krt5 transitions and mechanical-stretch-driven KRT5 reduction","pmids":[],"confidence":"Low","gaps":["Preprint findings lack direct KRT5 functional perturbation","Causal role of KRT5 level in transitional state not tested","Mechanotransduction pathway to KRT5 promoter unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2,5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,12]}],"complexes":[],"partners":["KRT14","TRIM29","DSG1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P13647","full_name":"Keratin, type II cytoskeletal 5","aliases":["58 kDa cytokeratin","Cytokeratin-5","CK-5","Keratin-5","K5","Type-II keratin Kb5"],"length_aa":590,"mass_kda":62.4,"function":"Required for the formation of keratin intermediate filaments in the basal epidermis and maintenance of the skin barrier in response to mechanical stress (By similarity). Regulates the recruitment of Langerhans cells to the epidermis, potentially by modulation of the abundance of macrophage chemotactic cytokines, macrophage inflammatory cytokines and CTNND1 localization in keratinocytes (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P13647/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT5","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT5","total_profiled":1310},"omim":[{"mim_id":"620150","title":"EPIDERMOLYTIC HYPERKERATOSIS 2A, AUTOSOMAL DOMINANT; EHK2A","url":"https://www.omim.org/entry/620150"},{"mim_id":"619599","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 2D, GENERALIZED, INTERMEDIATE OR SEVERE, AUTOSOMAL RECESSIVE; EBS2D","url":"https://www.omim.org/entry/619599"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":2249.7},{"tissue":"esophagus","ntpm":6496.3},{"tissue":"skin 1","ntpm":5566.5},{"tissue":"vagina","ntpm":2417.1}],"url":"https://www.proteinatlas.org/search/KRT5"},"hgnc":{"alias_symbol":["KRT5A","CK-5"],"prev_symbol":["EBS2"]},"alphafold":{"accession":"P13647","domains":[{"cath_id":"1.20.5","chopping":"227-321","consensus_level":"medium","plddt":94.6644,"start":227,"end":321},{"cath_id":"1.20.5","chopping":"335-454","consensus_level":"medium","plddt":94.8868,"start":335,"end":454}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13647","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13647-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13647-F1-predicted_aligned_error_v6.png","plddt_mean":65.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRT5","jax_strain_url":"https://www.jax.org/strain/search?query=KRT5"},"sequence":{"accession":"P13647","fasta_url":"https://rest.uniprot.org/uniprotkb/P13647.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13647/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13647"}},"corpus_meta":[{"pmid":"25383540","id":"PMC_25383540","title":"p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/25383540","citation_count":433,"is_preprint":false},{"pmid":"34969962","id":"PMC_34969962","title":"Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells.","date":"2021","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34969962","citation_count":209,"is_preprint":false},{"pmid":"18091384","id":"PMC_18091384","title":"The diagnostic value of TTF-1, CK 5/6, and p63 immunostaining in classification of lung carcinomas.","date":"2007","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/18091384","citation_count":132,"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":"9036937","id":"PMC_9036937","title":"Primers for exon-specific amplification of the KRT5 gene: identification of novel and recurrent mutations in epidermolysis bullosa simplex patients.","date":"1997","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/9036937","citation_count":70,"is_preprint":false},{"pmid":"24658685","id":"PMC_24658685","title":"A time- and matrix-dependent TGFBR3-JUND-KRT5 regulatory circuit in single breast epithelial cells and basal-like premalignancies.","date":"2014","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24658685","citation_count":66,"is_preprint":false},{"pmid":"28074276","id":"PMC_28074276","title":"In stage pT1 non-muscle-invasive bladder cancer (NMIBC), high KRT20 and low KRT5 mRNA expression identify the luminal subtype and predict recurrence and survival.","date":"2017","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28074276","citation_count":59,"is_preprint":false},{"pmid":"37758700","id":"PMC_37758700","title":"Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37758700","citation_count":48,"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":"29236513","id":"PMC_29236513","title":"Depletion of Airway Submucosal Glands and TP63+KRT5+ Basal Cells in Obliterative Bronchiolitis.","date":"2018","source":"American journal of respiratory and 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hybrids and multicolor fluorescence in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic mapping by two orthogonal methods, single lab, establishes chromosomal localization and partner identity\",\n      \"pmids\": [\"1377166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KRT5 encodes the primary structural component of 10-nm intermediate filaments in mitotic epidermal basal cells; single missense mutations in the highly conserved KLLEGE motif at the end of the central rod domain (e.g., E477K) disrupt the keratin intermediate filament cytoskeleton, causing EBS skin fragility and blistering.\",\n      \"method\": \"Direct sequencing of KRT5 exons amplified from leukocyte genomic DNA; identification of recurrent missense mutations\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — mutation mapping with functional inference from conserved domain; replicated across many subsequent studies\",\n      \"pmids\": [\"9036937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutations in KRT5 affecting helix boundary motifs of the rod domain disrupt keratin intermediate filament (KIF) formation; mutations at the helix initiation motif of KRT14 and helix boundary motifs of KRT5 are associated with the most severe EBS phenotype (Dowling-Meara), establishing structure-function correlation for keratin filament assembly.\",\n      \"method\": \"Sequence analysis of entire coding sequences of KRT5 and KRT14 in EBS patients; analysis of implications for protein structure and KIF formation\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — mutation analysis replicated across multiple studies establishing helix boundary motifs as critical for filament assembly\",\n      \"pmids\": [\"16786515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EBS keratinocytes carrying a KRT5 mutation (V186L) form cytoplasmic keratin filament aggregates in response to heat stress, demonstrating that mutant KRT5 causes keratin cytoskeleton instability under mechanical/thermal stress; the chemical chaperone TMAO reduces aggregate formation, indicating that protein misfolding underlies the cytoskeletal disruption.\",\n      \"method\": \"Immortalized cell lines from EBS patients (KRT5 V186L mutation); heat stress experiments; assessment of keratin aggregate formation; TMAO treatment\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cell-based functional assay with KRT5 mutant lines and chemical rescue, single lab\",\n      \"pmids\": [\"19157792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Different KRT5 missense mutations (I183M, E475G, V186L) produce distinct degrees of cellular fragility under heat stress in primary keratinocytes, establishing genotype-phenotype relationships at the cellular level; TMAO pretreatment dose-dependently reduces keratin aggregate formation and cell loss in all three mutant backgrounds, suggesting protein stabilization as a therapeutic mechanism.\",\n      \"method\": \"Primary EBS keratinocyte cultures from patients with identified KRT5 mutations; heat stress assays; TMAO treatment; quantification of aggregate-containing cells and cell loss\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay in primary patient-derived cells, multiple mutant alleles compared, single lab\",\n      \"pmids\": [\"20128788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mutations in KRT5 and KRT14 affecting highly conserved helix boundary motifs of the rod domains, and the KRT14 helix initiation motif in particular, are associated with the severest EBS (Dowling-Meara) phenotype, reinforcing that these structural motifs are critical for keratin filament assembly and mechanical integrity of basal keratinocytes.\",\n      \"method\": \"Genomic DNA and cDNA sequencing of KRT5 and KRT14 in 76 EBS probands; immunofluorescence microscopy with K5 and K14 antibodies on skin biopsies\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — largest cohort study with IF validation; replicated genotype-phenotype correlation across multiple independent studies\",\n      \"pmids\": [\"21375516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Pre-existing p63+/Krt5+ distal airway stem cells (DASCp63/Krt5) undergo proliferative expansion in response to influenza-induced lung damage and assemble into nascent alveoli; selective ablation of DASCp63/Krt5 in vivo prevents lung regeneration, leading to pre-fibrotic lesions and deficient oxygen exchange; single DASCp63/Krt5-derived pedigrees differentiate to type I and II pneumocytes as well as bronchiolar secretory cells after transplantation.\",\n      \"method\": \"In vivo selective ablation of Krt5+ cells; transplantation of single-cell-derived pedigrees into infected lung; lineage tracing in mouse influenza model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with specific phenotypic readout plus transplantation differentiation assay, replicated in multiple experimental paradigms\",\n      \"pmids\": [\"25383540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TGFBR3 and JUND form a negative-feedback circuit that regulates KRT5 expression in single basal-like breast epithelial cells during 3D organotypic culture; the circuit depends on ECM engagement, as cell detachment causes rewiring triggered by RPS6 dephosphorylation and maintained by juxtacrine tenascin C, establishing KRT5 as part of a dynamic ECM-dependent gene expression program.\",\n      \"method\": \"Single-cell gene expression analysis; 3D organotypic culture; genetic perturbation of TGFBR3 and JUND; detachment assays; in vivo intraductal colonization assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (single-cell analysis, genetic perturbation, in vivo), single lab\",\n      \"pmids\": [\"24658685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Biallelic (homozygous) KRT5 null mutations cause complete absence of KRT5 RNA and protein expression (human KRT5 knockout), resulting in perinatal lethal EBS, demonstrating that KRT5 is essential for basal keratinocyte survival; two homozygous KRT5 missense variants disrupt keratin 5 expression detected by immunofluorescence, causing generalized EBS with recessive inheritance.\",\n      \"method\": \"Whole exome sequencing and NGS panel; expression profiling; immunofluorescence microscopy on skin tissue; ultrastructural analysis\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complete human knockout with expression and ultrastructural validation, multiple orthogonal methods\",\n      \"pmids\": [\"31302245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Krt5+/Krt15+ foregut basal progenitor cells give rise to tumors in response to gastric acid stress in a Cyclooxygenase-2 (COX-2)-dependent manner, establishing that KRT5+ basal progenitors are the cell of origin for these tumors and that COX-2 is required downstream of Krt5+ cell activation.\",\n      \"method\": \"Genetically engineered mouse models; lineage tracing of Krt5+ cells; COX-2 genetic/pharmacological manipulation; tumor formation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lineage tracing with genetic epistasis in mouse model, single lab\",\n      \"pmids\": [\"31110179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FoxM1 directly binds to a consensus AP-2 cis element in the KRT5 promoter to regulate KRT5 gene expression; KRT5 knockdown prevents migration (but not proliferation) of ovarian cancer cells, establishing KRT5 as a downstream transcriptional target of FoxM1 required for cell migration.\",\n      \"method\": \"ChIP-seq; RNA-seq; qPCR; Western blot; wound healing and migration assays in KRT5-knockdown SK-OV-3 cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and RNA-seq with functional KD validation, single lab\",\n      \"pmids\": [\"32659254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Trp53 mutation in Krt5-expressing basal cells results in more efficient tumorigenesis of muscle-invasive bladder cancer with squamous differentiation compared to Trp53 mutation in Upk2-expressing luminal cells, establishing Krt5+ basal cells as a cell of origin for basal squamous subtype bladder cancer.\",\n      \"method\": \"Lineage-specific Cre-mediated Trp53 mutation in Krt5+ vs. Upk2+ cells in mouse chemical carcinogenesis model; morphological and genetic tumor characterization\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific genetic manipulation with defined tumor phenotype, single lab\",\n      \"pmids\": [\"32339497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human alveolar type 2 cells (hAEC2s) transdifferentiate into KRT5+ basal cells in response to TGF-β1 signaling and anti-BMP signaling from fibrotic mesenchyme; this transdifferentiation proceeds through alveolar-basal intermediate cell states, establishing a causal lineage trajectory from hAEC2 to metaplastic KRT5+ basal cells in human lung fibrosis.\",\n      \"method\": \"Organoid co-culture of hAEC2s with lung mesenchyme; single-cell RNA sequencing; TGF-β1 and BMP pathway perturbation; trajectory analysis; in vivo transplantation; histologic analysis of IPF lung\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (scRNA-seq, organoid functional assays, in vivo transplantation, patient tissue validation), single lab with comprehensive evidence\",\n      \"pmids\": [\"34969962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KRT5 mutation causes collapsed keratin intermediate filaments and intraepidermal blisters without altering the interaction between keratin 5 and keratin 14 or the quantitative protein levels; additionally, KRT5 mutation inhibits MAPK signaling and upregulates desmosomal protein DSG1, and EGFR phosphorylation inhibition upregulates DSG1 in vitro, establishing that KRT5 maintains DSG1 expression through MAPK/EGFR signaling.\",\n      \"method\": \"Biochemical experiments in patient keratinocytes with homozygous KRT5 mutation; immunofluorescence; co-immunoprecipitation of K5 and K14; Western blot for MAPK and DSG1; EGFR inhibitor treatment in vitro\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays including Co-IP and pathway inhibition with functional readout, single lab\",\n      \"pmids\": [\"34912369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM29 physically interacts with KRT5 (confirmed by co-immunoprecipitation) and promotes ubiquitination-mediated degradation of KRT5; TRIM29 knockdown decreases KRT5 ubiquitination levels and enhances KRT5 protein stability and expression, and KRT5 knockdown neutralizes the anti-proliferative effect of TRIM29 knockdown in colon cancer cells.\",\n      \"method\": \"Co-immunoprecipitation; cycloheximide chase assay; Western blot; CCK-8, colony formation and EDU assays; KRT5 and TRIM29 knockdown in colon cancer cells\",\n      \"journal\": \"Open life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional epistasis (KRT5 KD rescues TRIM29 KD phenotype) and protein stability assay, single lab\",\n      \"pmids\": [\"37671092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KRT5 downregulation in keratinocytes (via CRISPR/Cas9 or shRNA) decreases expression of Notch ligands in keratinocytes and Notch1 intracellular domain in melanocytes, leading to increased TYR and decreased Fascin1 expression in melanocytes; activation of Notch signaling reverses these effects on melanogenesis, establishing that KRT5 in keratinocytes regulates melanin metabolism in melanocytes through a Notch signaling pathway.\",\n      \"method\": \"CRISPR/Cas9 site-directed mutation and lentivirus-mediated shRNA KRT5 knockdown in keratinocytes; Notch inhibitor and activator treatment of melanocytes; Western blot; immunohistochemistry of DDD patient lesions with KRT5 mutations\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent KO/KD methods with rescue experiment and patient tissue validation, single lab\",\n      \"pmids\": [\"36809573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KRT5+ basal cell migration within the fibrotic lung is modulated by ECM composition and organisation; SPARC overexpression in IPF fibroblast-derived ECM restricts KRT5+ cell migration in vitro, identifying SPARC as an ECM component that regulates KRT5+ cell behavior in pulmonary fibrosis.\",\n      \"method\": \"In vitro migration assays on defined ECM; mass spectrometry-based proteomics of ECM from IPF vs. control fibroblasts; SPARC overexpression in fibroblast-derived matrix; KRT5+ cell migratory assays on fibrotic lung collagen\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics with functional in vitro validation using gain-of-function approach, single lab\",\n      \"pmids\": [\"37758700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"p63 regulates the Krt8-to-Krt5 transition during ameloblast cell differentiation in the enamel organ, paralleling its function in skin development; this regulation involves chromatin landscape remodeling by p63 at shared transcription factor binding sites (p63 and AP-2 family members).\",\n      \"method\": \"Single-cell RNA sequencing from mouse incisors; trajectory reconstruction; comparative transcriptome analysis; comparative motif discovery; chromatin accessibility analyses (ATAC-seq)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, scRNA-seq trajectory and chromatin analyses without direct KRT5 functional perturbation\",\n      \"pmids\": [\"39990386\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Epithelial detachment and cyclical mechanical stretch drive reduction of KRT5 expression in airway epithelial cells, providing a mechanism for the emergence of a KRT5low/KRT17+ transitional basal cell state in IPF fibrotic niches.\",\n      \"method\": \"Monolayer airway epithelial cell cultures subjected to detachment and cyclical mechanical stretch; keratin expression measurements; spatial transcriptomics and imaging mass cytometry of IPF lung tissue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, in vitro functional assay is straightforward but single method, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KRT5 encodes keratin 5, the major type II keratin that partners with keratin 14 (KRT14) to form the primary 10-nm intermediate filament cytoskeleton of basal keratinocytes; mutations in conserved helix boundary rod domain motifs disrupt filament assembly, causing skin fragility (EBS), and complete KRT5 loss is perinatally lethal; in the lung, KRT5+/p63+ basal stem cells serve as injury-responsive progenitors that can regenerate alveolar epithelium, are regulated by TGF-β/BMP signaling from fibrotic mesenchyme (driving transdifferentiation from AEC2s), and their migration is restricted by SPARC-enriched ECM; KRT5 expression is transcriptionally regulated by FoxM1 (via AP-2 cis elements) and retinoic acid signaling, post-translationally regulated by TRIM29-mediated ubiquitination, and KRT5 itself signals through MAPK/EGFR to maintain DSG1 and through Notch ligand expression to regulate melanogenesis in adjacent melanocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KRT5 encodes keratin 5, the major type II keratin of basal cells in epidermis and stratified epithelia, which pairs with its type I partner keratin 14 to form the primary 10-nm intermediate filament cytoskeleton of mitotic basal keratinocytes [#0, #1]. Filament assembly depends on highly conserved helix boundary motifs of the central rod domain; missense mutations in these motifs (e.g., the KLLEGE motif, E477K) collapse the keratin filament network and cause epidermolysis bullosa simplex (EBS), with helix boundary lesions producing the most severe Dowling-Meara phenotype [#1, #2, #5]. Mutant KRT5 destabilizes the cytoskeleton under mechanical and thermal stress, driving formation of cytoplasmic keratin aggregates through protein misfolding that chemical chaperones such as TMAO can mitigate [#3, #4]. Complete biallelic KRT5 loss abolishes keratin 5 expression and causes perinatally lethal EBS, establishing KRT5 as essential for basal keratinocyte survival [#8]. Beyond its structural role, KRT5 functions in signaling: it maintains the desmosomal protein DSG1 through MAPK/EGFR signaling [#13] and, via keratinocyte Notch ligand expression, regulates melanogenesis in adjacent melanocytes [#15]. KRT5 expression is controlled transcriptionally by FoxM1 acting through an AP-2 cis element in the promoter [#10] and post-translationally by TRIM29-mediated ubiquitination and degradation [#14]. Distinct from its epidermal role, KRT5 marks p63+ basal stem/progenitor cells that act as injury-responsive progenitors regenerating lung epithelium after damage [#6], that arise by TGF-\\u03b2/anti-BMP-driven transdifferentiation of alveolar type 2 cells in fibrosis [#12], and that serve as a cell of origin for squamous and basal tumors [#9, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing where KRT5 sits in the genome and what it does at the protein level defined keratin 5 as the major type II keratin of basal epithelial cells partnering with keratin 14.\",\n      \"evidence\": \"PCR of somatic cell hybrids and FISH mapping to chromosome 12q with protein identification\",\n      \"pmids\": [\"1377166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish the structural requirements for filament assembly\", \"No functional perturbation of KRT5\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linking specific rod-domain mutations to disease showed that conserved helix boundary motifs are essential for keratin filament integrity and that their disruption causes EBS skin fragility.\",\n      \"evidence\": \"Direct sequencing of KRT5 exons from EBS patient genomic DNA identifying recurrent missense mutations\",\n      \"pmids\": [\"9036937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence inferred from conservation rather than measured directly\", \"Cellular mechanism of filament collapse not yet shown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Correlating mutation position with phenotype severity established structure-function rules, with helix boundary motif lesions producing the most severe Dowling-Meara EBS.\",\n      \"evidence\": \"Full coding sequence analysis of KRT5 and KRT14 in EBS patients with structural inference\",\n      \"pmids\": [\"16786515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not directly test filament assembly biochemically\", \"Genotype-phenotype mechanism inferred from sequence\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A large cohort with immunofluorescence validation reinforced that helix boundary motifs underlie the severest EBS, anchoring the structure-function model.\",\n      \"evidence\": \"Genomic and cDNA sequencing of 76 EBS probands plus K5/K14 immunofluorescence on skin biopsies\",\n      \"pmids\": [\"21375516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative; no in vitro assembly reconstitution\", \"Modifier contributions not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Testing patient keratinocytes under stress showed that mutant KRT5 causes allele-specific cellular fragility via protein misfolding, and that chemical chaperones can stabilize the cytoskeleton.\",\n      \"evidence\": \"Heat stress and TMAO treatment of primary and immortalized EBS keratinocytes carrying defined KRT5 mutations\",\n      \"pmids\": [\"19157792\", \"20128788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TMAO efficacy shown in vitro only\", \"Misfolding pathway not structurally resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying KRT5+/p63+ distal airway stem cells as injury-responsive progenitors extended KRT5 biology beyond skin into regenerative lung epithelium.\",\n      \"evidence\": \"In vivo ablation of Krt5+ cells and single-cell pedigree transplantation in a mouse influenza model\",\n      \"pmids\": [\"25383540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of KRT5 protein itself versus the cell population not separated\", \"Signals initiating expansion not defined in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generating complete human KRT5 knockouts showed that total loss is perinatally lethal, establishing KRT5 as essential for basal keratinocyte survival rather than merely modulatory.\",\n      \"evidence\": \"Whole exome/NGS sequencing with expression, immunofluorescence and ultrastructural validation in EBS patients\",\n      \"pmids\": [\"31302245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cause of cell death downstream of KRT5 loss not dissected\", \"Compensation by other keratins not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining FoxM1-driven transcription and KRT5+ cell-of-origin roles in cancer connected KRT5 to migration programs and tumorigenesis.\",\n      \"evidence\": \"ChIP-seq/RNA-seq with KRT5 knockdown migration assays in ovarian cancer cells; lineage-specific Trp53 mutation in Krt5+ bladder cells\",\n      \"pmids\": [\"32659254\", \"32339497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking KRT5 to migration not resolved\", \"Whether KRT5 is driver or marker in these tumors unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapping AEC2-to-KRT5+ basal transdifferentiation defined a causal fibrotic lineage trajectory driven by TGF-\\u03b2 and anti-BMP signaling from mesenchyme.\",\n      \"evidence\": \"hAEC2-mesenchyme organoid co-culture, scRNA-seq trajectory analysis, pathway perturbation and IPF tissue validation\",\n      \"pmids\": [\"34969962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reversibility of the metaplastic state not established\", \"Role of KRT5 protein in the transition itself unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating KRT5 signaling outputs showed that beyond structure it maintains DSG1 via MAPK/EGFR, regulates melanogenesis via Notch in neighboring melanocytes, and is degraded by TRIM29 ubiquitination.\",\n      \"evidence\": \"Patient keratinocyte biochemistry with Co-IP and EGFR inhibition; CRISPR/shRNA KRT5 knockdown with Notch modulation; TRIM29 Co-IP and CHX chase in colon cancer cells\",\n      \"pmids\": [\"34912369\", \"36809573\", \"37671092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each signaling link rests on single-lab assays\", \"Direct versus indirect coupling of KRT5 to MAPK/Notch not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying SPARC as an ECM regulator of KRT5+ cell migration linked the fibrotic matrix microenvironment to aberrant basal cell behavior.\",\n      \"evidence\": \"Mass spectrometry of IPF versus control fibroblast ECM with SPARC gain-of-function migration assays\",\n      \"pmids\": [\"37758700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SPARC receptor on KRT5+ cells unidentified\", \"In vivo relevance shown only in vitro\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How mechanical stress and chromatin regulation toggle KRT5 expression to generate transitional basal cell states remains incompletely defined.\",\n      \"evidence\": \"Preprint scRNA-seq/ATAC-seq of p63-driven Krt8-to-Krt5 transitions and mechanical-stretch-driven KRT5 reduction\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint findings lack direct KRT5 functional perturbation\", \"Causal role of KRT5 level in transitional state not tested\", \"Mechanotransduction pathway to KRT5 promoter unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KRT14\", \"TRIM29\", \"DSG1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}