{"gene":"KRT1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2015,"finding":"A C-terminal frameshift mutation in KRT1 (replacing 22 C-terminal amino acids with an alternate 30-residue peptide) causes partial collapse of the cytoplasmic intermediate filament network and mislocalization of mutant KRT1 to the nucleus. Reversion of the mutation occurs via mitotic recombination, restoring normal skin clones.","method":"Patient skin biopsy analysis, immunofluorescence, genetic sequencing of revertant clones","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cellular localization experiment with functional consequence, mutant protein characterized in patient tissue, single lab","pmids":["25774499"],"is_preprint":false},{"year":2022,"finding":"Homozygous nonsense mutations in KRT1 (leading to absence of KRT1 protein via nonsense-mediated mRNA decay) result in EPPK rather than epidermolytic ichthyosis; loss of KRT1 is compensated by upregulation of keratin 2 (forming heterodimer with keratin 10), while keratin 9 shows aberrant clumped staining pattern in palmar skin.","method":"qRT-PCR, immunofluorescence, Western blot, transmission electron microscopy of patient skin biopsies","journal":"Journal of the European Academy of Dermatology and Venereology : JEADV","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (qRT-PCR, IF, WB, EM) in patient tissue, single lab","pmids":["35490383"],"is_preprint":false},{"year":2022,"finding":"GPR115/ADGRF4 deletion in HaCaT keratinocytes abrogates KRT1 expression and reduces keratinocyte stratification. Endogenous GPR115 localizes intracellularly along KRT1/10-positive keratin filaments, indicating GPR115 associates with cytoskeletal KRT1 and regulates epidermal differentiation.","method":"ADGRF4 deletion in organotypic HaCaT cultures, immunofluorescence colocalization","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined differentiation phenotype plus direct colocalization, single lab","pmids":["36231117"],"is_preprint":false},{"year":2024,"finding":"CEA binds directly to KRT1 at the cell surface/cytoskeleton, and this interaction activates the PI3K/AKT signaling pathway, contributing to oxaliplatin resistance in gastric cancer cells. The small molecule inhibitor evacetrapib competitively inhibits the CEA-KRT1 interaction.","method":"Proteomic analysis, Co-IP, GST pull-down, immunofluorescence colocalization, virtual screening, surface plasmon resonance, in vitro and in vivo xenograft assays","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct binding confirmed by multiple orthogonal methods (Co-IP, GST pull-down, SPR), functional pathway activation demonstrated, single lab","pmids":["39644827"],"is_preprint":false},{"year":2025,"finding":"USP28 deubiquitinase interacts with KRT1 and exerts deubiquitination on KRT1, thereby maintaining KRT1 protein stability. USP28 knockdown leads to decreased KRT1 levels and reduced IFITM3 expression, inhibiting HCC cell proliferation.","method":"IP-MS analysis, co-immunoprecipitation, immunofluorescence, USP28 knockdown/overexpression, CCK-8 and clone formation assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and IP-MS establish interaction, deubiquitination activity inferred from stability changes, single lab","pmids":["40222446"],"is_preprint":false},{"year":2023,"finding":"CD63 directly interacts with KRT1 (identified by mass spectrometry and co-immunoprecipitation), and this interaction mediates cell cycle arrest, reducing progression and metastasis of head and neck squamous cell carcinoma cells.","method":"Mass spectrometry, co-immunoprecipitation, in vitro and in vivo overexpression experiments","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by MS and Co-IP, functional consequence demonstrated in vitro and in vivo, single lab","pmids":["37455999"],"is_preprint":false},{"year":2003,"finding":"Splice site mutations in KRT1 causing deletion of 22 codons (Δ176-197) from the 1A helical domain result in epidermolytic hyperkeratosis with palmoplantar keratoderma. Deletion of up to 46 amino acids from KRT1 can result in surprisingly mild phenotypes, indicating that genotype-phenotype relationships depend on both the mutation type and interactions of mutant protein with the cellular environment.","method":"Genomic DNA sequencing, mRNA analysis, clinical phenotyping of patient families","journal":"The Journal of investigative dermatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mutation characterization in patient samples establishes structural requirements for KRT1 function, no direct in vitro reconstitution or mechanistic assay","pmids":["14708600"],"is_preprint":false},{"year":2005,"finding":"A splice site mutation (intronic 4-bp deletion) in KRT1 leads to aberrant splicing producing a KRT1 protein lacking 22 amino acids including the conserved helix initiation motif, causing epidermolytic hyperkeratosis type PS-1, demonstrating the functional necessity of the helix initiation motif for normal KRT1 intermediate filament assembly.","method":"Genomic DNA sequencing, mRNA analysis from patient skin, RT-PCR","journal":"Clinical and experimental dermatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mutation characterization in patient sample, identifies structurally critical domain, no in vitro reconstitution","pmids":["15663507"],"is_preprint":false}],"current_model":"KRT1 (keratin 1) is a type II intermediate filament protein that forms obligate heterodimers with type I keratins (principally KRT10) to constitute the cytoskeletal intermediate filament network in suprabasal keratinocytes; pathogenic mutations in its conserved helical rod domain (particularly the helix initiation motif and 1A/2B regions) or C-terminal frameshift disrupts filament assembly and causes mislocalization of the mutant protein to the nucleus; KRT1 stability is post-translationally regulated by USP28-mediated deubiquitination; KRT1 interacts with the adhesion receptor GPR115 along keratin filaments to support epidermal differentiation; it binds CEA to activate PI3K/AKT signaling; and it associates with CD63 tetraspanin to mediate cell cycle arrest, placing KRT1 at the intersection of structural cytoskeletal function and signaling pathway regulation."},"narrative":{"mechanistic_narrative":"KRT1 is a type II keratin that forms the suprabasal keratinocyte intermediate filament network required for epidermal differentiation and stratification [PMID:36231117]. Its conserved helical rod domain governs filament assembly: a C-terminal frameshift collapses the cytoplasmic filament network and drives mutant protein into the nucleus [PMID:25774499], while loss of KRT1 protein through homozygous nonsense alleles is compensated by upregulation of keratin 2 and produces a palmoplantar (EPPK) rather than epidermolytic phenotype [PMID:35490383]. KRT1 stability is post-translationally controlled by the deubiquitinase USP28, which binds and deubiquitinates KRT1 to maintain its protein level [PMID:40222446]. Beyond its structural role, KRT1 participates in surface and signaling interactions: it colocalizes with the adhesion receptor GPR115/ADGRF4 along keratin filaments, an association required for normal keratinocyte differentiation [PMID:36231117]; it binds CEA to activate PI3K/AKT signaling and confer oxaliplatin resistance [PMID:39644827]; and it interacts with the tetraspanin CD63 to mediate cell cycle arrest [PMID:37455999]. Inherited KRT1 rod-domain and splice mutations cause epidermolytic hyperkeratosis with palmoplantar keratoderma [PMID:25774499].","teleology":[{"year":2003,"claim":"Defined which structural elements of KRT1 are required for function by linking rod-domain deletions to skin disease, establishing that filament integrity depends on the 1A helical region.","evidence":"Genomic and mRNA analysis with clinical phenotyping of patient families carrying Δ176-197 1A-domain deletions","pmids":["14708600"],"confidence":"Low","gaps":["No in vitro reconstitution or filament-assembly assay to confirm the structural mechanism","Genotype-phenotype variability not mechanistically explained","Does not define how mutant protein perturbs the network at the molecular level"]},{"year":2005,"claim":"Pinpointed the helix initiation motif as functionally essential for KRT1 filament assembly by characterizing a splice mutation removing this conserved motif.","evidence":"Genomic DNA sequencing, mRNA analysis and RT-PCR from patient skin in epidermolytic hyperkeratosis type PS-1","pmids":["15663507"],"confidence":"Low","gaps":["No direct in vitro reconstitution of assembly defect","Effect on heterodimer partner interaction not measured"]},{"year":2015,"claim":"Showed that a C-terminal frameshift not only disrupts the cytoplasmic filament network but mislocalizes mutant KRT1 to the nucleus, and that mitotic recombination can revert the defect.","evidence":"Patient skin biopsy immunofluorescence and genetic sequencing of revertant clones","pmids":["25774499"],"confidence":"Medium","gaps":["Mechanism of nuclear mislocalization unknown","Functional consequence of nuclear KRT1 not characterized"]},{"year":2022,"claim":"Distinguished KRT1 loss-of-protein from dominant-negative mutation by showing nonsense alleles yield EPPK with keratin 2 compensation, clarifying that complete absence has a milder, compensable phenotype.","evidence":"qRT-PCR, immunofluorescence, Western blot and TEM of patient palmar skin biopsies","pmids":["35490383"],"confidence":"Medium","gaps":["Molecular basis of keratin 2 compensation not established","Reason for aberrant keratin 9 clumping unresolved"]},{"year":2022,"claim":"Connected KRT1 to an upstream regulator of differentiation by showing GPR115/ADGRF4 colocalizes along KRT1/10 filaments and its loss abrogates KRT1 expression and stratification.","evidence":"ADGRF4 deletion in organotypic HaCaT cultures with immunofluorescence colocalization","pmids":["36231117"],"confidence":"Medium","gaps":["Whether GPR115 binds KRT1 directly versus colocalizes is not resolved","Signaling mechanism linking GPR115 to KRT1 expression unknown"]},{"year":2023,"claim":"Extended KRT1 beyond structural roles by identifying a direct CD63 interaction that mediates cell cycle arrest in head and neck squamous cell carcinoma.","evidence":"Mass spectrometry, co-immunoprecipitation and in vitro/in vivo overexpression","pmids":["37455999"],"confidence":"Medium","gaps":["Mechanism by which the KRT1-CD63 complex enforces arrest not defined","Single lab, no reciprocal structural validation"]},{"year":2024,"claim":"Established KRT1 as a signaling scaffold by showing direct CEA binding activates PI3K/AKT and drives chemoresistance, with a druggable interface.","evidence":"Proteomics, Co-IP, GST pull-down, SPR, immunofluorescence, virtual screening and xenograft assays in gastric cancer","pmids":["39644827"],"confidence":"Medium","gaps":["How KRT1 transduces CEA binding to PI3K/AKT mechanistically unresolved","Single lab"]},{"year":2025,"claim":"Identified post-translational control of KRT1 abundance by USP28-mediated deubiquitination, linking KRT1 stability to tumor cell proliferation.","evidence":"IP-MS, reciprocal Co-IP, immunofluorescence, USP28 knockdown/overexpression and proliferation assays in HCC","pmids":["40222446"],"confidence":"Medium","gaps":["Direct deubiquitination of KRT1 inferred from stability rather than enzymatic assay","Ubiquitin ligase that opposes USP28 not identified"]},{"year":null,"claim":"It remains unresolved how KRT1's structural filament function mechanistically integrates with its signaling interactions (CEA/PI3K-AKT, CD63, GPR115) and stability control by USP28.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the KRT1-partner interfaces","Whether signaling roles depend on assembled filaments versus soluble KRT1 unknown","In vitro reconstitution of filament assembly defects from disease mutations lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3]}],"complexes":[],"partners":["KRT10","GPR115","CEA","USP28","CD63"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P04264","full_name":"Keratin, type II cytoskeletal 1","aliases":["67 kDa cytokeratin","Cytokeratin-1","CK-1","Hair alpha protein","Keratin-1","K1","Type-II keratin Kb1"],"length_aa":644,"mass_kda":66.0,"function":"May regulate the activity of kinases such as PKC and SRC via binding to integrin beta-1 (ITB1) and the receptor of activated protein C kinase 1 (RACK1). In complex with C1QBP is a high affinity receptor for kininogen-1/HMWK","subcellular_location":"Cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P04264/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT1","total_profiled":1310},"omim":[{"mim_id":"620411","title":"PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC, 2; EPPK2","url":"https://www.omim.org/entry/620411"},{"mim_id":"620150","title":"EPIDERMOLYTIC HYPERKERATOSIS 2A, AUTOSOMAL DOMINANT; EHK2A","url":"https://www.omim.org/entry/620150"},{"mim_id":"620148","title":"ICHTHYOSIS, ANNULAR EPIDERMOLYTIC, 2; AEI2","url":"https://www.omim.org/entry/620148"},{"mim_id":"614594","title":"OLMSTED SYNDROME 1; OLMS1","url":"https://www.omim.org/entry/614594"},{"mim_id":"614428","title":"TRANSCRIPTION FACTOR AP2-EPSILON; TFAP2E","url":"https://www.omim.org/entry/614428"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":12288.0}],"url":"https://www.proteinatlas.org/search/KRT1"},"hgnc":{"alias_symbol":["KRT1A"],"prev_symbol":["EHK1"]},"alphafold":{"accession":"P04264","domains":[{"cath_id":"1.20.5","chopping":"254-332","consensus_level":"medium","plddt":95.59,"start":254,"end":332}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P04264","model_url":"https://alphafold.ebi.ac.uk/files/AF-P04264-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P04264-F1-predicted_aligned_error_v6.png","plddt_mean":63.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRT1","jax_strain_url":"https://www.jax.org/strain/search?query=KRT1"},"sequence":{"accession":"P04264","fasta_url":"https://rest.uniprot.org/uniprotkb/P04264.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P04264/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P04264"}},"corpus_meta":[{"pmid":"7523376","id":"PMC_7523376","title":"Characterization and chromosomal 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The Adhesion G-Protein-Coupled Receptor GPR115/ADGRF4 Regulates Epidermal Differentiation and Associates with Cytoskeletal KRT1. Cells 2022, 11, 3151.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/37443844","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.15.676359","title":"Under Pressure: A unique mechanoresponsive mechanism of body site-specific keratin regulation in palmoplantar epidermis","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.15.676359","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.01.651662","title":"Modeling epithelial and endothelial cell tropism for SARS-CoV-2 through restricted transgenic hACE2 expression in mice","date":"2025-05-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.01.651662","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.27.630544","title":"Keratin 16 spatially inhibits type I interferon responses in stressed and diseased skin","date":"2024-12-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.27.630544","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.13.603037","title":"Differential expression of keratin and keratin associated proteins are linked with hair loss condition in spontaneously mutated inbred mice","date":"2024-07-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.13.603037","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.16.633456","title":"A Single-Cell Atlas of the Upper Respiratory Epithelium Reveals Heterogeneity in Cell Types and Patterning Strategies","date":"2025-01-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.16.633456","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18982,"output_tokens":2030,"usd":0.043698,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9056,"output_tokens":2787,"usd":0.057478,"stage2_stop_reason":"end_turn"},"total_usd":0.101176,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"A C-terminal frameshift mutation in KRT1 (replacing 22 C-terminal amino acids with an alternate 30-residue peptide) causes partial collapse of the cytoplasmic intermediate filament network and mislocalization of mutant KRT1 to the nucleus. Reversion of the mutation occurs via mitotic recombination, restoring normal skin clones.\",\n      \"method\": \"Patient skin biopsy analysis, immunofluorescence, genetic sequencing of revertant clones\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cellular localization experiment with functional consequence, mutant protein characterized in patient tissue, single lab\",\n      \"pmids\": [\"25774499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Homozygous nonsense mutations in KRT1 (leading to absence of KRT1 protein via nonsense-mediated mRNA decay) result in EPPK rather than epidermolytic ichthyosis; loss of KRT1 is compensated by upregulation of keratin 2 (forming heterodimer with keratin 10), while keratin 9 shows aberrant clumped staining pattern in palmar skin.\",\n      \"method\": \"qRT-PCR, immunofluorescence, Western blot, transmission electron microscopy of patient skin biopsies\",\n      \"journal\": \"Journal of the European Academy of Dermatology and Venereology : JEADV\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (qRT-PCR, IF, WB, EM) in patient tissue, single lab\",\n      \"pmids\": [\"35490383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GPR115/ADGRF4 deletion in HaCaT keratinocytes abrogates KRT1 expression and reduces keratinocyte stratification. Endogenous GPR115 localizes intracellularly along KRT1/10-positive keratin filaments, indicating GPR115 associates with cytoskeletal KRT1 and regulates epidermal differentiation.\",\n      \"method\": \"ADGRF4 deletion in organotypic HaCaT cultures, immunofluorescence colocalization\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined differentiation phenotype plus direct colocalization, single lab\",\n      \"pmids\": [\"36231117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CEA binds directly to KRT1 at the cell surface/cytoskeleton, and this interaction activates the PI3K/AKT signaling pathway, contributing to oxaliplatin resistance in gastric cancer cells. The small molecule inhibitor evacetrapib competitively inhibits the CEA-KRT1 interaction.\",\n      \"method\": \"Proteomic analysis, Co-IP, GST pull-down, immunofluorescence colocalization, virtual screening, surface plasmon resonance, in vitro and in vivo xenograft assays\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding confirmed by multiple orthogonal methods (Co-IP, GST pull-down, SPR), functional pathway activation demonstrated, single lab\",\n      \"pmids\": [\"39644827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP28 deubiquitinase interacts with KRT1 and exerts deubiquitination on KRT1, thereby maintaining KRT1 protein stability. USP28 knockdown leads to decreased KRT1 levels and reduced IFITM3 expression, inhibiting HCC cell proliferation.\",\n      \"method\": \"IP-MS analysis, co-immunoprecipitation, immunofluorescence, USP28 knockdown/overexpression, CCK-8 and clone formation assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and IP-MS establish interaction, deubiquitination activity inferred from stability changes, single lab\",\n      \"pmids\": [\"40222446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD63 directly interacts with KRT1 (identified by mass spectrometry and co-immunoprecipitation), and this interaction mediates cell cycle arrest, reducing progression and metastasis of head and neck squamous cell carcinoma cells.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, in vitro and in vivo overexpression experiments\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by MS and Co-IP, functional consequence demonstrated in vitro and in vivo, single lab\",\n      \"pmids\": [\"37455999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Splice site mutations in KRT1 causing deletion of 22 codons (Δ176-197) from the 1A helical domain result in epidermolytic hyperkeratosis with palmoplantar keratoderma. Deletion of up to 46 amino acids from KRT1 can result in surprisingly mild phenotypes, indicating that genotype-phenotype relationships depend on both the mutation type and interactions of mutant protein with the cellular environment.\",\n      \"method\": \"Genomic DNA sequencing, mRNA analysis, clinical phenotyping of patient families\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mutation characterization in patient samples establishes structural requirements for KRT1 function, no direct in vitro reconstitution or mechanistic assay\",\n      \"pmids\": [\"14708600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A splice site mutation (intronic 4-bp deletion) in KRT1 leads to aberrant splicing producing a KRT1 protein lacking 22 amino acids including the conserved helix initiation motif, causing epidermolytic hyperkeratosis type PS-1, demonstrating the functional necessity of the helix initiation motif for normal KRT1 intermediate filament assembly.\",\n      \"method\": \"Genomic DNA sequencing, mRNA analysis from patient skin, RT-PCR\",\n      \"journal\": \"Clinical and experimental dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mutation characterization in patient sample, identifies structurally critical domain, no in vitro reconstitution\",\n      \"pmids\": [\"15663507\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT1 (keratin 1) is a type II intermediate filament protein that forms obligate heterodimers with type I keratins (principally KRT10) to constitute the cytoskeletal intermediate filament network in suprabasal keratinocytes; pathogenic mutations in its conserved helical rod domain (particularly the helix initiation motif and 1A/2B regions) or C-terminal frameshift disrupts filament assembly and causes mislocalization of the mutant protein to the nucleus; KRT1 stability is post-translationally regulated by USP28-mediated deubiquitination; KRT1 interacts with the adhesion receptor GPR115 along keratin filaments to support epidermal differentiation; it binds CEA to activate PI3K/AKT signaling; and it associates with CD63 tetraspanin to mediate cell cycle arrest, placing KRT1 at the intersection of structural cytoskeletal function and signaling pathway regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KRT1 is a type II keratin that forms the suprabasal keratinocyte intermediate filament network required for epidermal differentiation and stratification [#2]. Its conserved helical rod domain governs filament assembly: a C-terminal frameshift collapses the cytoplasmic filament network and drives mutant protein into the nucleus [#0], while loss of KRT1 protein through homozygous nonsense alleles is compensated by upregulation of keratin 2 and produces a palmoplantar (EPPK) rather than epidermolytic phenotype [#1]. KRT1 stability is post-translationally controlled by the deubiquitinase USP28, which binds and deubiquitinates KRT1 to maintain its protein level [#4]. Beyond its structural role, KRT1 participates in surface and signaling interactions: it colocalizes with the adhesion receptor GPR115/ADGRF4 along keratin filaments, an association required for normal keratinocyte differentiation [#2]; it binds CEA to activate PI3K/AKT signaling and confer oxaliplatin resistance [#3]; and it interacts with the tetraspanin CD63 to mediate cell cycle arrest [#5]. Inherited KRT1 rod-domain and splice mutations cause epidermolytic hyperkeratosis with palmoplantar keratoderma [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined which structural elements of KRT1 are required for function by linking rod-domain deletions to skin disease, establishing that filament integrity depends on the 1A helical region.\",\n      \"evidence\": \"Genomic and mRNA analysis with clinical phenotyping of patient families carrying Δ176-197 1A-domain deletions\",\n      \"pmids\": [\"14708600\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vitro reconstitution or filament-assembly assay to confirm the structural mechanism\",\n        \"Genotype-phenotype variability not mechanistically explained\",\n        \"Does not define how mutant protein perturbs the network at the molecular level\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Pinpointed the helix initiation motif as functionally essential for KRT1 filament assembly by characterizing a splice mutation removing this conserved motif.\",\n      \"evidence\": \"Genomic DNA sequencing, mRNA analysis and RT-PCR from patient skin in epidermolytic hyperkeratosis type PS-1\",\n      \"pmids\": [\"15663507\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct in vitro reconstitution of assembly defect\",\n        \"Effect on heterodimer partner interaction not measured\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that a C-terminal frameshift not only disrupts the cytoplasmic filament network but mislocalizes mutant KRT1 to the nucleus, and that mitotic recombination can revert the defect.\",\n      \"evidence\": \"Patient skin biopsy immunofluorescence and genetic sequencing of revertant clones\",\n      \"pmids\": [\"25774499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of nuclear mislocalization unknown\",\n        \"Functional consequence of nuclear KRT1 not characterized\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Distinguished KRT1 loss-of-protein from dominant-negative mutation by showing nonsense alleles yield EPPK with keratin 2 compensation, clarifying that complete absence has a milder, compensable phenotype.\",\n      \"evidence\": \"qRT-PCR, immunofluorescence, Western blot and TEM of patient palmar skin biopsies\",\n      \"pmids\": [\"35490383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis of keratin 2 compensation not established\",\n        \"Reason for aberrant keratin 9 clumping unresolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected KRT1 to an upstream regulator of differentiation by showing GPR115/ADGRF4 colocalizes along KRT1/10 filaments and its loss abrogates KRT1 expression and stratification.\",\n      \"evidence\": \"ADGRF4 deletion in organotypic HaCaT cultures with immunofluorescence colocalization\",\n      \"pmids\": [\"36231117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether GPR115 binds KRT1 directly versus colocalizes is not resolved\",\n        \"Signaling mechanism linking GPR115 to KRT1 expression unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended KRT1 beyond structural roles by identifying a direct CD63 interaction that mediates cell cycle arrest in head and neck squamous cell carcinoma.\",\n      \"evidence\": \"Mass spectrometry, co-immunoprecipitation and in vitro/in vivo overexpression\",\n      \"pmids\": [\"37455999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which the KRT1-CD63 complex enforces arrest not defined\",\n        \"Single lab, no reciprocal structural validation\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established KRT1 as a signaling scaffold by showing direct CEA binding activates PI3K/AKT and drives chemoresistance, with a druggable interface.\",\n      \"evidence\": \"Proteomics, Co-IP, GST pull-down, SPR, immunofluorescence, virtual screening and xenograft assays in gastric cancer\",\n      \"pmids\": [\"39644827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How KRT1 transduces CEA binding to PI3K/AKT mechanistically unresolved\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified post-translational control of KRT1 abundance by USP28-mediated deubiquitination, linking KRT1 stability to tumor cell proliferation.\",\n      \"evidence\": \"IP-MS, reciprocal Co-IP, immunofluorescence, USP28 knockdown/overexpression and proliferation assays in HCC\",\n      \"pmids\": [\"40222446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct deubiquitination of KRT1 inferred from stability rather than enzymatic assay\",\n        \"Ubiquitin ligase that opposes USP28 not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how KRT1's structural filament function mechanistically integrates with its signaling interactions (CEA/PI3K-AKT, CD63, GPR115) and stability control by USP28.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of the KRT1-partner interfaces\",\n        \"Whether signaling roles depend on assembled filaments versus soluble KRT1 unknown\",\n        \"In vitro reconstitution of filament assembly defects from disease mutations lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KRT10\", \"GPR115\", \"CEA\", \"USP28\", \"CD63\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}