Affinage

KRT1

Keratin, type II cytoskeletal 1 · UniProt P04264

Length
644 aa
Mass
66.0 kDa
Annotated
2026-06-10
32 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 Low

    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

    PMID:14708600

    Open questions at the time
    • 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
  2. 2005 Low

    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

    PMID:15663507

    Open questions at the time
    • No direct in vitro reconstitution of assembly defect
    • Effect on heterodimer partner interaction not measured
  3. 2015 Medium

    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

    PMID:25774499

    Open questions at the time
    • Mechanism of nuclear mislocalization unknown
    • Functional consequence of nuclear KRT1 not characterized
  4. 2022 Medium

    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

    PMID:35490383

    Open questions at the time
    • Molecular basis of keratin 2 compensation not established
    • Reason for aberrant keratin 9 clumping unresolved
  5. 2022 Medium

    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

    PMID:36231117

    Open questions at the time
    • Whether GPR115 binds KRT1 directly versus colocalizes is not resolved
    • Signaling mechanism linking GPR115 to KRT1 expression unknown
  6. 2023 Medium

    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

    PMID:37455999

    Open questions at the time
    • Mechanism by which the KRT1-CD63 complex enforces arrest not defined
    • Single lab, no reciprocal structural validation
  7. 2024 Medium

    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

    PMID:39644827

    Open questions at the time
    • How KRT1 transduces CEA binding to PI3K/AKT mechanistically unresolved
    • Single lab
  8. 2025 Medium

    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

    PMID:40222446

    Open questions at the time
    • Direct deubiquitination of KRT1 inferred from stability rather than enzymatic assay
    • Ubiquitin ligase that opposes USP28 not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 1 R-HSA-162582 Signal Transduction 1
Partners
CD63CEAGPR115KRT10USP28

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 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. Patient skin biopsy analysis, immunofluorescence, genetic sequencing of revertant clones The Journal of clinical investigation Medium 25774499
2022 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. qRT-PCR, immunofluorescence, Western blot, transmission electron microscopy of patient skin biopsies Journal of the European Academy of Dermatology and Venereology : JEADV Medium 35490383
2022 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. ADGRF4 deletion in organotypic HaCaT cultures, immunofluorescence colocalization Cells Medium 36231117
2024 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. Proteomic analysis, Co-IP, GST pull-down, immunofluorescence colocalization, virtual screening, surface plasmon resonance, in vitro and in vivo xenograft assays Drug resistance updates Medium 39644827
2025 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. IP-MS analysis, co-immunoprecipitation, immunofluorescence, USP28 knockdown/overexpression, CCK-8 and clone formation assays Experimental cell research Medium 40222446
2023 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. Mass spectrometry, co-immunoprecipitation, in vitro and in vivo overexpression experiments Heliyon Medium 37455999
2003 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. Genomic DNA sequencing, mRNA analysis, clinical phenotyping of patient families The Journal of investigative dermatology Low 14708600
2005 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. Genomic DNA sequencing, mRNA analysis from patient skin, RT-PCR Clinical and experimental dermatology Low 15663507

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Characterization and chromosomal localization of the cornea-specific murine keratin gene Krt1.12. The Journal of biological chemistry 96 7523376
2006 Allele-specific KRT1 expression is a complex trait. PLoS genetics 62 16789827
2015 Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti. The Journal of clinical investigation 55 25774499
2016 Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis. Acta dermato-venereologica 48 26581228
2018 microRNA-107 protects against inflammation and endoplasmic reticulum stress of vascular endothelial cells via KRT1-dependent Notch signaling pathway in a mouse model of coronary atherosclerosis. Journal of cellular physiology 42 30548623
2003 Splice site and deletion mutations in keratin (KRT1 and KRT10) genes: unusual phenotypic alterations in Scandinavian patients with epidermolytic hyperkeratosis. The Journal of investigative dermatology 29 14708600
2018 KRT1 gene silencing ameliorates myocardial ischemia-reperfusion injury via the activation of the Notch signaling pathway in mouse models. Journal of cellular physiology 23 30191968
2007 In vitro human keratinocyte migration rates are associated with SNPs in the KRT1 interval. PloS one 23 17668073
2002 Cis-regulatory elements of the mouse Krt1.12 gene. Molecular vision 18 11951085
2024 CEA-induced PI3K/AKT pathway activation through the binding of CEA to KRT1 contributes to oxaliplatin resistance in gastric cancer. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 15 39644827
2018 Analysis of KRT1, KRT10, KRT19, TP53 and MMP9 expression in pediatric and adult cholesteatoma. PloS one 11 30021014
2005 Epidermolytic hyperkeratosis type PS-1 caused by aberrant splicing of KRT1. Clinical and experimental dermatology 10 15663507
2000 Whiskers amiss, a new vibrissae and hair mutation near the Krt1 cluster on mouse chromosome 11. Mammalian genome : official journal of the International Mammalian Genome Society 6 10754100
2022 The Adhesion G-Protein-Coupled Receptor GPR115/ADGRF4 Regulates Epidermal Differentiation and Associates with Cytoskeletal KRT1. Cells 5 36231117
2018 A p.478I>T KRT1 mutation in a case of annular epidermolytic ichthyosis. Pediatric dermatology 5 30152556
1992 Localization by in situ hybridization of a type I keratin intermediate filament gene (Krt-1.14) to band D of mouse chromosome 11. Cytogenetics and cell genetics 5 1380418
2023 Tetraspanin CD63 reduces the progression and metastasis of head and neck squamous cell carcinoma via KRT1-mediated cell cycle arrest. Heliyon 4 37455999
2022 Nonsense mutations in KRT1 caused recessive epidermolytic palmoplantar keratoderma with knuckle pads. Journal of the European Academy of Dermatology and Venereology : JEADV 4 35490383
2020 A novel KRT1 c.1433A>G p.(Glu478Gly) mutation in a newborn with epidermolytic ichthyosis. Clinical case reports 4 33363884
2020 Bullous diseases caused by KRT1 gene mutations: from epidermolytic hyperkeratosis to a novel variant of epidermolysis bullosa simplex. Postepy dermatologii i alergologii 4 35126011
2022 A de novo variant in the keratin 1 gene (KRT1) in a Chinese shar-pei dog with severe congenital cornification disorder and non-epidermolytic ichthyosis. PloS one 3 36251712
2015 Next-generation sequencing detection and characterization of a heterozygous novel splice junction mutation in the 2B domain of KRT1 in a family with diffuse palmoplantar keratoderma. Experimental dermatology 3 25429721
2023 Two cases of KRT1 mutation-associated epidermolytic ichthyosis without typical epidermolytic hyperkeratosis in the neonatal skin lesions. Pediatric dermatology 2 37170713
2015 A KRT1 gene mutation related to epidermolytic ichthyosis in a Chinese family. Clinical and experimental dermatology 2 25808222
2025 USP28 knockdown and small molecule inhibitors promote KRT1 destabilization and sensitize hepatocellular carcinoma cells to sorafenib. Experimental cell research 1 40222446
2020 A novel frameshift truncation mutation in the V2 tail domain of KRT1 causes mild ichthyosis hystrix of Curth-Macklin. Clinical and experimental dermatology 1 32049370
2020 A de novo mutation of KRT1 in a baby girl causing epidermolytic ichthyosis with impressive epidermolytic palmoplantar keratoderma. Dermatology online journal 1 32898404
2025 CircPPP1CB subtype, hsa_circ_0007439, promotes nasopharyngeal carcinoma progression by upregulating KRT1. Discover oncology 0 41186844
2024 ABHD1 Facilitates Intermediate Filament-Mediated Endothelial Cell Chemotaxis by Regulating KRT1 and KRT2 in Diabetic Retinopathy. Journal of diabetes research 0 39619568
2023 Correction: Winkler et al. The Adhesion G-Protein-Coupled Receptor GPR115/ADGRF4 Regulates Epidermal Differentiation and Associates with Cytoskeletal KRT1. Cells 2022, 11, 3151. Cells 0 37443844
2023 De Novo Mutation in KRT1 Leads to Epidermolytic Palmoplantar Keratoderma: from Chinese Traditional Treatment to Prenatal Diagnosis Using Whole-Exome Sequencing-Plus. DNA and cell biology 0 37566479
2018 Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree. Genetic testing and molecular biomarkers 0 30452289

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