Affinage

KRT1

Keratin, type II cytoskeletal 1 · UniProt P04264

Length
644 aa
Mass
66.0 kDa
Annotated
2026-04-28
35 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KRT1 is a type II intermediate filament keratin that heterodimerizes with KRT10 to build the 10-nm cytoskeletal network of suprabasal keratinocytes undergoing terminal differentiation, with KRT9 serving as an additional partner in palmoplantar epidermis. Dominant missense mutations in the conserved 1A and 2B rod domains collapse the filament network and cause epidermolytic hyperkeratosis, whereas C-terminal frameshift mutations mislocalise mutant KRT1 to the nucleus and underlie ichthyosis with confetti, in which revertant mosaicism arises through mitotic recombination; homozygous loss-of-function mutations produce epidermolytic palmoplantar keratoderma with compensatory upregulation of keratin 2 (PMID:14708600, PMID:25774499, PMID:35490383). KRT1 protein stability is maintained by USP28-mediated deubiquitination, and KRT1 can engage non-cytoskeletal signalling partners: binding CEA activates PI3K/AKT signalling and contributes to chemoresistance, while interaction with CD63 mediates cell-cycle arrest in squamous carcinoma cells (PMID:40222446, PMID:39644827, PMID:37455999). KRT1 expression in suprabasal keratinocytes is regulated in part by the adhesion GPCR ADGRF4, whose deletion abrogates KRT1 expression and impairs epidermal stratification (PMID:36231117).

Mechanistic history

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

    Establishing KRT1's core function: mapping of patient mutations to the conserved 1A and 2B helical rod domains demonstrated that KRT1/KRT10 heterodimers are essential structural units of suprabasal intermediate filaments and that their disruption causes epidermolytic hyperkeratosis.

    Evidence Genotype–phenotype analysis of multiple epidermolytic hyperkeratosis families with domain mapping of KRT1 mutations

    PMID:14708600

    Open questions at the time
    • No in vitro reconstitution of mutant vs. wild-type filament assembly in this study
    • Quantitative structure–function relationship between specific rod-domain residues and filament stability not resolved
  2. 2015 High

    Resolving how C-terminal mutations produce a distinct disease: frameshift mutations in the KRT1 tail domain were shown to cause nuclear mislocalization and partial filament collapse rather than complete network disruption, explaining the milder ichthyosis with confetti phenotype and its characteristic revertant mosaicism via mitotic recombination.

    Evidence Immunofluorescence of patient keratinocytes showing nuclear KRT1, molecular analysis of revertant clones demonstrating loss-of-heterozygosity by mitotic recombination

    PMID:25774499

    Open questions at the time
    • Mechanism by which C-terminal frameshift directs nuclear import is unknown
    • Whether nuclear KRT1 has any functional consequence beyond filament loss is untested
  3. 2018 Low

    Extending KRT1's reach beyond structural roles: miR-107 was shown to directly target the KRT1 3ʹ-UTR, and KRT1 suppression activated Notch signalling in vascular endothelial cells and cardiomyocytes, suggesting KRT1 can modulate signalling pathways in non-epithelial contexts.

    Evidence Dual-luciferase reporter assay confirming miR-107 binding to KRT1 3ʹ-UTR; siRNA knockdown with Notch pathway readouts (NICD, Hes1) and DAPT rescue in mouse atherosclerosis and MIRI models

    PMID:30191968 PMID:30548623

    Open questions at the time
    • KRT1 expression in vascular endothelial cells and cardiomyocytes is atypical for a suprabasal keratin; independent confirmation of endogenous expression in these cell types is lacking
    • Epistasis with Notch was inferred from inhibitor experiments without direct biochemical mechanism
    • Single-lab findings not replicated
  4. 2022 Medium

    Defining consequences of complete KRT1 loss: homozygous nonsense mutations causing nonsense-mediated decay demonstrated that KRT1 absence triggers compensatory KRT2/KRT10 pairing and aberrant KRT9 distribution, resulting in palmoplantar keratoderma rather than generalised epidermolysis.

    Evidence NGS, qRT-PCR, Western blot, immunofluorescence, and TEM in patient skin biopsies

    PMID:35490383

    Open questions at the time
    • Whether KRT2/KRT10 filaments fully substitute mechanically for KRT1/KRT10 is unknown
    • Why the phenotype is restricted to palmoplantar skin despite widespread KRT1 expression is unexplained
  5. 2022 Medium

    Identifying an upstream regulator of KRT1 expression: ADGRF4 (GPR115) was shown to associate with KRT1/KRT10 filaments and to be required for KRT1 expression and keratinocyte stratification.

    Evidence CRISPR deletion of ADGRF4 in HaCaT cells with organotypic culture; immunofluorescence colocalization

    PMID:36231117

    Open questions at the time
    • Signal transduction pathway between ADGRF4 and KRT1 transcription is uncharacterised
    • Physical association versus functional regulation not fully separated
  6. 2023 Medium

    Revealing a non-cytoskeletal signalling role: CD63 was identified as a direct KRT1 interactor whose binding mediates KRT1-dependent cell-cycle arrest and metastasis suppression in head and neck squamous cell carcinoma.

    Evidence Mass spectrometry and co-immunoprecipitation with overexpression/knockdown phenotypic assays in vitro and in vivo

    PMID:37455999

    Open questions at the time
    • Structural basis of KRT1–CD63 interaction is unknown
    • Whether this interaction occurs in normal epithelial differentiation or only in carcinoma is untested
  7. 2024 Medium

    Defining a signalling axis through which KRT1 promotes chemoresistance: CEA was shown to bind KRT1 directly and activate PI3K/AKT signalling; competitive disruption of this interaction by evacetrapib restored oxaliplatin sensitivity in gastric cancer.

    Evidence Co-IP, GST pull-down, SPR for direct binding; virtual screening and in vivo xenograft drug sensitivity assays

    PMID:39644827

    Open questions at the time
    • Binding interface and stoichiometry of CEA–KRT1 complex not determined
    • Mechanism linking CEA–KRT1 binding to PI3K activation is undefined
  8. 2025 Medium

    Establishing post-translational control of KRT1 stability: USP28 was identified as a deubiquitinase that directly interacts with and stabilises KRT1 protein, linking KRT1 turnover to the ubiquitin–proteasome system.

    Evidence IP-MS and co-immunoprecipitation; USP28 knockdown/overexpression with protein stability assays in hepatocellular carcinoma cells and xenografts

    PMID:40222446

    Open questions at the time
    • Specific ubiquitin linkage type and lysine residues on KRT1 targeted by USP28 are not mapped
    • E3 ligase responsible for KRT1 ubiquitination is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of KRT1's non-filament signalling interactions (with CEA, CD63, and Notch pathway components) and how these are coordinated with its primary cytoskeletal role remain unresolved.
  • No atomic-resolution structure of KRT1 in complex with any signalling partner
  • Whether cytoplasmic soluble KRT1 pool versus filament-incorporated KRT1 mediates signalling is unknown
  • Interplay between USP28-mediated KRT1 stabilisation and KRT1's signalling functions has not been tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005856 cytoskeleton 4 GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 2
Partners
ADGRF4CD63CEACAM5KRT10KRT9USP28
Complex memberships
KRT1/KRT10 heterodimerKRT1/KRT9 heterodimer

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 KRT1 C-terminal frameshift mutations cause partial collapse of the cytoplasmic intermediate filament network and mislocalization of mutant KRT1 to the nucleus; reversion of these mutations occurs via mitotic recombination, explaining the revertant mosaicism seen in ichthyosis with confetti. Clinical genetics, histopathology, cell biology (immunofluorescence showing nuclear mislocalization), and molecular analysis of revertant clones demonstrating mitotic recombination The Journal of clinical investigation High 25774499
2003 KRT1 and KRT10 form heterodimers that constitute the intermediate filaments in suprabasal keratinocytes committed to terminal differentiation; mutations in the conserved 1A and 2B helical rod domains disrupt this function and cause epidermolytic hyperkeratosis. Genetic analysis of patients combined with structural domain mapping of mutations; functional inference from dominant-negative phenotypes The Journal of investigative dermatology Medium 14708600
2022 Loss of KRT1 via homozygous nonsense mutations (leading to nonsense-mediated mRNA decay and absence of KRT1 protein) results in epidermolytic palmoplantar keratoderma, with compensatory upregulation of keratin 2 (which forms heterodimers with keratin 10), while keratin 9 shows aberrant clumped distribution in palmar skin. Next-generation sequencing, qRT-PCR, immunofluorescence, Western blot, transmission electron microscopy Journal of the European Academy of Dermatology and Venereology : JEADV Medium 35490383
2022 The adhesion G-protein-coupled receptor GPR115/ADGRF4 associates with KRT1/KRT10-positive keratin filaments intracellularly and regulates epidermal differentiation; deletion of ADGRF4 in keratinocytes abrogates KRT1 expression and reduces keratinocyte stratification. Organotypic culture, ADGRF4 CRISPR deletion in HaCaT cells, immunofluorescence colocalization of GPR115 with KRT1/10 filaments Cells Medium 36231117
2024 CEA (carcinoembryonic antigen) directly binds KRT1, and this interaction activates the PI3K/AKT signaling pathway, contributing to oxaliplatin resistance in gastric cancer; competitive inhibition of the CEA-KRT1 interaction with the small molecule evacetrapib reverses resistance. Proteomic analysis, Co-IP, GST pull-down, immunofluorescence colocalization, virtual screening, surface plasmon resonance, in vitro and in vivo drug sensitivity assays Drug resistance updates Medium 39644827
2025 USP28 (a deubiquitinating enzyme) directly interacts with KRT1 and exerts deubiquitination on KRT1, thereby maintaining KRT1 protein stability; USP28 knockdown leads to KRT1 destabilization and decreased IFITM3 expression in hepatocellular carcinoma cells. IP-MS analysis, co-immunoprecipitation, immunofluorescence, USP28 knockdown/overexpression with functional assays, xenograft mouse model Experimental cell research Medium 40222446
2023 CD63 directly interacts with KRT1 (identified by mass spectrometry and co-immunoprecipitation), and this interaction mediates KRT1-dependent cell cycle arrest to suppress metastasis in head and neck squamous cell carcinoma. Mass spectrometry, co-immunoprecipitation, in vitro and in vivo functional assays (overexpression/knockdown) Heliyon Medium 37455999
2018 miR-107 directly binds the KRT1 3'UTR (validated by dual-luciferase reporter assay); miR-107-mediated suppression of KRT1 activates the Notch signaling pathway in vascular endothelial cells, reducing inflammation and ER stress in a coronary atherosclerosis model. Dual-luciferase reporter assay, ectopic expression and depletion experiments, Western blot, ELISA, flow cytometry in mouse atherosclerosis model Journal of cellular physiology Medium 30548623
2018 KRT1 silencing activates the Notch signaling pathway (increased NICD and Hes1 expression) in myocardial cells, reducing apoptosis and improving cell proliferation; this effect is abolished by Notch pathway inhibition with DAPT, placing KRT1 upstream of Notch in cardiomyocyte injury context. siRNA-mediated KRT1 knockdown, Notch activator (Jagged1) and inhibitor (DAPT) treatment, Western blot, MTT assay, flow cytometry in mouse MIRI model Journal of cellular physiology Low 30191968

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Ehk-1 and Ehk-2: two novel members of the Eph receptor-like tyrosine kinase family with distinctive structures and neuronal expression. Oncogene 99 7504232
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 54 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
1994 Expression and developmental regulation of Ehk-1, a neuronal Elk-like receptor tyrosine kinase in brain. Neuroscience 31 7898646
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 14 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
1997 Extensive splice variation and localization of the EHK-1 receptor tyrosine kinase in adult human brain and glial tumors. Brain research. Molecular brain research 8 9191074
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