{"gene":"KRT10","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1999,"finding":"Ectopic expression of K10 inhibits proliferation of human keratinocytes by acting on the retinoblastoma (Rb) pathway: K10 reduces pRb phosphorylation and cyclin D1 expression; this inhibition is rescued by cyclins, CDKs, cyclin-CDK complexes, or co-expression of pRb/p107 but not p130, and does not occur in Rb-deficient cells. The inhibitory function was mapped to the non-helical terminal domains of K10 using deletion mutants. K16 co-expression reverses K10-induced growth arrest.","method":"Ectopic expression in human keratinocytes, cotransfection with viral oncoproteins/cyclins/CDKs, Rb-deficient cell rescue experiments, K10 deletion mutant analysis, pRb phosphorylation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional and biochemical methods (rescue experiments, deletion mutagenesis, phosphorylation assays) in a single rigorous study, replicated in subsequent in vivo work","pmids":["10082575"],"is_preprint":false},{"year":2001,"finding":"K10 physically interacts with Akt (PKB) and atypical PKCζ via its non-alpha-helical amino-terminal domain (NTerm), sequesters these kinases within the cytoskeleton, inhibits their intracellular translocation and activation, and thereby impedes pRb phosphorylation and reduces cyclin D1 and E expression to arrest the cell cycle.","method":"Co-immunoprecipitation of K10 with Akt/PKCζ, kinase activity assays, K10 deletion mutant transfections, cyclin/pRb Western blotting","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP identifying physical interaction, kinase activity assays, and deletion mutagenesis mapping the interacting domain, replicated in vivo in transgenic mice","pmids":["11585925"],"is_preprint":false},{"year":2002,"finding":"In transgenic mice ectopically expressing K10 in proliferative basal epidermal cells, K10 causes hypoplastic/hyperkeratotic epidermis via dramatic decrease in keratinocyte proliferation associated with inhibition of Akt and PKCζ activities in vivo, confirming K10's in vivo role in controlling epithelial proliferation and resistance to skin tumorigenesis.","method":"Transgenic mouse model with K10 driven by basal-layer keratin promoter; Akt and PKCζ activity assays; BrdU proliferation assay; tumor induction assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo KO/transgenic model with defined proliferation and signaling phenotype, replicating in vitro mechanistic findings","pmids":["11889133"],"is_preprint":false},{"year":2003,"finding":"K10 expression in basal epidermal cells of transgenic mice leads to impaired NF-κB activation through decreased expression of IKKβ and IKKγ, a consequence of K10-mediated Akt inhibition. This is accompanied by increased TNF-α production and JNK activation in the epidermis.","method":"Transgenic mouse model; IKKβ/γ Western blotting; NF-κB reporter assays; TNF-α ELISA; JNK activity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with multiple biochemical readouts in a single lab","pmids":["12566451"],"is_preprint":false},{"year":2010,"finding":"Dominant KRT10 frameshift mutations in ichthyosis with confetti result in a C-terminal arginine-rich peptide that redirects keratin 10 protein from the cytokeratin filament network to the nucleolus. Reversion of these mutations via mitotic recombination (loss of heterozygosity on chr17q) restores normal skin.","method":"Whole-genome mapping using mitotic reversion clones; DNA sequencing of KRT10 mutations; immunofluorescence/cellular localization of mutant K10 protein","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — disease-mapping combined with direct protein localization showing nucleolar mislocalization, confirmed in multiple patient-derived revertant clones","pmids":["20798280"],"is_preprint":false},{"year":1994,"finding":"Mouse keratin 10 is tightly bound to the cornified envelope and may function as a covalently cross-linked transglutaminase substrate, providing a mechanism by which keratin filaments interact with the cornified envelope to enhance structural integrity of the stratum corneum.","method":"Dansylcadaverine labeling of transglutaminase substrates; immunoscreening of cDNA library; DNA sequencing; immunoelectron microscopy with anti-K10 antibodies; proteolytic fragmentation of purified cornified envelope + Western blot","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoelectron microscopy and biochemical fractionation identifying K10 in cornified envelope, single lab with multiple orthogonal methods","pmids":["7528240"],"is_preprint":false},{"year":1992,"finding":"In epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma), tonofilament aggregates in suprabasal epidermis selectively and predominantly express K1 and K10 rather than other keratins (K5, K14, K16), localizing the cytoskeletal abnormality specifically to K1/K10-containing filaments.","method":"Immunoelectron microscopy with keratin-specific antibodies on skin biopsies from EHK patients; electron microscopy; immunocytochemistry on cultured keratinocytes","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoelectron microscopy with multiple keratin antibodies, patient tissue plus cultured cells, single study","pmids":["1376754"],"is_preprint":false},{"year":1994,"finding":"Mutations at or near the conserved ends of the K10 alpha-helical rod domain (e.g., R156C in the 1A region, mutations in the 2B region) are functionally responsible for keratin filament aberrations in EHK keratinocytes; the severity of filament network disruption correlates with disease severity, with mutations closer to the helix termini causing more severe perturbations.","method":"Genetic engineering and gene transfection of mutant KRT10 alleles into keratinocytes; keratin filament network analysis by immunofluorescence","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional reconstitution by expressing engineered mutant keratins in cells and demonstrating filament disruption, multiple mutations and multiple families","pmids":["7512983"],"is_preprint":false},{"year":1994,"finding":"K10 is unable to form a normal keratin intermediate filament network on its own in fibroblasts and requires a pre-existing keratin cytoskeleton (epithelial cell context) to integrate. K10 alone forms stable, regularly sized round aggregates that interact with endogenous keratins, actin, vimentin, and tubulin. K10 integrates into pre-existing IF networks through a dynamic process involving rearrangement of the endogenous cytoskeleton, not direct incorporation.","method":"Transient and stable transfection of K1/K10 into fibroblasts and epithelial cell lines; kinetic immunofluorescence experiments in PtK2 cells","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell kinetics and immunofluorescence in multiple cell types, single lab","pmids":["7526994"],"is_preprint":false},{"year":2012,"finding":"Deletion of both K1 and K10 in mice abolishes IFs in suprabasal epidermis (without compensatory upregulation by K5/K14), reduces desmosomal protein expression (desmoplakin, desmocollin 1, desmoglein 1) and desmosome size, causes premature nuclear loss during differentiation, and lowers levels of emerin, lamin A/C and Sun1—revealing a role for K1/K10 IFs in desmosome dynamics and nuclear integrity in the upper epidermis. Notably, epidermal stratification and water barrier formation were surprisingly independent of K1/K10 IFs.","method":"Krt1-/-; Krt10-/- double knockout mice; electron microscopy; immunofluorescence; dye exclusion barrier assay; Western blot","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean double KO with multiple orthogonal structural and biochemical readouts, in vivo","pmids":["22375063"],"is_preprint":false},{"year":2014,"finding":"In the absence of K2, K10 forms massive protein aggregates in suprabasal keratinocytes; conversely, absence of K10 causes K2 clumping. Deletion of both K2 and K10 suppresses aggregate formation, demonstrating that K2 is a necessary and sufficient binding partner of K10 at distinct body sites (ear, sole, tail) and that imbalanced expression of these keratins causes aggregate formation.","method":"Krt2-/- and Krt2-/-;Krt10-/- knockout mice; immunofluorescence; Western blot; histology","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — double and single KO genetic epistasis cleanly demonstrating K2/K10 obligate partnership, in vivo with multiple orthogonal methods","pmids":["24751727"],"is_preprint":false},{"year":2020,"finding":"Tp63 directly binds the KRT10 promoter region and activates KRT10 transcription in basal keratinocytes; ozone treatment promotes K10 expression and keratinocyte differentiation via upregulation of Tp63, an effect reversed by Tp63 silencing.","method":"Chromatin immunoprecipitation (Tp63 binding to KRT10 promoter); siRNA knockdown of Tp63; qRT-PCR and Western blot for KRT10/Tp63; immunofluorescence in patient and mouse psoriatic tissues","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus siRNA rescue, single lab","pmids":["32168425"],"is_preprint":false},{"year":2014,"finding":"KRT10 was identified as a protein that directly interacts with PTEN by co-immunoprecipitation in ovarian cancer cells. KRT10 expression is upregulated by cisplatin downstream of PTEN, and forced KRT10 overexpression enhances cisplatin-induced proliferation inhibition and apoptosis; KRT10 siRNA blocks this effect in PTEN-expressing cells.","method":"Co-immunoprecipitation of KRT10 with PTEN; KRT10 siRNA knockdown; MTT proliferation assay; apoptosis assay; qRT-PCR/Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP identifying interaction, supported by siRNA functional rescue, single lab","pmids":["24434152"],"is_preprint":false},{"year":2023,"finding":"KRT10 physically interacts with influenza virus NS2 protein (identified by GST-pulldown and mass spectrometry). KRT10 knockdown reduces viral NP mRNA and protein expression, traps AIV particles in late endosomes/lysosomes, increases endosomal/lysosomal pH, and prevents viral fusion/uncoating—indicating KRT10 facilitates release of viral RNPs from late endosomes during AIV infection.","method":"GST-pulldown with NS2; mass spectrometry; KRT10 siRNA knockdown; immunofluorescence colocalization with Lamp1/NP; endosomal pH measurement; offspring virus titer assay","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST-pulldown plus functional KD with multiple cellular readouts, single lab","pmids":["37406407"],"is_preprint":false},{"year":2019,"finding":"TALE nuclease-mediated disruption of dominant-negative mutant KRT10 alleles in patient-derived keratinocytes (ex vivo) restores keratin intermediate filament stability, as confirmed by immunofluorescence and ultrastructural analysis of murine xenograft models, demonstrating that the dominant negative disease mechanism of KRT10 mutations can be reversed by allele-specific disruption.","method":"TALEN gene editing; immunofluorescence of keratin filament networks; electron microscopy of murine xenografts; off-target analysis","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — allele-specific gene editing with functional cellular and ultrastructural readouts, single lab","pmids":["30998984"],"is_preprint":false},{"year":2005,"finding":"K10 transgene expression in thymic epithelial cells (TEC) reduces Akt activity in TEC, alters Notch family member and ligand expression in both TEC and thymocytes, decreases Notch activity in TEC but increases it in thymocytes, and leads to altered T cell differentiation and premature thymus involution—demonstrating that K10-mediated Akt inhibition can non-cell-autonomously modulate cell-cell signaling via Notch.","method":"K5-promoter K10 transgenic mice; Akt kinase activity assays; Notch/ligand Western blot and RT-PCR; flow cytometry of thymocytes; histology","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with multiple signaling readouts, single lab","pmids":["15786499"],"is_preprint":false}],"current_model":"KRT10 encodes keratin 10, a type I intermediate filament protein that heterodimerizes obligately with type II keratins (K1 in most epidermis, K2 at select body sites) to form suprabasal intermediate filaments; beyond structural roles, K10 acts as a negative regulator of cell proliferation by physically sequestering Akt and PKCζ in the cytoskeleton via its non-helical N-terminal domain, thereby inhibiting their activation, reducing pRb phosphorylation and cyclin D1/E expression, and impairing NF-κB signaling; disease-causing dominant-negative mutations in the conserved rod-domain ends disrupt filament assembly, while C-terminal frameshift mutations generate an arginine-rich tail that mislocalizes K10 to the nucleolus; K10 filaments also support desmosome dynamics, nuclear envelope integrity, and cornified envelope cross-linking in the upper epidermis."},"narrative":{"mechanistic_narrative":"KRT10 encodes keratin 10, a type I intermediate filament protein that builds the suprabasal keratin cytoskeleton of the epidermis by obligate heterodimerization with type II partner keratins—K1 in most epidermis and K2 at distinct body sites (ear, sole, tail), where imbalanced K2/K10 stoichiometry drives protein aggregation [PMID:24751727]. K10 cannot assemble a filament network alone and integrates into a pre-existing keratin cytoskeleton through dynamic rearrangement of endogenous filaments [PMID:7526994]. Beyond its structural role, K10 functions as a negative regulator of keratinocyte proliferation: ectopic K10 inhibits proliferation through the Rb pathway, lowering pRb phosphorylation and cyclin D1 expression in an Rb-dependent manner, an activity mapped to its non-helical terminal domains [PMID:10082575]. Mechanistically, the K10 N-terminal domain physically binds and sequesters Akt and atypical PKCζ in the cytoskeleton, blocking their activation and thereby reducing cyclin D1/E expression and cell-cycle progression [PMID:11585925]; transgenic expression of K10 in basal cells confirms in vivo inhibition of Akt and PKCζ with reduced proliferation and tumor resistance [PMID:11889133], and the resulting Akt suppression in turn impairs NF-κB activation via decreased IKKβ/γ [PMID:12566451]. Loss of both K1 and K10 abolishes suprabasal filaments and reveals additional roles in desmosome dynamics and nuclear envelope integrity [PMID:22375063], while K10 is also a covalently cross-linked transglutaminase substrate of the cornified envelope [PMID:7528240]. KRT10 is a Mendelian disease gene: dominant mutations at the conserved ends of the rod domain disrupt filament assembly and cause epidermolytic hyperkeratosis [PMID:7512983], whereas C-terminal frameshift mutations generate an arginine-rich tail that mislocalizes K10 to the nucleolus in ichthyosis with confetti [PMID:20798280]. KRT10 transcription is directly activated by Tp63 in basal keratinocytes [PMID:32168425].","teleology":[{"year":1992,"claim":"Localized the cytoskeletal defect of epidermolytic hyperkeratosis specifically to K1/K10-containing suprabasal filaments rather than other keratins, implicating KRT10 in the disease.","evidence":"Immunoelectron microscopy with keratin-specific antibodies on EHK patient skin and cultured keratinocytes","pmids":["1376754"],"confidence":"Medium","gaps":["Did not identify the causative mutations","Did not establish how filament aggregation arises mechanistically"]},{"year":1994,"claim":"Established the dominant-negative disease mechanism by showing engineered rod-domain mutations disrupt filament assembly, with severity tracking mutation position near the helix termini.","evidence":"Transfection of engineered mutant KRT10 alleles into keratinocytes with filament network analysis","pmids":["7512983"],"confidence":"High","gaps":["Did not resolve atomic-level effect on dimer/filament structure","Did not address non-helical domain functions"]},{"year":1994,"claim":"Defined K10's assembly requirements, showing it cannot form filaments alone and must integrate into a pre-existing keratin network in an epithelial context.","evidence":"Transfection of K1/K10 into fibroblasts and epithelial lines with kinetic immunofluorescence","pmids":["7526994"],"confidence":"Medium","gaps":["Mechanism of dynamic integration into endogenous IFs not resolved","In vivo relevance not tested"]},{"year":1994,"claim":"Connected K10 filaments to the cornified envelope by identifying K10 as a covalently cross-linked transglutaminase substrate contributing to stratum corneum integrity.","evidence":"Dansylcadaverine labeling, immunoelectron microscopy, and biochemical fractionation of cornified envelope","pmids":["7528240"],"confidence":"Medium","gaps":["Specific cross-linking residues and transglutaminase isoform not defined","Quantitative contribution to barrier function unaddressed"]},{"year":1999,"claim":"Revealed an unexpected non-structural function: K10 inhibits keratinocyte proliferation through the Rb pathway, mapped to its non-helical terminal domains.","evidence":"Ectopic expression in keratinocytes with cyclin/CDK/Rb rescue, Rb-deficient cells, and deletion mutants","pmids":["10082575"],"confidence":"High","gaps":["Did not identify the direct molecular target of the terminal domains","Mechanism linking K10 to pRb phosphorylation unknown at this stage"]},{"year":2001,"claim":"Identified the molecular basis of K10's anti-proliferative activity—physical sequestration of Akt and PKCζ by the N-terminal domain to block their activation.","evidence":"Reciprocal co-immunoprecipitation, kinase activity assays, and deletion mutant transfections","pmids":["11585925"],"confidence":"High","gaps":["Structural basis of kinase binding not resolved","Stoichiometry and regulation of sequestration unknown"]},{"year":2002,"claim":"Confirmed in vivo that K10 controls epithelial proliferation and tumor resistance via Akt/PKCζ inhibition.","evidence":"Basal-promoter K10 transgenic mice with kinase activity assays, BrdU, and tumor induction","pmids":["11889133"],"confidence":"High","gaps":["Did not dissect relative contributions of Akt vs PKCζ","Downstream effectors beyond cyclins not fully mapped"]},{"year":2003,"claim":"Extended the K10-Akt axis to inflammatory signaling, showing K10-mediated Akt inhibition impairs NF-κB via reduced IKKβ/γ with elevated TNF-α and JNK.","evidence":"Transgenic mice with IKK Western blot, NF-κB reporter, TNF-α ELISA, and JNK assays","pmids":["12566451"],"confidence":"Medium","gaps":["Single-lab transgenic model","Mechanism linking Akt to IKK expression not detailed"]},{"year":2005,"claim":"Showed K10-mediated Akt inhibition can act non-cell-autonomously, modulating Notch signaling and T cell differentiation in thymic epithelium.","evidence":"K5-promoter K10 transgenic mice with Akt assays, Notch readouts, and thymocyte flow cytometry","pmids":["15786499"],"confidence":"Medium","gaps":["Physiological relevance outside the transgenic context unclear","Direct link between Akt and Notch ligand expression not established"]},{"year":2010,"claim":"Defined a distinct disease mechanism in which C-terminal frameshift mutations produce an arginine-rich tail that mislocalizes K10 to the nucleolus, with somatic reversion restoring normal skin.","evidence":"Whole-genome mapping of mitotic revertant clones, sequencing, and mutant protein localization","pmids":["20798280"],"confidence":"High","gaps":["Functional consequence of nucleolar K10 not defined","Why arginine-rich tail targets the nucleolus mechanistically unresolved"]},{"year":2012,"claim":"Established roles for K1/K10 filaments beyond mechanical support—in desmosome dynamics and nuclear envelope integrity—while showing stratification and barrier formation are surprisingly IF-independent.","evidence":"Krt1-/-;Krt10-/- double knockout mice with EM, immunofluorescence, barrier assay, and Western blot","pmids":["22375063"],"confidence":"High","gaps":["Molecular links between K1/K10 IFs and desmosomal/nuclear envelope proteins not defined","Mechanism of premature nuclear loss unresolved"]},{"year":2014,"claim":"Demonstrated by genetic epistasis that K2 is a necessary and sufficient type II partner of K10 at distinct body sites and that stoichiometric imbalance drives aggregation.","evidence":"Krt2-/- and Krt2-/-;Krt10-/- knockout mice with immunofluorescence, Western blot, histology","pmids":["24751727"],"confidence":"High","gaps":["Biophysical basis of imbalance-induced aggregation not defined","Site-specific regulation of K1 vs K2 pairing unaddressed"]},{"year":2014,"claim":"Reported a context-specific interaction with PTEN linking KRT10 to cisplatin-induced apoptosis in ovarian cancer cells.","evidence":"Co-immunoprecipitation with PTEN plus siRNA knockdown and proliferation/apoptosis assays","pmids":["24434152"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","Relevance of an epidermal keratin in ovarian cancer not independently confirmed"]},{"year":2019,"claim":"Provided proof-of-concept that allele-specific disruption of dominant-negative KRT10 reverses the filament instability disease mechanism.","evidence":"TALEN editing of patient-derived keratinocytes with immunofluorescence and xenograft ultrastructure","pmids":["30998984"],"confidence":"Medium","gaps":["Single-lab ex vivo demonstration","Long-term in vivo efficacy and off-target risks not fully resolved"]},{"year":2020,"claim":"Identified Tp63 as a direct transcriptional activator of KRT10 driving keratinocyte differentiation.","evidence":"ChIP of Tp63 on the KRT10 promoter with siRNA knockdown, qRT-PCR, and immunofluorescence","pmids":["32168425"],"confidence":"Medium","gaps":["Single-lab finding","Additional transcriptional regulators of KRT10 not mapped"]},{"year":2023,"claim":"Reported a non-epidermal role in which KRT10 facilitates release of influenza viral RNPs from late endosomes via interaction with NS2.","evidence":"GST-pulldown/mass spectrometry with NS2, siRNA knockdown, colocalization, and endosomal pH assays","pmids":["37406407"],"confidence":"Medium","gaps":["Single-lab finding","Mechanism by which KRT10 affects endosomal pH/fusion not defined"]},{"year":null,"claim":"How the structural and signaling functions of K10 are integrated—and the functional significance of nucleolar/non-epidermal localizations—remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the K10 N-terminal domain bound to Akt/PKCζ","Functional consequence of nucleolar mislocalization undefined","Mechanistic links between K1/K10 filaments and desmosome/nuclear envelope proteins unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[8,9,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,7]}],"complexes":[],"partners":["KRT1","KRT2","AKT1","PRKCZ","PTEN","TP63"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P13645","full_name":"Keratin, type I cytoskeletal 10","aliases":["Cytokeratin-10","CK-10","Keratin-10","K10"],"length_aa":584,"mass_kda":58.8,"function":"Plays a role in the establishment of the epidermal barrier on plantar skin (By similarity). Involved in the maintenance of cell layer development and keratin filament bundles in suprabasal cells of the epithelium (By similarity) (Microbial infection) Acts as a mediator of S.aureus adherence to desquamated nasal epithelial cells via clfB, and hence may play a role in nasal colonization (Microbial infection) Binds S.pneumoniae PsrP, mediating adherence of the bacteria to lung cell lines. Reduction of levels of KRT10 keratin decrease adherence, overexpression increases adherence. Neither protein has to be glycosylated for the interaction to occur","subcellular_location":"Secreted, extracellular space; Cell surface; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P13645/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT10","classification":"Not Classified","n_dependent_lines":120,"n_total_lines":1208,"dependency_fraction":0.09933774834437085},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT10","total_profiled":1310},"omim":[{"mim_id":"620707","title":"EPIDERMOLYTIC HYPERKERATOSIS 2B, AUTOSOMAL RECESSIVE; EHK2B","url":"https://www.omim.org/entry/620707"},{"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":"613924","title":"LIPASE FAMILY, MEMBER N; 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/28944608","citation_count":6,"is_preprint":false},{"pmid":"32113649","id":"PMC_32113649","title":"Ichthyosis with confetti caused by new and recurrent mutations in KRT10 associated with varying degrees of keratin 10 mis-localization.","date":"2020","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/32113649","citation_count":6,"is_preprint":false},{"pmid":"19689541","id":"PMC_19689541","title":"Bullous congenital ichthyosiform erythroderma: a sporadic case produced by a new KRT10 gene mutation.","date":"2009","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/19689541","citation_count":6,"is_preprint":false},{"pmid":"8029203","id":"PMC_8029203","title":"Solution structure of the DNA binding octapeptide repeat of the K10 gene product.","date":"1994","source":"Protein engineering","url":"https://pubmed.ncbi.nlm.nih.gov/8029203","citation_count":6,"is_preprint":false},{"pmid":"36029589","id":"PMC_36029589","title":"Cytokeratin 10 (CK10) expression in cancer: A tissue microarray study on 11,021 tumors.","date":"2022","source":"Annals of diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36029589","citation_count":5,"is_preprint":false},{"pmid":"36553210","id":"PMC_36553210","title":"Utility of CK8, CK10, CK13, and CK17 in Differential Diagnostics of Benign Lesions, Laryngeal Dysplasia, and Laryngeal Squamous Cell Carcinoma.","date":"2022","source":"Diagnostics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36553210","citation_count":5,"is_preprint":false},{"pmid":"24705378","id":"PMC_24705378","title":"Evaluation of specific marker CK13 and CK10/13 combined with APM staining for the diagnosis of amniotic fluid embolism and aspiration.","date":"2014","source":"Forensic science international","url":"https://pubmed.ncbi.nlm.nih.gov/24705378","citation_count":5,"is_preprint":false},{"pmid":"37406407","id":"PMC_37406407","title":"KRT10 plays an important role in the release of viral genome from endosomes during H9N2 subtype AIV replication in HeLa cells.","date":"2023","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37406407","citation_count":5,"is_preprint":false},{"pmid":"19344714","id":"PMC_19344714","title":"Keratin 10 (K10) is expressed suprabasally throughout the limbus of embryonic and neonatal rat corneas, with interrupted expression in the adult limbus.","date":"2009","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/19344714","citation_count":5,"is_preprint":false},{"pmid":"34199056","id":"PMC_34199056","title":"Post Zygotic, Somatic, Deletion in KERATIN 1 V1 Domain Generates Structural Alteration of the K1/K10 Dimer, Producing a Monolateral Palmar Epidermolytic Nevus.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34199056","citation_count":5,"is_preprint":false},{"pmid":"22217868","id":"PMC_22217868","title":"Montmorillonite K-10 mediated green synthesis of cyano pyridines: Their evaluation as potential inhibitors of PDE4.","date":"2011","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22217868","citation_count":5,"is_preprint":false},{"pmid":"37368195","id":"PMC_37368195","title":"Characterization and biocontrol efficacy of lytic phage (KPP-1) that infects multidrug resistant Klebsiella variicola.","date":"2023","source":"Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]","url":"https://pubmed.ncbi.nlm.nih.gov/37368195","citation_count":4,"is_preprint":false},{"pmid":"32045015","id":"PMC_32045015","title":"Mutations in KRT10 in epidermolytic acanthoma.","date":"2020","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32045015","citation_count":4,"is_preprint":false},{"pmid":"37295249","id":"PMC_37295249","title":"The novel KV7 channel activator URO-K10 exerts enhanced pulmonary vascular effects independent of the KCNE4 regulatory subunit.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/37295249","citation_count":4,"is_preprint":false},{"pmid":"11204523","id":"PMC_11204523","title":"Recurrent R156H mutation of KRT10 in a Japanese family with bullous congenital ichthyosiform erythroderma.","date":"2000","source":"Journal of the European Academy of Dermatology and Venereology : JEADV","url":"https://pubmed.ncbi.nlm.nih.gov/11204523","citation_count":4,"is_preprint":false},{"pmid":"24773427","id":"PMC_24773427","title":"Clinicopathological features and expression of four keratins (K10, K14, K17 and K19) in six cases of eruptive vellus hair cysts.","date":"2014","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/24773427","citation_count":4,"is_preprint":false},{"pmid":"34087563","id":"PMC_34087563","title":"Effect of the deletion of lprG and p55 genes in the K10 strain of Mycobacterium avium subspecies paratuberculosis.","date":"2021","source":"Research in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/34087563","citation_count":4,"is_preprint":false},{"pmid":"34929154","id":"PMC_34929154","title":"Selective Targeting of the Novel CK-10 Nanoparticles to the MDA-MB-231 Breast Cancer Cells.","date":"2021","source":"Journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34929154","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47370,"output_tokens":4311,"usd":0.103387,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12330,"output_tokens":4745,"usd":0.090137,"stage2_stop_reason":"end_turn"},"total_usd":0.193524,"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\": 1999,\n      \"finding\": \"Ectopic expression of K10 inhibits proliferation of human keratinocytes by acting on the retinoblastoma (Rb) pathway: K10 reduces pRb phosphorylation and cyclin D1 expression; this inhibition is rescued by cyclins, CDKs, cyclin-CDK complexes, or co-expression of pRb/p107 but not p130, and does not occur in Rb-deficient cells. The inhibitory function was mapped to the non-helical terminal domains of K10 using deletion mutants. K16 co-expression reverses K10-induced growth arrest.\",\n      \"method\": \"Ectopic expression in human keratinocytes, cotransfection with viral oncoproteins/cyclins/CDKs, Rb-deficient cell rescue experiments, K10 deletion mutant analysis, pRb phosphorylation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional and biochemical methods (rescue experiments, deletion mutagenesis, phosphorylation assays) in a single rigorous study, replicated in subsequent in vivo work\",\n      \"pmids\": [\"10082575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"K10 physically interacts with Akt (PKB) and atypical PKCζ via its non-alpha-helical amino-terminal domain (NTerm), sequesters these kinases within the cytoskeleton, inhibits their intracellular translocation and activation, and thereby impedes pRb phosphorylation and reduces cyclin D1 and E expression to arrest the cell cycle.\",\n      \"method\": \"Co-immunoprecipitation of K10 with Akt/PKCζ, kinase activity assays, K10 deletion mutant transfections, cyclin/pRb Western blotting\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP identifying physical interaction, kinase activity assays, and deletion mutagenesis mapping the interacting domain, replicated in vivo in transgenic mice\",\n      \"pmids\": [\"11585925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In transgenic mice ectopically expressing K10 in proliferative basal epidermal cells, K10 causes hypoplastic/hyperkeratotic epidermis via dramatic decrease in keratinocyte proliferation associated with inhibition of Akt and PKCζ activities in vivo, confirming K10's in vivo role in controlling epithelial proliferation and resistance to skin tumorigenesis.\",\n      \"method\": \"Transgenic mouse model with K10 driven by basal-layer keratin promoter; Akt and PKCζ activity assays; BrdU proliferation assay; tumor induction assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo KO/transgenic model with defined proliferation and signaling phenotype, replicating in vitro mechanistic findings\",\n      \"pmids\": [\"11889133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"K10 expression in basal epidermal cells of transgenic mice leads to impaired NF-κB activation through decreased expression of IKKβ and IKKγ, a consequence of K10-mediated Akt inhibition. This is accompanied by increased TNF-α production and JNK activation in the epidermis.\",\n      \"method\": \"Transgenic mouse model; IKKβ/γ Western blotting; NF-κB reporter assays; TNF-α ELISA; JNK activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with multiple biochemical readouts in a single lab\",\n      \"pmids\": [\"12566451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dominant KRT10 frameshift mutations in ichthyosis with confetti result in a C-terminal arginine-rich peptide that redirects keratin 10 protein from the cytokeratin filament network to the nucleolus. Reversion of these mutations via mitotic recombination (loss of heterozygosity on chr17q) restores normal skin.\",\n      \"method\": \"Whole-genome mapping using mitotic reversion clones; DNA sequencing of KRT10 mutations; immunofluorescence/cellular localization of mutant K10 protein\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — disease-mapping combined with direct protein localization showing nucleolar mislocalization, confirmed in multiple patient-derived revertant clones\",\n      \"pmids\": [\"20798280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Mouse keratin 10 is tightly bound to the cornified envelope and may function as a covalently cross-linked transglutaminase substrate, providing a mechanism by which keratin filaments interact with the cornified envelope to enhance structural integrity of the stratum corneum.\",\n      \"method\": \"Dansylcadaverine labeling of transglutaminase substrates; immunoscreening of cDNA library; DNA sequencing; immunoelectron microscopy with anti-K10 antibodies; proteolytic fragmentation of purified cornified envelope + Western blot\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoelectron microscopy and biochemical fractionation identifying K10 in cornified envelope, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"7528240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"In epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma), tonofilament aggregates in suprabasal epidermis selectively and predominantly express K1 and K10 rather than other keratins (K5, K14, K16), localizing the cytoskeletal abnormality specifically to K1/K10-containing filaments.\",\n      \"method\": \"Immunoelectron microscopy with keratin-specific antibodies on skin biopsies from EHK patients; electron microscopy; immunocytochemistry on cultured keratinocytes\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoelectron microscopy with multiple keratin antibodies, patient tissue plus cultured cells, single study\",\n      \"pmids\": [\"1376754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Mutations at or near the conserved ends of the K10 alpha-helical rod domain (e.g., R156C in the 1A region, mutations in the 2B region) are functionally responsible for keratin filament aberrations in EHK keratinocytes; the severity of filament network disruption correlates with disease severity, with mutations closer to the helix termini causing more severe perturbations.\",\n      \"method\": \"Genetic engineering and gene transfection of mutant KRT10 alleles into keratinocytes; keratin filament network analysis by immunofluorescence\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional reconstitution by expressing engineered mutant keratins in cells and demonstrating filament disruption, multiple mutations and multiple families\",\n      \"pmids\": [\"7512983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"K10 is unable to form a normal keratin intermediate filament network on its own in fibroblasts and requires a pre-existing keratin cytoskeleton (epithelial cell context) to integrate. K10 alone forms stable, regularly sized round aggregates that interact with endogenous keratins, actin, vimentin, and tubulin. K10 integrates into pre-existing IF networks through a dynamic process involving rearrangement of the endogenous cytoskeleton, not direct incorporation.\",\n      \"method\": \"Transient and stable transfection of K1/K10 into fibroblasts and epithelial cell lines; kinetic immunofluorescence experiments in PtK2 cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell kinetics and immunofluorescence in multiple cell types, single lab\",\n      \"pmids\": [\"7526994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Deletion of both K1 and K10 in mice abolishes IFs in suprabasal epidermis (without compensatory upregulation by K5/K14), reduces desmosomal protein expression (desmoplakin, desmocollin 1, desmoglein 1) and desmosome size, causes premature nuclear loss during differentiation, and lowers levels of emerin, lamin A/C and Sun1—revealing a role for K1/K10 IFs in desmosome dynamics and nuclear integrity in the upper epidermis. Notably, epidermal stratification and water barrier formation were surprisingly independent of K1/K10 IFs.\",\n      \"method\": \"Krt1-/-; Krt10-/- double knockout mice; electron microscopy; immunofluorescence; dye exclusion barrier assay; Western blot\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean double KO with multiple orthogonal structural and biochemical readouts, in vivo\",\n      \"pmids\": [\"22375063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In the absence of K2, K10 forms massive protein aggregates in suprabasal keratinocytes; conversely, absence of K10 causes K2 clumping. Deletion of both K2 and K10 suppresses aggregate formation, demonstrating that K2 is a necessary and sufficient binding partner of K10 at distinct body sites (ear, sole, tail) and that imbalanced expression of these keratins causes aggregate formation.\",\n      \"method\": \"Krt2-/- and Krt2-/-;Krt10-/- knockout mice; immunofluorescence; Western blot; histology\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double and single KO genetic epistasis cleanly demonstrating K2/K10 obligate partnership, in vivo with multiple orthogonal methods\",\n      \"pmids\": [\"24751727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tp63 directly binds the KRT10 promoter region and activates KRT10 transcription in basal keratinocytes; ozone treatment promotes K10 expression and keratinocyte differentiation via upregulation of Tp63, an effect reversed by Tp63 silencing.\",\n      \"method\": \"Chromatin immunoprecipitation (Tp63 binding to KRT10 promoter); siRNA knockdown of Tp63; qRT-PCR and Western blot for KRT10/Tp63; immunofluorescence in patient and mouse psoriatic tissues\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus siRNA rescue, single lab\",\n      \"pmids\": [\"32168425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KRT10 was identified as a protein that directly interacts with PTEN by co-immunoprecipitation in ovarian cancer cells. KRT10 expression is upregulated by cisplatin downstream of PTEN, and forced KRT10 overexpression enhances cisplatin-induced proliferation inhibition and apoptosis; KRT10 siRNA blocks this effect in PTEN-expressing cells.\",\n      \"method\": \"Co-immunoprecipitation of KRT10 with PTEN; KRT10 siRNA knockdown; MTT proliferation assay; apoptosis assay; qRT-PCR/Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP identifying interaction, supported by siRNA functional rescue, single lab\",\n      \"pmids\": [\"24434152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KRT10 physically interacts with influenza virus NS2 protein (identified by GST-pulldown and mass spectrometry). KRT10 knockdown reduces viral NP mRNA and protein expression, traps AIV particles in late endosomes/lysosomes, increases endosomal/lysosomal pH, and prevents viral fusion/uncoating—indicating KRT10 facilitates release of viral RNPs from late endosomes during AIV infection.\",\n      \"method\": \"GST-pulldown with NS2; mass spectrometry; KRT10 siRNA knockdown; immunofluorescence colocalization with Lamp1/NP; endosomal pH measurement; offspring virus titer assay\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST-pulldown plus functional KD with multiple cellular readouts, single lab\",\n      \"pmids\": [\"37406407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TALE nuclease-mediated disruption of dominant-negative mutant KRT10 alleles in patient-derived keratinocytes (ex vivo) restores keratin intermediate filament stability, as confirmed by immunofluorescence and ultrastructural analysis of murine xenograft models, demonstrating that the dominant negative disease mechanism of KRT10 mutations can be reversed by allele-specific disruption.\",\n      \"method\": \"TALEN gene editing; immunofluorescence of keratin filament networks; electron microscopy of murine xenografts; off-target analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — allele-specific gene editing with functional cellular and ultrastructural readouts, single lab\",\n      \"pmids\": [\"30998984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"K10 transgene expression in thymic epithelial cells (TEC) reduces Akt activity in TEC, alters Notch family member and ligand expression in both TEC and thymocytes, decreases Notch activity in TEC but increases it in thymocytes, and leads to altered T cell differentiation and premature thymus involution—demonstrating that K10-mediated Akt inhibition can non-cell-autonomously modulate cell-cell signaling via Notch.\",\n      \"method\": \"K5-promoter K10 transgenic mice; Akt kinase activity assays; Notch/ligand Western blot and RT-PCR; flow cytometry of thymocytes; histology\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with multiple signaling readouts, single lab\",\n      \"pmids\": [\"15786499\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT10 encodes keratin 10, a type I intermediate filament protein that heterodimerizes obligately with type II keratins (K1 in most epidermis, K2 at select body sites) to form suprabasal intermediate filaments; beyond structural roles, K10 acts as a negative regulator of cell proliferation by physically sequestering Akt and PKCζ in the cytoskeleton via its non-helical N-terminal domain, thereby inhibiting their activation, reducing pRb phosphorylation and cyclin D1/E expression, and impairing NF-κB signaling; disease-causing dominant-negative mutations in the conserved rod-domain ends disrupt filament assembly, while C-terminal frameshift mutations generate an arginine-rich tail that mislocalizes K10 to the nucleolus; K10 filaments also support desmosome dynamics, nuclear envelope integrity, and cornified envelope cross-linking in the upper epidermis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KRT10 encodes keratin 10, a type I intermediate filament protein that builds the suprabasal keratin cytoskeleton of the epidermis by obligate heterodimerization with type II partner keratins—K1 in most epidermis and K2 at distinct body sites (ear, sole, tail), where imbalanced K2/K10 stoichiometry drives protein aggregation [#10]. K10 cannot assemble a filament network alone and integrates into a pre-existing keratin cytoskeleton through dynamic rearrangement of endogenous filaments [#8]. Beyond its structural role, K10 functions as a negative regulator of keratinocyte proliferation: ectopic K10 inhibits proliferation through the Rb pathway, lowering pRb phosphorylation and cyclin D1 expression in an Rb-dependent manner, an activity mapped to its non-helical terminal domains [#0]. Mechanistically, the K10 N-terminal domain physically binds and sequesters Akt and atypical PKCζ in the cytoskeleton, blocking their activation and thereby reducing cyclin D1/E expression and cell-cycle progression [#1]; transgenic expression of K10 in basal cells confirms in vivo inhibition of Akt and PKCζ with reduced proliferation and tumor resistance [#2], and the resulting Akt suppression in turn impairs NF-κB activation via decreased IKKβ/γ [#3]. Loss of both K1 and K10 abolishes suprabasal filaments and reveals additional roles in desmosome dynamics and nuclear envelope integrity [#9], while K10 is also a covalently cross-linked transglutaminase substrate of the cornified envelope [#5]. KRT10 is a Mendelian disease gene: dominant mutations at the conserved ends of the rod domain disrupt filament assembly and cause epidermolytic hyperkeratosis [#7], whereas C-terminal frameshift mutations generate an arginine-rich tail that mislocalizes K10 to the nucleolus in ichthyosis with confetti [#4]. KRT10 transcription is directly activated by Tp63 in basal keratinocytes [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Localized the cytoskeletal defect of epidermolytic hyperkeratosis specifically to K1/K10-containing suprabasal filaments rather than other keratins, implicating KRT10 in the disease.\",\n      \"evidence\": \"Immunoelectron microscopy with keratin-specific antibodies on EHK patient skin and cultured keratinocytes\",\n      \"pmids\": [\"1376754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the causative mutations\", \"Did not establish how filament aggregation arises mechanistically\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the dominant-negative disease mechanism by showing engineered rod-domain mutations disrupt filament assembly, with severity tracking mutation position near the helix termini.\",\n      \"evidence\": \"Transfection of engineered mutant KRT10 alleles into keratinocytes with filament network analysis\",\n      \"pmids\": [\"7512983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve atomic-level effect on dimer/filament structure\", \"Did not address non-helical domain functions\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defined K10's assembly requirements, showing it cannot form filaments alone and must integrate into a pre-existing keratin network in an epithelial context.\",\n      \"evidence\": \"Transfection of K1/K10 into fibroblasts and epithelial lines with kinetic immunofluorescence\",\n      \"pmids\": [\"7526994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of dynamic integration into endogenous IFs not resolved\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Connected K10 filaments to the cornified envelope by identifying K10 as a covalently cross-linked transglutaminase substrate contributing to stratum corneum integrity.\",\n      \"evidence\": \"Dansylcadaverine labeling, immunoelectron microscopy, and biochemical fractionation of cornified envelope\",\n      \"pmids\": [\"7528240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific cross-linking residues and transglutaminase isoform not defined\", \"Quantitative contribution to barrier function unaddressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Revealed an unexpected non-structural function: K10 inhibits keratinocyte proliferation through the Rb pathway, mapped to its non-helical terminal domains.\",\n      \"evidence\": \"Ectopic expression in keratinocytes with cyclin/CDK/Rb rescue, Rb-deficient cells, and deletion mutants\",\n      \"pmids\": [\"10082575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the direct molecular target of the terminal domains\", \"Mechanism linking K10 to pRb phosphorylation unknown at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the molecular basis of K10's anti-proliferative activity—physical sequestration of Akt and PKCζ by the N-terminal domain to block their activation.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, kinase activity assays, and deletion mutant transfections\",\n      \"pmids\": [\"11585925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of kinase binding not resolved\", \"Stoichiometry and regulation of sequestration unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Confirmed in vivo that K10 controls epithelial proliferation and tumor resistance via Akt/PKCζ inhibition.\",\n      \"evidence\": \"Basal-promoter K10 transgenic mice with kinase activity assays, BrdU, and tumor induction\",\n      \"pmids\": [\"11889133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not dissect relative contributions of Akt vs PKCζ\", \"Downstream effectors beyond cyclins not fully mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended the K10-Akt axis to inflammatory signaling, showing K10-mediated Akt inhibition impairs NF-κB via reduced IKKβ/γ with elevated TNF-α and JNK.\",\n      \"evidence\": \"Transgenic mice with IKK Western blot, NF-κB reporter, TNF-α ELISA, and JNK assays\",\n      \"pmids\": [\"12566451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab transgenic model\", \"Mechanism linking Akt to IKK expression not detailed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed K10-mediated Akt inhibition can act non-cell-autonomously, modulating Notch signaling and T cell differentiation in thymic epithelium.\",\n      \"evidence\": \"K5-promoter K10 transgenic mice with Akt assays, Notch readouts, and thymocyte flow cytometry\",\n      \"pmids\": [\"15786499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance outside the transgenic context unclear\", \"Direct link between Akt and Notch ligand expression not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a distinct disease mechanism in which C-terminal frameshift mutations produce an arginine-rich tail that mislocalizes K10 to the nucleolus, with somatic reversion restoring normal skin.\",\n      \"evidence\": \"Whole-genome mapping of mitotic revertant clones, sequencing, and mutant protein localization\",\n      \"pmids\": [\"20798280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of nucleolar K10 not defined\", \"Why arginine-rich tail targets the nucleolus mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established roles for K1/K10 filaments beyond mechanical support—in desmosome dynamics and nuclear envelope integrity—while showing stratification and barrier formation are surprisingly IF-independent.\",\n      \"evidence\": \"Krt1-/-;Krt10-/- double knockout mice with EM, immunofluorescence, barrier assay, and Western blot\",\n      \"pmids\": [\"22375063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular links between K1/K10 IFs and desmosomal/nuclear envelope proteins not defined\", \"Mechanism of premature nuclear loss unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated by genetic epistasis that K2 is a necessary and sufficient type II partner of K10 at distinct body sites and that stoichiometric imbalance drives aggregation.\",\n      \"evidence\": \"Krt2-/- and Krt2-/-;Krt10-/- knockout mice with immunofluorescence, Western blot, histology\",\n      \"pmids\": [\"24751727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biophysical basis of imbalance-induced aggregation not defined\", \"Site-specific regulation of K1 vs K2 pairing unaddressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reported a context-specific interaction with PTEN linking KRT10 to cisplatin-induced apoptosis in ovarian cancer cells.\",\n      \"evidence\": \"Co-immunoprecipitation with PTEN plus siRNA knockdown and proliferation/apoptosis assays\",\n      \"pmids\": [\"24434152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Relevance of an epidermal keratin in ovarian cancer not independently confirmed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided proof-of-concept that allele-specific disruption of dominant-negative KRT10 reverses the filament instability disease mechanism.\",\n      \"evidence\": \"TALEN editing of patient-derived keratinocytes with immunofluorescence and xenograft ultrastructure\",\n      \"pmids\": [\"30998984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab ex vivo demonstration\", \"Long-term in vivo efficacy and off-target risks not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified Tp63 as a direct transcriptional activator of KRT10 driving keratinocyte differentiation.\",\n      \"evidence\": \"ChIP of Tp63 on the KRT10 promoter with siRNA knockdown, qRT-PCR, and immunofluorescence\",\n      \"pmids\": [\"32168425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Additional transcriptional regulators of KRT10 not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reported a non-epidermal role in which KRT10 facilitates release of influenza viral RNPs from late endosomes via interaction with NS2.\",\n      \"evidence\": \"GST-pulldown/mass spectrometry with NS2, siRNA knockdown, colocalization, and endosomal pH assays\",\n      \"pmids\": [\"37406407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Mechanism by which KRT10 affects endosomal pH/fusion not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the structural and signaling functions of K10 are integrated—and the functional significance of nucleolar/non-epidermal localizations—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the K10 N-terminal domain bound to Akt/PKCζ\", \"Functional consequence of nucleolar mislocalization undefined\", \"Mechanistic links between K1/K10 filaments and desmosome/nuclear envelope proteins unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [8, 9, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KRT1\", \"KRT2\", \"AKT1\", \"PRKCZ\", \"PTEN\", \"TP63\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}