KRT8

Summary

KRT8 (keratin 8, HGNC:6446) is a protein-coding gene on chromosome 12q13.13, encoding Keratin, type II cytoskeletal 8 (P05787). Required for the formation of KRT8/KRT18 filaments that are involved in ARHGEF40-mediated actin stress fiber formation and tensional force-induced stress fiber formation and reinforcement. It is a selective cancer dependency (DepMap: 57.2% of cell lines).

This gene is a member of the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. The product of this gene typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells. This protein plays a role in maintaining cellular structural integrity and also functions in signal transduction and cellular differentiation. Mutations in this gene cause cryptogenic cirrhosis. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 3856 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cirrhosis, familial (Limited, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 102 total
• Cancer dependency (DepMap): dependent in 57.2% of screened cell lines
• MANE Select transcript: NM_002273

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6446
Approved symbol	KRT8
Name	keratin 8
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Aliases	CARD2, K8, CK8, CK-8, CYK8, K2C8, KO
Ensembl gene	ENSG00000170421
Ensembl biotype	protein_coding
OMIM	148060
Entrez	3856

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 43 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000293308, ENST00000546542, ENST00000546583, ENST00000546826, ENST00000546897, ENST00000546900, ENST00000546921, ENST00000547031, ENST00000547176, ENST00000548998, ENST00000549176, ENST00000549198, ENST00000550170, ENST00000551318, ENST00000552150, ENST00000552551, ENST00000619952, ENST00000692008, ENST00000871781, ENST00000871782, ENST00000871783, ENST00000871784, ENST00000871785, ENST00000871786, ENST00000871787, ENST00000871788, ENST00000871789, ENST00000871790, ENST00000871791, ENST00000871792, ENST00000871793, ENST00000871794, ENST00000871795, ENST00000871796, ENST00000871797, ENST00000871798, ENST00000930377, ENST00000930378, ENST00000930379, ENST00000930380, ENST00000930381, ENST00000930382, ENST00000930383, ENST00000930384, ENST00000930385, ENST00000946834, ENST00000946835, ENST00000946836, ENST00000946837, ENST00000946838, ENST00000946839

RefSeq mRNA: 3 — MANE Select: NM_002273 NM_001256282, NM_001256293, NM_002273

CCDS: CCDS58234, CCDS8841

Canonical transcript exons

ENST00000692008 — 8 exons

Exon	Start	End
ENSE00003491433	52899775	52900065
ENSE00003588283	52898679	52898899
ENSE00003629715	52901159	52901219
ENSE00003644454	52898461	52898519
ENSE00003681245	52901864	52902072
ENSE00003789984	52900588	52900683
ENSE00003925803	52904658	52905076
ENSE00003931516	52897191	52897618

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 99.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 68.1564 / max 462.8625, expressed in 1360 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131182	39.3087	895
131190	17.5432	1303
131189	5.7627	1118
131181	1.5579	396
131180	0.7288	207
131187	0.5922	271
131188	0.5552	366
206723	0.5142	152
131177	0.4116	97
131178	0.2891	102

Top tissues by expression

159 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.93	gold quality
endometrium epithelium	UBERON:0004811	99.81	gold quality
duodenum	UBERON:0002114	99.75	gold quality
rectum	UBERON:0001052	99.73	gold quality
placenta	UBERON:0001987	99.63	gold quality
islet of Langerhans	UBERON:0000006	99.62	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.51	gold quality
pancreas	UBERON:0001264	99.47	gold quality
body of pancreas	UBERON:0001150	99.43	gold quality
gall bladder	UBERON:0002110	99.27	gold quality
epithelium of bronchus	UBERON:0002031	99.17	gold quality
left lobe of thyroid gland	UBERON:0001120	99.09	gold quality
thyroid gland	UBERON:0002046	98.97	gold quality
trachea	UBERON:0003126	98.97	gold quality
right lobe of thyroid gland	UBERON:0001119	98.84	gold quality
right uterine tube	UBERON:0001302	98.82	gold quality
vermiform appendix	UBERON:0001154	98.61	gold quality
right coronary artery	UBERON:0001625	98.61	gold quality
liver	UBERON:0002107	98.59	gold quality
metanephros cortex	UBERON:0010533	98.55	gold quality
right lobe of liver	UBERON:0001114	98.51	gold quality
adult mammalian kidney	UBERON:0000082	98.38	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.36	gold quality
small intestine	UBERON:0002108	98.30	gold quality
body of stomach	UBERON:0001161	98.13	gold quality
stomach	UBERON:0000945	98.03	gold quality
mucosa of stomach	UBERON:0001199	97.90	gold quality
transverse colon	UBERON:0001157	97.76	gold quality
upper lobe of left lung	UBERON:0008952	97.76	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.73	gold quality

Single-cell (SCXA)

Detected in 55 experiment(s), a significant marker in 48.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	29261.77
E-MTAB-6701	yes	8559.72
E-GEOD-130473	yes	7663.30
E-MTAB-8410	yes	7000.17
E-MTAB-5061	yes	6450.56
E-MTAB-8495	yes	6028.52
E-MTAB-6678	yes	5169.19
E-CURD-88	yes	4516.83
E-MTAB-8205	yes	4404.60
E-CURD-122	yes	4370.63
E-HCAD-24	yes	4329.22
E-MTAB-6108	yes	3800.47
E-GEOD-114530	yes	3546.46
E-MTAB-10283	yes	3395.50
E-MTAB-10018	yes	3340.75

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, BCL11B, ELF3, ELK3, ETS1, ETS2, HOXB2, KAT7, KMT2A, LITAF, MSC, SNAI2, TP53

miRNA regulators (miRDB)

9 targeting KRT8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-219A-2-3P	98.62	68.78	797
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-7850-5P	98.12	67.28	1111
HSA-MIR-4776-5P	97.14	66.63	405

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 57.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• novel cytoplasmic substrate for c-Jun N-terminal kinase (PMID:11781324)
• phsophorylation by p38 kinase regulates cellular keratin filament reorganization (PMID:11788583)
• Cancer-associated cleavage of cytokeratin 8/18 heterotypic complexes exposes a neoepitope in human adenocarcinomas. (PMID:11923318)
• K8 cytokeratin has a relevant role during the differentiation and tridimensional organization of the sensory and the supporting cells of the auditory receptor (PMID:12168793)
• specific interaction of the periplakin linker domain with keratin 8 and vimentin (PMID:12366696)
• CK8 preferentially expressed in NSCLC; increasing values of CK8 significantly associated with tumor progression and decerased survival in NSCLC (PMID:12367790)
• Data show that deregulated expression of keratin 18, or an imbalance between keratin 8 and keratin 18, may be an important determinant of Mallory body formation. (PMID:12388748)
• A mutation in this protein predisposes to cryptogenic liver failure. (PMID:12474161)
• Mutation of this protein is a risk factor for liver disease of multiple etiologies. (PMID:12724528)
• CK 8/18 degradation products are detected specifically in breast cancer and may determine its aggressiveness (PMID:14556659)
• Aberrantly spliced CK8 (AS-CK8) that lacks caspases cleavage site identified in lung cancer cell lines and primary tumors of NSCLC. Suggests that cancer cells expressing AS-CK8 may have resistance to apoptosis and may perturb keratin network formation. (PMID:14568682)
• A 20-residue region (313-332) in the rod domain of K8 specifically recognized by A45-B/B3 monoclonal antibody undergoes a conformational change following interaction with keratin K18 and plays a role in stabilization of the keratin cytoskeleton. (PMID:14756564)
• keratin 8 mutations disturb filament assembly and have a role in inflammatory bowel disease (PMID:15090596)
• K8 and K18 remain associated in heteropolymeric aggregates during apoptosis. At later stages, when the integrity of the cytoplasmic membrane becomes compromised, keratin aggregates are shed from the cells. (PMID:15194421)
• A study of 1668 liver disease patients showed that there is no association between the KRT8 mutations Y54H and G62C and chronic liver disease. (PMID:15235035)
• Both keratin 8 mutations, G62C and Y54H, do not play a relevant pathogenic role in inflammatory bowel disease (Crohn’s disease and ulcerative colitis). (PMID:15248378)
• Increased expression of CK8 in some way changes the phenotypic characteristics of stratified epithelial cells, resulting in malignant transformation (PMID:15252834)
• K8 alters the epidermal cell differentiation, favors the neoplastic transformation of cells, and is ultimately responsible of the invasive behavior of transformed epidermal cells leading of conversion of benign to malignant tumors (PMID:15319370)
• Keratin hyperphosphorylation on most K8/18 sites in all cirrhotic liver explants tested and in most liver biopsies from patients with chronic hepatitis C. (PMID:15368451)
• K8 and K18 may be involved in the traffic of WT-CFTR/deltaF508-CFTR (PMID:15529338)
• trichoplein is a keratin 8/18-binding protein that may be involved in the organization of the apical network of keratin filaments and desmosomes in simple epithelial cells (PMID:15731013)
• SLUG levels in the cell regulated the function of cytokeratins 8 and 19 gene promoters. (PMID:15737616)
• the changes in cytokeratin 8/18 in hepatocytes might be one of the sources of pathogenesis of de novo autoimmune hepatitis after liver transplantation (PMID:15838910)
• shear stress mediates the phosphorylation of serine residues in K8, leading to the disassembly of intermediate filaments in alveolar epithelial cells (PMID:15972820)
• Variants can alter keratin solubility or phosphorylation and may render individuals susceptible to end-stage liver disease. (PMID:16143128)
• Cytoskeletal protein Keratin 8, and possibly other keratins with the conserved S73-containing phosphoepitope, can protect tissue from injury by serving as a phosphate “sponge” for stress-activated kinases (PMID:16818723)
• the cytokeratin 8 mutation G61C, which has been found to be associated with cryptogenic liver cirrhosis (PMID:16911694)
• Cytokeratin 8 and 18 were induced by ethanol treatment of E47 cells (cells over expressing) CYP2E1 and polyubiquitinated forms of these proteins were found in the polyubiquitin smear upon western blots analysis. (PMID:17034788)
• KRT8 sequence variants were studied in patients with pancreatitis and pancreatic neoplasms. (PMID:17039343)
• Together, the data indicate that a proper alignment/deposition of desmoplakin with keratins and desmoglein in hepatocytes requires keratin 8, through a reciprocal phosphoserine-dependent process. (PMID:17126832)
• keratin-8 has a role in interleukin-6-induced barrier function alterations (PMID:17213200)
• A novel but rare keratin-8 Arg341-to-Cys is identified in IBD patients. (PMID:17509943)
• Invasive ductal carcinomas of the breast align with the KRT8/18 staining phenotypes. (PMID:17954264)
• Findings strongly demonstrate that retinoblastoma (RB) and cyclin-dependent kinase 2 (CDK2) on one side and cytokeratin 8 (CK8) and epidermal growth factor receptor 2 (HER2) on the other may affect the clinical course of the disease in 56% of patients. (PMID:18236071)
• In Down Syndrome placentas, an inverse relationship between the expression levels of keratin-8 and TRAIL was observed. (PMID:18343496)
• Our findings implicate an underlying molecular mechanism in which CK8 is required for cisplatin resistance. (PMID:18353540)
• Keratin 8 was up-regulated in atherosclerotic radial artery vascular smooth cells. (PMID:18432282)
• Apoptosis causes extracellular release of full-length CK8 in non-small cell lung cancer(NSCLC) cells; CK8 circulates predominantly in full length in NSCLC patients, illustrating fundamental differences in protein processing between type I and type II CKs. (PMID:18497550)
• eIF3k, originally identified as the smallest subunit of eukaryotic translation initiation factor 3 (eIF3) complexes, also localizes to keratin intermediate filaments and physically associates with K18 in epithelial cells. (PMID:18577580)
• Co-expression of cytokeratin 8 and breast cancer resistant protein indicates a multifactorial drug-resistant phenotype in human breast cancer cell line. (PMID:18725232)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Krt8	ENSMUSG00000049382
rattus_norvegicus	Krt8	ENSRNOG00000009779
rattus_norvegicus		ENSRNOG00000065592

Paralogs (68): KRT33A (ENSG00000006059), VIM (ENSG00000026025), KRT31 (ENSG00000094796), NEFM (ENSG00000104722), KRT23 (ENSG00000108244), KRT37 (ENSG00000108417), KRT32 (ENSG00000108759), KRT18 (ENSG00000111057), LMNB1 (ENSG00000113368), KRT36 (ENSG00000126337), KRT17 (ENSG00000128422), GFAP (ENSG00000131095), KRT34 (ENSG00000131737), KRT33B (ENSG00000131738), NES (ENSG00000132688), PRPH (ENSG00000135406), KRT85 (ENSG00000135443), KRT7 (ENSG00000135480), KRT71 (ENSG00000139648), INA (ENSG00000148798), LMNTD1 (ENSG00000152936), LMNA (ENSG00000160789), KRT84 (ENSG00000161849), KRT82 (ENSG00000161850), KRT80 (ENSG00000167767), KRT1 (ENSG00000167768), KRT24 (ENSG00000167916), KRT78 (ENSG00000170423), KRT86 (ENSG00000170442), KRT75 (ENSG00000170454), KRT6C (ENSG00000170465), KRT4 (ENSG00000170477), KRT74 (ENSG00000170484), KRT72 (ENSG00000170486), KRT83 (ENSG00000170523), BFSP2 (ENSG00000170819), KRT19 (ENSG00000171345), KRT15 (ENSG00000171346), KRT38 (ENSG00000171360), KRT13 (ENSG00000171401)

Protein

Protein identifiers

Keratin, type II cytoskeletal 8 — P05787 (reviewed: P05787)

Alternative names: Cytokeratin-8, Keratin-8, Type-II keratin Kb8

All UniProt accessions (7): P05787, A0A0U1RQU6, F8VP67, F8VQY3, F8VUG2, F8W1U3, H0YIB2

UniProt curated annotations — full annotation on UniProt →

Function. Required for the formation of KRT8/KRT18 filaments that are involved in ARHGEF40-mediated actin stress fiber formation and tensional force-induced stress fiber formation and reinforcement. Together with KRT19, helps to link the contractile apparatus to dystrophin at the costameres of striated muscle.

Subunit / interactions. Heterotetramer of two type I and two type II keratins. Forms a heterodimer with KRT18. Associates with KRT20. Interacts with PLEC isoform 1C, when in a heterodimer with KRT18. Interacts with PNN. When associated with KRT19, interacts with DMD. Interacts with TCHP. Interacts with APEX1. Interacts with GPER1. Interacts with EPPK1. Interacts with PKP1 and PKP2. (Microbial infection) Interacts with hepatitis C virus/HCV core protein.

Subcellular location. Cytoplasm. Nucleus. Nucleoplasm. Nucleus matrix. Cytoskeleton.

Tissue specificity. Observed in muscle fibers accumulating in the costameres of myoplasm at the sarcolemma membrane in structures that contain dystrophin and spectrin. Expressed in gingival mucosa and hard palate of the oral cavity.

Post-translational modifications. Phosphorylation on serine residues is enhanced during EGF stimulation and mitosis. Ser-74 phosphorylation plays an important role in keratin filament reorganization. O-glycosylated. O-GlcNAcylation at multiple sites increases solubility, and decreases stability by inducing proteasomal degradation. O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.

Disease relevance. Cirrhosis (CIRRH) [MIM:215600] A liver disease characterized by severe panlobular liver-cell swelling with Mallory body formation, prominent pericellular fibrosis, and marked deposits of copper. Clinical features include abdomen swelling, jaundice and pulmonary hypertension. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. There are two types of cytoskeletal and microfibrillar keratin: I (acidic; 40-55 kDa) and II (neutral to basic; 56-70 kDa).

Similarity. Belongs to the intermediate filament family.

Isoforms (2)

UniProt ID	Names	Canonical?
P05787-1	1	yes
P05787-2	2

RefSeq proteins (3): NP_001243211, NP_001243222, NP_002264* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003054	Keratin_II	Family
IPR018039	IF_conserved	Conserved_site
IPR032444	Keratin_2_head	Domain
IPR039008	IF_rod_dom	Domain

Pfam: PF00038, PF16208

UniProt features (92 total): modified residue 39, cross-link 13, sequence conflict 13, region of interest 9, sequence variant 7, mutagenesis site 3, compositionally biased region 2, strand 2, chain 1, domain 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7K3C	X-RAY DIFFRACTION	1.1
7K3Y	X-RAY DIFFRACTION	1.1
7K3X	X-RAY DIFFRACTION	1.71

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05787-F1	76.13	0.54

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 342 (stutter)

Post-translational modifications (52): 9, 13, 15, 21, 22, 23, 24, 26, 27, 31, 32, 34, 37, 39, 40, 43, 44, 47, 47, 74 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
72	increases phosphorylation.
74	generates normal-appearing filaments, that remain stable after okadaic acid treatment.
74	generates normal-appearing filaments, that are destabilized by okadaic acid.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6805567	Keratinization
R-HSA-6809371	Formation of the cornified envelope
R-HSA-9927418	Developmental Lineage of Mammary Gland Luminal Epithelial Cells
R-HSA-9927426	Developmental Lineage of Mammary Gland Alveolar Cells
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 302 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, AP1_01, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GU_PDEF_TARGETS_DN, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_RESPONSE_TO_PEPTIDE, ENK_UV_RESPONSE_KERATINOCYTE_UP, GCANCTGNY_MYOD_Q6, AREB6_03, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, AREB6_01, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_SARCOMERE_ORGANIZATION, ONDER_CDH1_TARGETS_3_DN, GOBP_CELL_DIFFERENTIATION_INVOLVED_IN_EMBRYONIC_PLACENTA_DEVELOPMENT

GO Biological Process (5): tumor necrosis factor-mediated signaling pathway (GO:0033209), response to other organism (GO:0051707), cell differentiation involved in embryonic placenta development (GO:0060706), extrinsic apoptotic signaling pathway (GO:0097191), hepatocyte apoptotic process (GO:0097284)

GO Molecular Function (2): scaffold protein binding (GO:0097110), protein binding (GO:0005515)

GO Cellular Component (14): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), intermediate filament (GO:0005882), cell-cell junction (GO:0005911), apicolateral plasma membrane (GO:0016327), nuclear matrix (GO:0016363), Z disc (GO:0030018), sarcolemma (GO:0042383), keratin filament (GO:0045095), intermediate filament cytoskeleton (GO:0045111), extracellular exosome (GO:0070062), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Developmental Lineages of the Mammary Gland	2
Developmental Biology	1
Keratinization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
nuclear lumen	2
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
response to external biotic stimulus	1
biological process involved in interspecies interaction between organisms	1
embryonic placenta development	1
developmental process involved in reproduction	1
cell differentiation	1
cell surface receptor signaling pathway	1
apoptotic signaling pathway	1
epithelial cell apoptotic process	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
intermediate filament cytoskeleton	1
polymeric cytoskeletal fiber	1
anchoring junction	1
plasma membrane region	1
I band	1
plasma membrane	1
intermediate filament	1
cytoskeleton	1
extracellular vesicle	1

Protein interactions and networks

STRING

3122 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KRT8	KRT18	P05783	986
KRT8	SQSTM1	Q13501	782
KRT8	EPCAM	P16422	761
KRT8	DSP	P15924	752
KRT8	PLEC	Q15149	731
KRT8	TP53	P04637	727
KRT8	LIAT1	Q6ZQX7	720
KRT8	EGFR	P00533	708
KRT8	TNFRSF1B	P20333	708
KRT8	CDH1	P12830	703
KRT8	DEDD2	Q8WXF8	668
KRT8	ACTB	P02570	662
KRT8	PLG	P00747	647
KRT8	CD24	P25063	630
KRT8	SYP	P08247	621
KRT8	PTPRC	P08575	621

IntAct

223 interactions, top by confidence:

A	B	Type	Score
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
KRT8	KRT18	psi-mi:“MI:0915”(physical association)	0.940
KRT18	KRT8	psi-mi:“MI:0915”(physical association)	0.940
KRT18	KRT8	psi-mi:“MI:0403”(colocalization)	0.940
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
KRT38	KRT8	psi-mi:“MI:0915”(physical association)	0.780
KRT8	KRT38	psi-mi:“MI:0915”(physical association)	0.780
KRT15	KRT8	psi-mi:“MI:0915”(physical association)	0.720
KRT31	KRT8	psi-mi:“MI:0915”(physical association)	0.720
KRT8	KRT40	psi-mi:“MI:0915”(physical association)	0.720
KRT8	KRT31	psi-mi:“MI:0915”(physical association)	0.720
KRT40	KRT8	psi-mi:“MI:0915”(physical association)	0.720
KRT8	KRT15	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710

BioGRID (570): KRT13 (Two-hybrid), KRT15 (Two-hybrid), KRT31 (Two-hybrid), KRT38 (Two-hybrid), TFIP11 (Two-hybrid), KRT40 (Two-hybrid), KRT8 (Affinity Capture-MS), KRT8 (Affinity Capture-MS), CAV1 (Co-fractionation), KRT8 (Reconstituted Complex), KRT8 (Biochemical Activity), KRT8 (Affinity Capture-MS), KRT8 (Affinity Capture-Western), KRT8 (Affinity Capture-MS), KRT8 (Affinity Capture-MS)

ESM2 similar proteins: A1KQY9, A1L595, A5A6M0, A6QQQ9, O57607, O57611, O77727, O93256, P02533, P05781, P05783, P05784, P05786, P05787, P08727, P08728, P08730, P08776, P08777, P08778, P08802, P11679, P19001, P19012, P25030, P35900, P51856, Q04695, Q07427, Q10758, Q5BJY9, Q5K2N3, Q5K2N9, Q5K2P6, Q5R8S9, Q61414, Q63279, Q6IFU7, Q6IFU8, Q6IFV1

Diamond homologs: A0A8C0N8E3, A5A6M8, A5A6N0, A6QQJ3, B4F721, O62654, O77788, O93532, O95678, P02538, P02540, P02541, P02542, P02543, P02544, P02547, P02548, P03995, P04259, P05786, P05787, P07196, P07197, P08551, P08552, P08553, P08670, P08729, P08776, P09654, P11679, P12035, P12036, P12839, P13647, P14136, P15331, P16053, P16878, P16884

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
MAPK8	up-regulates	KRT8	phosphorylation
MAPK11	up-regulates	KRT8	phosphorylation
MAPK12	up-regulates	KRT8	phosphorylation
MAPK13	up-regulates	KRT8	phosphorylation
MAPK14	up-regulates	KRT8	phosphorylation
MAPK3	unknown	KRT8	phosphorylation
PTP4A3	“down-regulates activity”	KRT8	dephosphorylation
PPP2CB	unknown	KRT8	dephosphorylation
PPP2CA	unknown	KRT8	dephosphorylation
PRKCD	up-regulates	KRT8	phosphorylation
PTPN1	“down-regulates activity”	KRT8	dephosphorylation
p38	up-regulates	KRT8	phosphorylation
CDK1	up-regulates	KRT8	phosphorylation
MAPK1	unknown	KRT8	phosphorylation
Gbeta	unknown	KRT8	phosphorylation
ERK1/2	unknown	KRT8	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	7	63.4×	8e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	56.0×	2e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	56.0×	2e-09
Activation of BH3-only proteins	7	41.4×	2e-08
RHO GTPases activate PKNs	7	26.4×	4e-07
Intrinsic Pathway for Apoptosis	7	24.4×	6e-07
FOXO-mediated transcription	5	20.0×	1e-04
Formation of the cornified envelope	17	17.8×	2e-14

GO biological processes:

GO term	Partners	Fold	FDR
morphogenesis of an epithelium	16	52.4×	2e-21
intermediate filament organization	19	43.6×	1e-23
epithelial cell differentiation	15	25.1×	8e-15
protein targeting	5	17.4×	2e-03
intracellular protein localization	9	9.0×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

102 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	13
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

1495 predictions. Top by Δscore:

Variant	Effect	Δscore
12:52897615:CCAC:C	acceptor_gain	1.0000
12:52897616:CACC:C	acceptor_gain	1.0000
12:52897622:G:GC	acceptor_gain	1.0000
12:52898671:ACAC:A	donor_gain	1.0000
12:52898672:CA:C	donor_gain	1.0000
12:52898672:CACC:C	donor_gain	1.0000
12:52898678:CCGG:C	donor_gain	1.0000
12:52898685:T:A	donor_gain	1.0000
12:52898691:C:CA	donor_gain	1.0000
12:52898700:AGCTT:A	donor_gain	1.0000
12:52898704:T:A	donor_gain	1.0000
12:52898895:GCCCT:G	acceptor_gain	1.0000
12:52898896:CCCT:C	acceptor_gain	1.0000
12:52898896:CCCTC:C	acceptor_gain	1.0000
12:52898897:CCTC:C	acceptor_gain	1.0000
12:52898898:CT:C	acceptor_gain	1.0000
12:52898900:C:CC	acceptor_gain	1.0000
12:52898900:CTGTG:C	acceptor_loss	1.0000
12:52898902:G:C	acceptor_gain	1.0000
12:52898907:G:C	acceptor_gain	1.0000
12:52898907:G:GC	acceptor_gain	1.0000
12:52899769:CCATA:C	donor_loss	1.0000
12:52899772:TAC:T	donor_loss	1.0000
12:52899773:A:AC	donor_gain	1.0000
12:52899773:ACC:A	donor_loss	1.0000
12:52899774:C:CA	donor_loss	1.0000
12:52899774:C:CC	donor_gain	1.0000
12:52899799:AG:A	donor_gain	1.0000
12:52900061:ATCTC:A	acceptor_gain	1.0000
12:52900063:CTC:C	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000026319 (12:52942062 C>G), RS1000109664 (12:52932950 G>A), RS1000110203 (12:52935620 T>A,C), RS1000142820 (12:52934883 C>T), RS1000218800 (12:52903624 G>C), RS1000243972 (12:52912738 A>G), RS1000380966 (12:52939516 T>C,G), RS1000456432 (12:52926072 AG>A), RS1000465287 (12:52945311 C>T), RS1000566070 (12:52917163 G>A), RS1000713621 (12:52911347 G>A), RS1000812886 (12:52902444 C>G), RS1000824320 (12:52905086 T>A,C), RS1000875249 (12:52903596 G>A), RS1000891990 (12:52920440 A>C,T)

Disease associations

OMIM: gene MIM:148060 | disease phenotypes: MIM:609532, MIM:266600

GenCC curated gene-disease

Disease	Classification	Inheritance
cirrhosis, familial	Limited	Autosomal recessive

Mondo (3): hepatitis C virus, susceptibility to (MONDO:0012292), inflammatory bowel disease (MONDO:0005265), cirrhosis, familial (MONDO:0007329)

Orphanet (1): Rare inflammatory bowel disease (Orphanet:104012)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001147_14	Prostate cancer	5.000000e-09
GCST003588_16	Cancer (pleiotropy)	2.000000e-15
GCST006019_37	Gamma glutamyl transferase levels	7.000000e-09
GCST011352_2	Alanine aminotransferase levels	5.000000e-08
GCST011360_2	Sick sinus syndrome	9.000000e-14
GCST012222_7	Opioid dependence (time to event)	7.000000e-07
GCST90002396_526	Mean reticulocyte volume	2.000000e-09
GCST90011898_17	Alanine aminotransferase levels	1.000000e-08
GCST90011899_17	Aspartate aminotransferase levels	2.000000e-10
GCST90013663_69	Alanine aminotransferase levels	2.000000e-08
GCST90013664_99	Aspartate aminotransferase levels	1.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:1001515	ovarian endometrioid carcinoma
EFO:1001516	ovarian serous carcinoma
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0010701	mean reticulocyte volume
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D015212	Inflammatory Bowel Diseases	C06.405.205.731; C06.405.469.432
C566123	Cirrhosis, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

108 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	7
sodium arsenite	affects cotreatment, increases abundance, increases expression, affects binding, increases reaction (+1 more)	6
trichostatin A	affects cotreatment, increases expression, affects expression, decreases expression	4
Arsenic	decreases expression, affects cotreatment, increases abundance	4
Estradiol	decreases reaction, increases expression, increases activity, increases reaction, affects cotreatment (+1 more)	4
Particulate Matter	increases abundance, increases expression, decreases expression, decreases reaction	4
Arsenic Trioxide	decreases expression, increases expression, decreases response to substance	3
Air Pollutants	decreases expression, increases abundance, increases expression	3
Benzo(a)pyrene	decreases methylation, increases expression	3
Smoke	decreases expression, increases abundance, increases expression, increases metabolic processing	3
Tretinoin	increases expression	3
methylmercuric chloride	decreases expression, increases expression	2
bisphenol A	increases expression, affects expression	2
mercuric bromide	increases expression, affects cotreatment	2
U 0126	increases phosphorylation, decreases reaction	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
4-(1H-imidazol-1-yl)retinoic acid	increases expression	2
Temozolomide	increases expression, affects response to substance	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	increases expression, decreases expression	2
Acrolein	increases metabolic processing, increases phosphorylation	2
Doxorubicin	affects expression, increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Quercetin	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Metribolone	increases expression	2
Genistein	decreases expression, increases expression, increases reaction	2
p-Chloromercuribenzoic Acid	increases expression, affects cotreatment	2
aristolochic acid I	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1VD	Abcam HeLa KRT8 KO	Cancer cell line	Female
CVCL_SV10	HAP1 KRT8 (-) 1	Cancer cell line	Male
CVCL_SV11	HAP1 KRT8 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

302 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00167882	PHASE4	COMPLETED	The Influence of 5-Aminosalicylates on Thiopurine Metabolite Levels
NCT00205062	PHASE4	TERMINATED	Positron Emission Tomography (PET)-Computed Tomography (CT) in Inflammatory Bowel Disease (IBD)
NCT00567593	PHASE4	COMPLETED	Gene Regulation by Thiazolidinediones
NCT00746395	PHASE4	COMPLETED	Randomized, Placebo-controlled Trial of Lubiprostone as a Preparation for Capsule Endoscopy
NCT01034358	PHASE4	COMPLETED	Immune Response to the Human Papillomavirus Vaccine in Young Women With Inflammatory Bowel Disease
NCT01056913	PHASE4	COMPLETED	NITI CAR27 (ColonRing) Compression Anastomosis in Colorectal Surgery
NCT01067547	PHASE4	COMPLETED	A Trial of Iron Replacement in Patients With Iron Deficiency.
NCT01341808	PHASE4	COMPLETED	Immunogenicity of Hepatitis A Vaccine in Inflammatory Bowel Disease (IBD) Patients
NCT01908283	PHASE4	COMPLETED	Induction of Immunity Against Streptococcus Pneumoniae in Adults With Inflammatory Bowel Disease
NCT01934088	PHASE4	COMPLETED	Satisfaction With Nurse Administered Propofol Sedation vs. Midazolam With Fentanyl Sedation for Endoscopy
NCT02162862	PHASE4	COMPLETED	Treating Disrupted Sleep in Individuals With Inflammatory Bowel Disease
NCT02248337	PHASE4	COMPLETED	Low Volume Colon Preparation for IBD
NCT02281799	PHASE4	WITHDRAWN	Thiopurine Induced Pancreatitis in IBD Patients
NCT02392286	PHASE4	TERMINATED	Corticosteroid Dosage for Crohn’s Disease Flare
NCT02437591	PHASE4	COMPLETED	Study to Evaluate the Pharmacokinetics of Fidaxomicin in Inflammatory Bowel Disease (IBD) Subjects With Clostridium Difficile Infection (CDI)
NCT02453776	PHASE4	COMPLETED	Precision Dosing of Infliximab Versus Conventional Dosing of Infliximab
NCT02461758	PHASE4	COMPLETED	Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory Bowel Disease Patients
NCT02566889	PHASE4	TERMINATED	An Efficacy and Safety Study of Infliximab Dose Escalation in Pediatric Participants With Inflammatory Bowel Disease
NCT02774057	PHASE4	UNKNOWN	Trial of Captafer® vs. Oral Iron Sulfate in the Treatment of Iron Deficiency Anemia in Patients With IBD
NCT02806206	PHASE4	UNKNOWN	Prucalopride Prior to Small Bowel Capsule Endoscopy
NCT02946203	PHASE4	COMPLETED	Comparison of VoLumen and Breeza Oral Contrast Agents in Pediatric Patients
NCT02994836	PHASE4	COMPLETED	GIS-SUSANTI-TNF-2015 (Anti-TNF Discontinuation )
NCT03220841	PHASE4	UNKNOWN	Stricture Definition and Treatment (STRIDENT) Drug Therapy Study
NCT03351972	PHASE4	COMPLETED	Differences in Preparation for Small Bowel Capsule Endoscopy
NCT03466983	PHASE4	COMPLETED	A Trial Comparing the Incidence of Hypophosphatemia in Relation to Treatment With Iron Isomaltoside and Ferric Carboxymaltose in Subjects With Iron Deficiency Anaemia Due to Inflammatory Bowel Disease
NCT03591770	PHASE4	TERMINATED	Shingrix Vaccine in Patients With Moderate to Severe Ulcerative Colitis on Tofacitinib
NCT03629379	PHASE4	COMPLETED	Response to Ustekinumab for Anti-tnf Induced Psoriasiform Skin Lesions
NCT03723447	PHASE4	COMPLETED	Intraoperative TAP Block With Bupivacaine/Dexamethasone Against Liposomal Bupivacaine (Exparel®)
NCT03798691	PHASE4	COMPLETED	Immunogenicity of Herpes Zoster Subunit Vaccine in Inflammatory Bowel Disease Patients Treated With Vedolizumab
NCT03860012	PHASE4	UNKNOWN	Folic Acid in Pediatric Inflammatory Bowel Disease
NCT03885713	PHASE4	COMPLETED	Identification of Predictive Biomarkers for Response to Biologic Therapies and Tofacitinib in Inflammatory Bowel Disease
NCT03917303	PHASE4	RECRUITING	Control Crohn Safe Trial
NCT04045782	PHASE4	COMPLETED	Evaluation of the Safety and Effectiveness of Switching From Humira® to Imraldi® in Flanders
NCT04304950	PHASE4	COMPLETED	Chronotherapy in Inflammatory Bowel Disease
NCT04626947	PHASE4	TERMINATED	Prevention of Recurrent Clostridium Difficile Infection (CDI) in Patients With Inflammatory Bowel Disease (IBD).
NCT04646187	PHASE4	ENROLLING_BY_INVITATION	De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
NCT04835506	PHASE4	ACTIVE_NOT_RECRUITING	Proactive Infliximab Optimization Using a Pharmacokinetic Dashboard Versus Standard of Care in Patients With Inflammatory Bowel Disease: The OPTIMIZE Trial
NCT04982172	PHASE4	COMPLETED	Model-informed Dose De-escalation of Infliximab in Patients With Inflammatory Bowel Diseases
NCT05180175	PHASE4	COMPLETED	The Nordic IBD Treatment Strategy Trial
NCT05280405	PHASE4	UNKNOWN	Early Proactive Therapeutic Drug Monitoring of Infliximab in Children: EPIC Study