KRT18

Summary

KRT18 (keratin 18, HGNC:6430) is a protein-coding gene on chromosome 12q13.13, encoding Keratin, type I cytoskeletal 18 (P05783). 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.

KRT18 encodes the type I intermediate filament chain keratin 18. Keratin 18, together with its filament partner keratin 8, are perhaps the most commonly found members of the intermediate filament gene family. They are expressed in single layer epithelial tissues of the body. Mutations in this gene have been linked to cryptogenic cirrhosis. Two transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 3875 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cirrhosis, familial (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 77 total
• Phenotypes (HPO): 16
• Druggable target: yes
• MANE Select transcript: NM_000224

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6430
Approved symbol	KRT18
Name	keratin 18
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111057
Ensembl biotype	protein_coding
OMIM	148070
Entrez	3875

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 19 protein_coding, 4 retained_intron

ENST00000388835, ENST00000388837, ENST00000546656, ENST00000548015, ENST00000548496, ENST00000549078, ENST00000550600, ENST00000872037, ENST00000872038, ENST00000872039, ENST00000872040, ENST00000872041, ENST00000872042, ENST00000872043, ENST00000930587, ENST00000930588, ENST00000930589, ENST00000930590, ENST00000930591, ENST00000930592, ENST00000930593, ENST00000946970, ENST00000946971

RefSeq mRNA: 2 — MANE Select: NM_000224 NM_000224, NM_199187

CCDS: CCDS31809

Canonical transcript exons

ENST00000388835 — 7 exons

Exon	Start	End
ENSE00000745901	52952119	52952342
ENSE00001700293	52950328	52950410
ENSE00002335324	52952722	52952906
ENSE00002411645	52949118	52949590
ENSE00003502582	52951481	52951645
ENSE00003562882	52950750	52950906
ENSE00003667903	52951731	52951856

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 99.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1038.0499 / max 23149.0607, expressed in 1433 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125670	1024.2841	1389
125677	4.6594	536
125669	4.3912	1105
125674	2.2901	369
125671	1.2419	265
125675	0.4991	149
125676	0.4150	140
125673	0.2691	112

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	99.99	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.74	gold quality
colonic mucosa	UBERON:0000317	99.72	gold quality
ileal mucosa	UBERON:0000331	99.66	gold quality
mucosa of transverse colon	UBERON:0004991	99.60	gold quality
rectum	UBERON:0001052	99.44	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.43	gold quality
body of pancreas	UBERON:0001150	99.41	gold quality
parotid gland	UBERON:0001831	99.40	gold quality
placenta	UBERON:0001987	99.38	gold quality
islet of Langerhans	UBERON:0000006	99.34	gold quality
nasal cavity epithelium	UBERON:0005384	99.32	gold quality
right uterine tube	UBERON:0001302	99.08	gold quality
metanephros cortex	UBERON:0010533	99.04	gold quality
duodenum	UBERON:0002114	99.02	gold quality
pancreas	UBERON:0001264	98.98	gold quality
nasal cavity mucosa	UBERON:0001826	98.97	gold quality
gall bladder	UBERON:0002110	98.93	gold quality
left lobe of thyroid gland	UBERON:0001120	98.89	gold quality
amniotic fluid	UBERON:0000173	98.83	gold quality
germinal epithelium of ovary	UBERON:0001304	98.79	gold quality
trachea	UBERON:0003126	98.74	gold quality
epithelium of bronchus	UBERON:0002031	98.70	gold quality
bronchus	UBERON:0002185	98.69	gold quality
right lobe of thyroid gland	UBERON:0001119	98.67	gold quality
right lobe of liver	UBERON:0001114	98.59	gold quality
jejunal mucosa	UBERON:0000399	98.57	gold quality
thyroid gland	UBERON:0002046	98.57	gold quality
bronchial epithelial cell	CL:0002328	98.54	gold quality
saliva-secreting gland	UBERON:0001044	98.35	gold quality

Single-cell (SCXA)

Detected in 51 experiment(s), a significant marker in 48.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	11826.75
E-MTAB-10018	yes	11038.00
E-HCAD-13	yes	10601.03
E-MTAB-8410	yes	9790.36
E-GEOD-81547	yes	9353.40
E-GEOD-114530	yes	6135.04
E-MTAB-8530	yes	5835.36
E-CURD-126	yes	5694.91
E-MTAB-6108	yes	5503.87
E-GEOD-124472	yes	5171.71
E-CURD-122	yes	4982.12
E-MTAB-6678	yes	4883.50
E-CURD-88	yes	4530.99
E-MTAB-9906	yes	4498.47
E-MTAB-10283	yes	4169.32

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, BRCA1, CTBP1, ESR1, FOS, HNF1B, JUN, JUNB, SP1

Literature-anchored findings (GeneRIF, showing 40)

• Cancer-associated cleavage of cytokeratin 8/18 heterotypic complexes exposes a neoepitope in human adenocarcinomas. (PMID:11923318)
• non-small cell lung carcinoma subtypes have specific patterns of desmoplakin 1 and 2 and cytokeratin 18 gene expression, protein content and biodistribution (PMID:11955647)
• 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)
• K18 mutation and its consequent keratin filament disruption predispose hepatocytes to Fas- but not TNF-mediated apoptotic injury. (PMID:12717381)
• 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)
• The expression of green fluorescent protein-tagged cytokeratin18 arg89cys induced aggregations and loss of the intermediate filament network composed of cytokeratins in liver-derived epithelial cells. (PMID:14648556)
• CYK18 has a role in suppressing breast cancer progression (PMID:15102669)
• 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)
• The detection of CK18 neoepitope M30 in the serum might be a useful marker in tracing apoptotic epithelium in septic patients. (PMID:15316390)
• Data show that the host intermediate filament protein cytokeratin 18 (CK18) is an interacting partner of EspF during enteropathogenic Escherichia coli (EPEC) pathogenesis. (PMID:15339273)
• 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)
• results lead to conclusion that, in colon epithelial cells, the expression level of the K18 gene is kept in check by a repression mechanism involving CtBP1, HDAC & BRCA1; mechanism is altered in SW613-S colon carcinoma cells that overexpress the K18 gene (PMID:15831101)
• 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)
• findings show that Ese-2 upregulates K18 gene expression through specific interactions within ETS binding sites in the regulatory first intron of the gene (PMID:15987600)
• keratin 18 (K18) expression in tumor cells is associated with reduced invasiveness in vitro. (PMID:16046547)
• Variants can alter keratin solubility or phosphorylation and may render individuals susceptible to end-stage liver disease. (PMID:16143128)
• CK18-mRNA is preserved through metaplasia, and metaplastic squamous cells differentiate with a decrease of CK18 and an increase of CK13 expression. (PMID:16836912)
• 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)
• Squamous cell carcinoma (SCC) in mature cystic teratoma (MCT) expressed CK10 less frequently, but CK18 more frequently. SCC in MCT may be derived from metaplastic squamous epithelium. (PMID:17542994)
• Docetaxel induced increased levels of caspase-cleaved CK18 in serum from breast cancer patients, indicating apoptosis (PMID:17545523)
• study demonstrates that the dominant mutation hK18 R89C, that is highly similar to hK14 R125C, causing epidermolysis bullosa in humans, leads to cell type-specific lethality in mice, depending on the ratio of mutant to endogenous keratins (PMID:17617404)
• Better basal gene expression was observed by co-cultured respiratory epithelial cells compared to dispase dissociated cells. (PMID:17891046)
• Invasive ductal carcinomas of the breast align with the KRT8/18 staining phenotypes. (PMID:17954264)
• Knockdown the plectin mRNA in Chang cells altered the organization of cytokeratin18. (PMID:18038249)
• Keratin absence or mutation is well tolerated after pancreatic but not liver injury, whereas excessive overexpression is toxic to the pancreas but not the liver when induced under basal conditions. (PMID:18349119)
• Keratin 18 was up-regulated in atherosclerotic radial artery vascular smooth cells. (PMID:18432282)
• CK18 is expressed in gallbladder epithelial cells. The levels of total CK18, as well as caspase-cleaved CK18, do not seem to differ between active and inactive chronic cholecystitis. (PMID:18460214)
• 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)
• Micrometastases of gastric cancer can be detected in circulating peripheral blood using quantitative real-time RT-PCR. CK19 is a better marker than CK18, CK20 and CEA. (PMID:18705345)
• expression of histone 3 is highly related to modulation of cytokeratin 18 and might play an important role in tumorigenesis of hepatocellular carcinoma (PMID:18712172)
• gene expression of krt8, krt18, and krt19 and correlation with gene expression profiles and cell differentiation are compared in human and mouse embryonic stem cells (PMID:18941637)
• Human eccrine sweat glands express CK7, CK8, CK14, CK18, CK19, CEA, EMA, Ki67, p63, EGF and EGFR. In skin, CEA can be used as a specific immunological marker of sweat glands. (PMID:19032382)
• silencing CK18 by transient RNAi, inhibits intracellular multiplication of the Y and CL strain of T. cruzi in HeLa cells, but not trypanosome binding and invasion (PMID:19087356)
• Shear stress affects on keratin intermediate filament were accompanied by the disappearance of most keratin particles and by increased phosphorylation of K8 and K18, which were closely associated with KIFs (PMID:19246484)
• Elevated serum levels of the caspase-cleaved fragment in patients with locally advanced head and neck tumors (PMID:19249390)
• CK18-Asp396 {a caspase-degraded product of CK18} and total CK18 levels in the circulation of colorectal cancer patients are predictive of tumor progression and prognosis and might be helpful for treatment selection and monitoring of these patients. (PMID:19302716)
• Data suggest that shear stress mediates the phosphorylation of K18pSer33, which is required for the reorganization of the KIF network, resulting in changes in mechanical properties of the cell that help maintain the integrity of alveolar epithelial cells. (PMID:19357195)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Krt18	ENSMUSG00000023043
rattus_norvegicus	Krt18l1	ENSRNOG00000047393
rattus_norvegicus	Krt18	ENSRNOG00000069468

Paralogs (68): KRT33A (ENSG00000006059), VIM (ENSG00000026025), KRT31 (ENSG00000094796), NEFM (ENSG00000104722), KRT23 (ENSG00000108244), KRT37 (ENSG00000108417), KRT32 (ENSG00000108759), 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), KRT8 (ENSG00000170421), 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 I cytoskeletal 18 — P05783 (reviewed: P05783)

Alternative names: Cell proliferation-inducing gene 46 protein, Cytokeratin-18, Keratin-18

All UniProt accessions (2): P05783, F8VZY9

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. Also acts downstream of ROCK kinase activation as part of a positive feedback mechanism in response to cellular mechanical stress loading. Organization and orientation of KRT18 filaments are responsible for the properly elongated morphology of epithelial tubules. Involved in the uptake of thrombin-antithrombin complexes by hepatic cells. When phosphorylated, plays a role in filament reorganization. Involved in the delivery of mutated CFTR to the plasma membrane. Together with KRT8, is involved in interleukin-6 (IL-6)-mediated barrier protection.

Subunit / interactions. Heterotetramer of two type I and two type II keratins. KRT18 associates with KRT8. Interacts with PLEC isoform 1C, when in a heterodimer with KRT8. Interacts with the thrombin-antithrombin complex. Interacts with PNN and mutated CFTR. Interacts with YWHAE, YWHAH and YWHAZ only when phosphorylated. Interacts with DNAJB6, TCHP and TRADD. Interacts with FAM83H. Interacts with EPPK1. Interacts with PKP1 and PKP2. KRT8/KRT18 heterodimers interact with ARHGEF40 (via N-terminal, central and C-terminal domains). The interaction facilitates actin stress fiber formation, force-induced stress fiber reinforcement and organization of KRT8/KRT18 networks. (Microbial infection) Interacts with hepatitis C virus/HCV core protein.

Subcellular location. Nucleus matrix. Cytoplasm. Perinuclear region. Nucleus. Nucleolus.

Tissue specificity. Expressed in colon, placenta, liver and very weakly in exocervix. Increased expression observed in lymph nodes of breast carcinoma.

Post-translational modifications. Phosphorylation at Ser-34 increases during mitosis. Hyperphosphorylated at Ser-53 in diseased cirrhosis liver. Phosphorylation increases by IL-6. Proteolytically cleaved by caspases during epithelial cell apoptosis. Cleavage occurs at Asp-238 by either caspase-3, caspase-6 or caspase-7. O-GlcNAcylation increases solubility, and decreases stability by inducing proteasomal degradation.

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.

Induction. By IL6/interleukin-6.

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.

RefSeq proteins (2): NP_000215, NP_954657 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002957	Keratin_I	Family
IPR018039	IF_conserved	Conserved_site
IPR039008	IF_rod_dom	Domain

Pfam: PF00038

UniProt features (86 total): modified residue 31, mutagenesis site 18, region of interest 10, cross-link 7, sequence conflict 6, sequence variant 5, site 3, glycosylation site 3, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05783-F1	80.18	0.58

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 (3): 238–239 (cleavage; by caspase-3, caspase-6 or caspase-7); 271 (stutter); 331 (stutter)

Post-translational modifications (38): 2, 7, 10, 15, 18, 30, 31, 34, 36, 42, 45, 49, 51, 52, 53, 55, 60, 65, 93, 100 …

Glycosylation sites (3): 30, 31, 49

Mutagenesis-validated functional residues (18):

Position	Phenotype
2	no effect on phosphorylation; when associated with a-7 and a-10.
7	no effect on phosphorylation; when associated with a-2 and a-10.
10	no effect on phosphorylation; when associated with a-2 and a-7.
15	no effect on phosphorylation; when associated with a-18 and a-23. abolishes phosphorylation; when associated with a-18;
18	no effect on phosphorylation; when associated with a-15 and a-23. abolishes phosphorylation; when associated with a-15;
23	no effect on phosphorylation; when associated with a-15 and a-18.
30	no effect on phosphorylation; when associated with a-31 and a-34, or with a-31; a-44 and a-51. abolishes glycosylation b
31	no effect on phosphorylation; when associated with a-30 and a-34, or with a-30; a-44 and a-51. abolishes glycosylation b
34	no effect on phosphorylation; when associated with a-30 and a-31. abolishes phosphorylation; when associated with a-15;
34	abolishes binding to ywhae and ywhaz.
42	no effect on phosphorylation; when associated with a-44.
44	no effect on phosphorylation; when associated with a-42, or with a-30; a-31 and a-51.
47	no effect on phosphorylation; when associated with a-49. abolishes phosphorylation; when associated with a-49; a-51 and
49	no effect on phosphorylation; when associated with a-47. abolishes phosphorylation; when associated with a-47; a-51 and
51	no effect on phosphorylation; when associated with a-30; a-31 and a-47. abolishes phosphorylation; when associated with
53	abolishes phosphorylation; when associated with a-47; a-49 and a-51, or with a-15; a-18; a-34; a-47; a-49 and a-51. abol
90	in transgenic mice, induces marked disruption of liver and pancreas keratin filament network. increases phosphorylation
238	prevents cleavage by caspase-6 during apoptosis. induces aggregates of keratin filaments in an altered organization.

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: 367 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, MODULE_52, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GU_PDEF_TARGETS_DN, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_RESPONSE_TO_PEPTIDE, ENK_UV_RESPONSE_KERATINOCYTE_UP, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, BOYLAN_MULTIPLE_MYELOMA_D_DN, GOCC_MICROTUBULE_ORGANIZING_CENTER, RODRIGUES_NTN1_TARGETS_DN

GO Biological Process (8): anatomical structure morphogenesis (GO:0009653), tumor necrosis factor-mediated signaling pathway (GO:0033209), Golgi to plasma membrane protein transport (GO:0043001), negative regulation of apoptotic process (GO:0043066), intermediate filament cytoskeleton organization (GO:0045104), extrinsic apoptotic signaling pathway (GO:0097191), hepatocyte apoptotic process (GO:0097284), cell-cell adhesion (GO:0098609)

GO Molecular Function (5): RNA binding (GO:0003723), structural molecule activity (GO:0005198), scaffold protein binding (GO:0097110), cadherin binding involved in cell-cell adhesion (GO:0098641), protein binding (GO:0005515)

GO Cellular Component (14): nucleolus (GO:0005730), cytoplasm (GO:0005737), microtubule organizing center (GO:0005815), cytosol (GO:0005829), cytoskeleton (GO:0005856), intermediate filament (GO:0005882), adherens junction (GO:0005912), nuclear matrix (GO:0016363), centriolar satellite (GO:0034451), keratin filament (GO:0045095), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), cell periphery (GO:0071944), nucleus (GO:0005634)

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	7
nuclear lumen	2
intracellular membraneless organelle	2
cytoplasm	2
developmental process	1
anatomical structure development	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
Golgi to plasma membrane transport	1
protein transport	1
establishment of protein localization to plasma membrane	1
protein localization to plasma membrane	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cytoskeleton organization	1
intermediate filament-based process	1
cell surface receptor signaling pathway	1
apoptotic signaling pathway	1
epithelial cell apoptotic process	1
cell adhesion	1
nucleic acid binding	1
molecular_function	1
protein binding	1
cadherin binding	1
cell-cell adhesion	1
cell-cell adhesion mediator activity	1
binding	1
intracellular anatomical structure	1
microtubule cytoskeleton	1
intermediate filament cytoskeleton	1
polymeric cytoskeletal fiber	1
cell-cell junction	1
centrosome	1
intermediate filament	1
extracellular vesicle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

3588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KRT18	KRT8	P05787	986
KRT18	TNFRSF1B	P20333	921
KRT18	DSP	P15924	849
KRT18	CDH1	P12830	801
KRT18	LIAT1	Q6ZQX7	801
KRT18	KRT19	P08727	761
KRT18	EGFR	P00533	754
KRT18	GAPDH	P00354	706
KRT18	PLEC	Q15149	697
KRT18	EPCAM	P16422	696
KRT18	CTNNB1	P35222	693
KRT18	AFP	P02771	670
KRT18	DEDD2	Q8WXF8	669
KRT18	KLK3	P07288	659
KRT18	TRADD	Q15628	653

IntAct

284 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
KRT18	GOLGA2	psi-mi:“MI:0915”(physical association)	0.780
GOLGA2	KRT18	psi-mi:“MI:0915”(physical association)	0.780
KRT18	HGS	psi-mi:“MI:0915”(physical association)	0.780
HGS	KRT18	psi-mi:“MI:0915”(physical association)	0.780
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
KRT18	KRT6C	psi-mi:“MI:0915”(physical association)	0.680
TSG101	KRT18	psi-mi:“MI:0915”(physical association)	0.670
KRT18	NME7	psi-mi:“MI:0915”(physical association)	0.670
KRT18	TSG101	psi-mi:“MI:0915”(physical association)	0.670
tir	KRT18	psi-mi:“MI:0915”(physical association)	0.660

BioGRID (537): KRT18 (Two-hybrid), KRT18 (Two-hybrid), CCDC146 (Two-hybrid), HAUS1 (Two-hybrid), KRT18 (Affinity Capture-MS), KRT18 (Affinity Capture-MS), KRT18 (Affinity Capture-MS), KRT18 (Affinity Capture-MS), KRT18 (Affinity Capture-MS), KRT18 (Affinity Capture-MS), KRT18 (Reconstituted Complex), TUBGCP4 (Two-hybrid), KRT18 (Two-hybrid), LDOC1 (Two-hybrid), EXOC8 (Two-hybrid)

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: A1KQY9, A1L317, A1L595, A5A6M0, A5A6M5, A5A6N2, A5A6P3, A6BLY7, A6QQQ9, A7YWM2, B0LKP1, B1AQ75, O57607, O57611, O76009, O76013, O77727, O93256, P02533, P02534, P02535, P02537, P05781, P05783, P05784, P06394, P08727, P08728, P08730, P08777, P08778, P08779, P08802, P13645, P13646, P19001, P19012, P25030, P25690, P35527

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CAMK1	unknown	KRT18	phosphorylation
CDK1	up-regulates	KRT18	phosphorylation
PRKCE	unknown	KRT18	phosphorylation
PRKCA	unknown	KRT18	phosphorylation
RPS6KA3	unknown	KRT18	phosphorylation
CAMK2A	unknown	KRT18	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 105 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
Cargo trafficking to the periciliary membrane	5	17.5×	9e-04
Cilium Assembly	7	10.7×	5e-04
Recruitment of NuMA to mitotic centrosomes	6	9.8×	1e-03
Clathrin-mediated endocytosis	8	9.6×	5e-04
Recruitment of mitotic centrosome proteins and complexes	5	9.6×	4e-03
Cargo recognition for clathrin-mediated endocytosis	6	8.8×	2e-03
Formation of the cornified envelope	7	8.7×	9e-04
SARS-CoV-2-host interactions	5	8.4×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
intermediate filament organization	10	26.8×	3e-09
non-motile cilium assembly	5	16.1×	2e-03
keratinization	5	13.0×	5e-03
cilium assembly	10	8.2×	2e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	4
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

963 predictions. Top by Δscore:

Variant	Effect	Δscore
12:52949588:CAG:C	donor_loss	1.0000
12:52949589:AG:A	donor_loss	1.0000
12:52949590:GG:G	donor_loss	1.0000
12:52949591:G:GA	donor_loss	1.0000
12:52949591:G:GG	donor_gain	1.0000
12:52950316:C:G	acceptor_gain	1.0000
12:52950317:A:AG	acceptor_gain	1.0000
12:52950318:A:G	acceptor_gain	1.0000
12:52950324:CCAG:C	acceptor_loss	1.0000
12:52950325:CA:C	acceptor_loss	1.0000
12:52950326:A:AG	acceptor_gain	1.0000
12:52950326:A:T	acceptor_loss	1.0000
12:52950327:G:GA	acceptor_gain	1.0000
12:52950327:GA:G	acceptor_gain	1.0000
12:52950327:GAT:G	acceptor_gain	1.0000
12:52950327:GATC:G	acceptor_gain	1.0000
12:52950327:GATCT:G	acceptor_gain	1.0000
12:52950406:GTCAA:G	donor_gain	1.0000
12:52950407:TC:T	donor_gain	1.0000
12:52950407:TCAA:T	donor_gain	1.0000
12:52950407:TCAAG:T	donor_loss	1.0000
12:52950408:CAA:C	donor_gain	1.0000
12:52950409:AA:A	donor_gain	1.0000
12:52950409:AAGT:A	donor_loss	1.0000
12:52950410:AGT:A	donor_loss	1.0000
12:52950411:G:GG	donor_gain	1.0000
12:52950748:AG:A	acceptor_gain	1.0000
12:52950749:GG:G	acceptor_gain	1.0000
12:52950749:GGT:G	acceptor_gain	1.0000
12:52950749:GGTA:G	acceptor_gain	1.0000

AlphaMissense

2813 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:52950379:G:C	A157P	0.998
12:52950391:G:C	A161P	0.998
12:52949445:T:A	L91Q	0.997
12:52949445:T:C	L91P	0.997
12:52950750:G:C	K167N	0.997
12:52950750:G:T	K167N	0.997
12:52950773:G:C	R175P	0.997
12:52950878:T:C	L210P	0.997
12:52949433:T:C	L87P	0.996
12:52950374:A:T	D155V	0.996
12:52950386:T:C	L159P	0.996
12:52950397:G:C	D163H	0.996
12:52950399:C:A	D163E	0.996
12:52950399:C:G	D163E	0.996
12:52950803:T:C	L185P	0.996
12:52952288:T:C	L373P	0.996
12:52949442:G:C	R90P	0.995
12:52949496:T:C	L108P	0.995
12:52949508:T:C	I112T	0.995
12:52949580:T:C	L136P	0.995
12:52950365:T:C	L152P	0.995
12:52950378:T:A	N156K	0.995
12:52950378:T:G	N156K	0.995
12:52950388:G:C	A160P	0.995
12:52950389:C:A	A160D	0.995
12:52950409:A:G	K167E	0.995
12:52950836:G:C	R196P	0.995
12:52950845:T:C	L199P	0.995
12:52950866:T:C	L206P	0.995
12:52952293:G:C	A375P	0.995

dbSNP variants (sampled 300 via entrez): RS1000081371 (12:52952054 A>C), RS1000447422 (12:52953096 G>A,T), RS1000629681 (12:52952768 A>G), RS1001443119 (12:52949804 G>C), RS1001812608 (12:52951796 C>A,T), RS1002074343 (12:52950512 G>A), RS1002552520 (12:52950273 C>A,G,T), RS1003682897 (12:52948882 G>A,T), RS1004256586 (12:52949855 G>A), RS1004292248 (12:52951134 T>A), RS1004477427 (12:52948488 T>A), RS1006229583 (12:52952737 G>A), RS1006610943 (12:52952452 A>G), RS1007449580 (12:52949112 G>C,T), RS1007617675 (12:52953154 C>G)

Disease associations

OMIM: gene MIM:148070 | disease phenotypes: MIM:215600, MIM:609532

GenCC curated gene-disease

Disease	Classification	Inheritance
cirrhosis, familial	Limited	Autosomal recessive

Mondo (3): cirrhosis, familial (MONDO:0007329), cirrhosis, noncryptogenic, susceptibility to (MONDO:0800422), hepatitis C virus, susceptibility to (MONDO:0012292)

Orphanet (1): Idiopathic copper-associated cirrhosis (Orphanet:209919)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000822	Hypertension
HP:0000952	Jaundice
HP:0001254	Lethargy
HP:0001394	Cirrhosis
HP:0001413	Micronodular cirrhosis
HP:0001541	Ascites
HP:0001945	Fever
HP:0002040	Esophageal varix
HP:0002092	Pulmonary arterial hypertension
HP:0002613	Biliary cirrhosis
HP:0003270	Abdominal distention
HP:0003584	Late onset
HP:0004787	Fulminant hepatitis
HP:0410067	Increased level of L-fucose in urine
HP:0410069	Increased level of propylene glycol in blood

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004166_20	Nonsyndromic cleft lip with cleft palate	4.000000e-12
GCST007637_15	Diffusing capacity of carbon monoxide	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0003959	cleft lip
EFO:0009369	diffusing capacity of the lung for carbon monoxide

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566123	Cirrhosis, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066464 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.24	Kd	580.9	nM	CHEMBL5653589
6.24	ED50	580.9	nM	CHEMBL5653589
5.13	Kd	7349	nM	CHEMBL3752910
5.13	ED50	7349	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148630: Binding affinity to human KRT18 incubated for 45 mins by Kinobead based pull down assay	kd	0.5809	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148630: Binding affinity to human KRT18 incubated for 45 mins by Kinobead based pull down assay	kd	7.3493	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, affects cotreatment, affects methylation, decreases expression	7
Tretinoin	affects cotreatment, increases expression, decreases expression	7
Valproic Acid	affects cotreatment, increases expression	7
Estradiol	increases activity, decreases reaction, increases expression, decreases expression, increases reaction	6
bisphenol A	increases expression, affects cotreatment, affects expression, decreases expression	5
Arsenic	affects methylation, decreases expression, affects cotreatment, increases abundance	4
trichostatin A	increases expression, affects cotreatment	3
sodium arsenite	affects expression, affects cotreatment, decreases expression, increases abundance, increases expression	3
Acetaminophen	decreases expression, increases expression, decreases response to substance	3
Doxorubicin	affects expression, increases expression, affects response to substance	3
Silicon Dioxide	affects expression, affects reaction, affects secretion, decreases expression	3
Smoke	increases expression, increases metabolic processing, decreases expression, increases abundance	3
Tobacco Smoke Pollution	increases expression, affects expression, decreases expression	3
deoxynivalenol	increases expression	2
mercuric bromide	increases expression, affects cotreatment	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
belinostat	increases expression, affects cotreatment	2
4-(1H-imidazol-1-yl)retinoic acid	increases expression	2
Fulvestrant	increases methylation, decreases reaction, increases activity, increases reaction, increases degradation	2
Panobinostat	affects cotreatment, increases expression	2
Acrolein	affects cotreatment, affects expression, increases metabolic processing, increases abundance	2
Air Pollutants	increases expression, affects cotreatment, affects expression, increases abundance	2
Ethanol	increases expression, affects cotreatment	2
Caffeine	decreases expression, affects phosphorylation	2
Fluorouracil	affects expression, affects cotreatment, increases cleavage	2
Griseofulvin	increases reaction, increases expression, decreases response to substance, affects binding	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases reaction, increases expression	2

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651672	Binding	Binding affinity to human KRT18 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SV08	HAP1 KRT18 (-) 1	Cancer cell line	Male
CVCL_SV09	HAP1 KRT18 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02595710	Not specified	COMPLETED	Bartonella in Liver Transplant Patients
NCT05740358	Not specified	ACTIVE_NOT_RECRUITING	Liver Cirrhosis Network Cohort Study