GKN2

Summary

GKN2 (gastrokine 2, HGNC:24588) is a protein-coding gene on chromosome 2p13.3, encoding Gastrokine-2 (Q86XP6).

The secretory protein encoded by this gene is produced in gastric surface mucous cells, where it can bind trefoil factor family peptide 1 or gastrokine-1. This gene may be a tumor suppressor gene, as its expression is markedly decreased in gastric cancer tissues. The encoded protein interacts with gastrokine-1 and regulates homeostasis of the gastric mucosa.

Source: NCBI Gene 200504 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 25 total
• MANE Select transcript: NM_182536

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24588
Approved symbol	GKN2
Name	gastrokine 2
Location	2p13.3
Locus type	gene with protein product
Status	Approved
Aliases	TFIZ1, PRO813, VLTI465, blottin, GDDR, BRICD1B
Ensembl gene	ENSG00000183607
Ensembl biotype	protein_coding
OMIM	618589
Entrez	200504

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000328895, ENST00000481498, ENST00000872203, ENST00000967689

RefSeq mRNA: 1 — MANE Select: NM_182536 NM_182536

CCDS: CCDS33215

Canonical transcript exons

ENST00000328895 — 6 exons

Exon	Start	End
ENSE00001298891	68950702	68950755
ENSE00001299542	68946304	68946460
ENSE00001316043	68950126	68950263
ENSE00001323544	68947147	68947257
ENSE00001338920	68952850	68952893
ENSE00001906685	68945232	68945450

Expression profiles

Bgee: expression breadth ubiquitous, 128 present calls, max score 98.45.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.2288 / max 1633.9987, expressed in 22 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28896	1.0636	15
28897	0.0877	14
28900	0.0297	6
28899	0.0287	7
28898	0.0113	4
28901	0.0077	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	98.45	gold quality
ileal mucosa	UBERON:0000331	95.81	gold quality
pylorus	UBERON:0001166	94.94	gold quality
upper lobe of lung	UBERON:0008948	93.91	gold quality
upper lobe of left lung	UBERON:0008952	93.76	gold quality
lower lobe of lung	UBERON:0008949	92.00	gold quality
right lung	UBERON:0002167	91.41	gold quality
body of stomach	UBERON:0001161	90.34	gold quality
lung	UBERON:0002048	88.29	gold quality
stomach	UBERON:0000945	87.55	gold quality
cardia of stomach	UBERON:0001162	85.73	gold quality
tibialis anterior	UBERON:0001385	83.34	silver quality
pancreatic ductal cell	CL:0002079	80.93	silver quality
fundus of stomach	UBERON:0001160	79.77	gold quality
epithelial cell of pancreas	CL:0000083	69.19	gold quality
visceral pleura	UBERON:0002401	66.50	gold quality
adult organism	UBERON:0007023	63.97	gold quality
upper arm skin	UBERON:0004263	63.58	gold quality
deltoid	UBERON:0001476	63.04	gold quality
oocyte	CL:0000023	60.34	gold quality
kidney epithelium	UBERON:0004819	55.32	gold quality
upper leg skin	UBERON:0004262	55.17	silver quality
cardiac muscle of right atrium	UBERON:0003379	54.92	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
nasal cavity epithelium	UBERON:0005384	53.65	gold quality
cerebellar vermis	UBERON:0004720	52.18	gold quality
myocardium	UBERON:0002349	50.50	gold quality
right uterine tube	UBERON:0001302	50.45	gold quality
duodenum	UBERON:0002114	50.32	gold quality
quadriceps femoris	UBERON:0001377	50.18	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-86618	yes	328.36
E-HCAD-1	yes	89.27
E-ANND-3	yes	15.27

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB1, RELA

miRNA regulators (miRDB)

23 targeting GKN2, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-1265	98.36	66.46	598
HSA-MIR-4259	95.68	65.25	582

Literature-anchored findings (GeneRIF, showing 19)

• TFIZ1 is an 18.31 kDa binding partner of trefoil factor 1 (TFF1) protein in normal gastric mucosa; it contains an approximately 100 amino acid brichos domain and has homology with surfactant protein C. (TFIZ1; trefoil factor interactions 1) (PMID:15924415)
• The TFF1-GKN2 heterodimer and TFF2 differ characteristically by their binding to gastric mucins. (PMID:17982272)
• GKN1 and GKN2 expression occurs frequently in gastric adenocarcinomas, especially in the diffuse subtype (PMID:18593995)
• in gastric cancer, expression of TFF1 in the absence of TFIZ1 is associated with lymph node metastasis (PMID:18722547)
• GKN2 was expressed in 33 non-tumoral mucosae (66%) and 35 tumoral mucosae (70%). (PMID:21151392)
• gastrointestinal tract specific gene GDDR might inhibit gastric cancer growth in a TFF1 dependent manner (PMID:21870107)
• These data demonstrate that in the presence of GKN2, GKN1 loses its ability to decrease cell proliferation, induce apoptosis, and inhibit epigenetic alterations in gastric cancer cells. (PMID:24151046)
• GKN2 could inhibit the proliferation, migration, and invasion of gastric cancer cells and might represent a novel therapeutic target for gastric cancer. (PMID:24408014)
• Epstein-Barr virus EBNA1 binds to the divergent promoter of the GKN1 and GKN2 genes and contributes to the complex transcriptional and epigenetic deregulation of the GKN1 and GKN2 tumor suppressor genes. (PMID:24460791)
• the gestational age-dependent and compartment-specific expression pattern of GKN2 points to a role for placental development (PMID:26070363)
• Our results suggested, for the first time, that the gradual change in GDDR expression might not only be directly related to H. pylori infection but also be an early molecular event in the development of gastric carcinoma. (PMID:26842925)
• these results reveal an antiinflammatory role for GKN2, provide in vivo evidence that links GKN2 loss to GC pathogenesis, and suggest GKN restoration as a strategy to restrain GC progression. (PMID:26974160)
• These findings suggested that GDDR expression was significantly associated with the progression of gastric cancer and GDDR may function as a tumor suppressor via inhibiting the epithelial-mesenchymal transition. (PMID:27017226)
• GKN2 suppressed epithelial mesenchymal transition of gastric cancer cells by downregulation of snail through PI3K/AKT/GSK3beta signaling pathway. (PMID:27323966)
• Co-expression of GKN2 and TFF1 massively suppressed the expression of positive cell cycle regulators and induced G1/S arrest, synergistically enhancing the inhibition of cell viability and proliferation of gastric cancer cells (PMID:28150071)
• we demonstrated GKN2 might increase sensitivity of GC cells to the drugs which increase ROS levels in tumors. Inhibition of the interaction between GKN2 and Hsc70 could attenuate the effects induced by GKN2. (PMID:31382983)
• Study computationally predicted and experimentally validated specific mechanisms of anticancer effects of GKN2 in gastric cancer proliferation and invasion in vitro. (PMID:31463974)
• Coordinate expression loss of GKN1 and GKN2 in gastric cancer via impairment of a glucocorticoid-responsive enhancer. (PMID:32538140)
• NK6 Homeobox 2 Regulated Gastrokin-2 Suppresses Gastric Cancer Cell Proliferation and Invasion via Akt Signaling Pathway. (PMID:33009998)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gkn2	ENSMUSG00000030049
rattus_norvegicus	Gkn2	ENSRNOG00000009256

Paralogs (2): GKN1 (ENSG00000169605), BRICD5 (ENSG00000182685)

Protein

Protein identifiers

Gastrokine-2 — Q86XP6 (reviewed: Q86XP6)

Alternative names: Blottin, Down-regulated in gastric cancer, Trefoil factor interactions(z) 1

All UniProt accessions (2): Q86XP6, E5RHQ8

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with TFF2. Heterodimer with TFF1; disulfide linked.

Subcellular location. Secreted.

Tissue specificity. Expressed in gastric mucosa.

RefSeq proteins (1): NP_872342* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007084	BRICHOS_dom	Domain
IPR051772	Gastrokine	Family

Pfam: PF04089

UniProt features (7 total): sequence conflict 2, signal peptide 1, chain 1, domain 1, disulfide bond 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86XP6-F1	86.40	0.60

Functional residue map

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

Disulfide bonds (1): 81–143

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 79 (showing top): GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_MYELOID_LEUKOCYTE_ACTIVATION, GOBP_RESPONSE_TO_KETONE, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_RESPONSE_TO_STEROID_HORMONE, GOBP_RESPONSE_TO_HORMONE, GOBP_RESPONSE_TO_LIPID, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS

GO Biological Process (9): neutrophil activation involved in immune response (GO:0002283), response to wounding (GO:0009611), response to bacterium (GO:0009617), gene expression (GO:0010467), regulation of cell population proliferation (GO:0042127), NLRP3 inflammasome complex assembly (GO:0044546), response to cortisol (GO:0051414), response to stress (GO:0006950), inflammatory response (GO:0006954)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), basal part of cell (GO:0045178), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
myeloid cell activation involved in immune response	1
immune response	1
neutrophil activation	1
response to stress	1
response to other organism	1
macromolecule biosynthetic process	1
cell population proliferation	1
regulation of cellular process	1
canonical inflammasome complex assembly	1
response to glucocorticoid	1
response to alcohol	1
response to ketone	1
response to stimulus	1
defense response	1
binding	1

Protein interactions and networks

STRING

428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GKN2	TFF1	P04155	877
GKN2	TFF2	Q03403	753
GKN2	UQCC4	Q4G0I0	509
GKN2	TFF3	Q07654	490
GKN2	FCGBP	Q9Y6R7	465
GKN2	MUC6	Q6W4X9	451
GKN2	TSC22D2	O75157	438
GKN2	LIPF	P07098	424
GKN2	MYL9	P24844	410
GKN2	MUC5AC	P98088	404
GKN2	SFMBT2	Q5VUG0	399
GKN2	PGA4	P00790	398
GKN2	MYL4	P11783	387
GKN2	MYL6	P16475	383
GKN2	CBLIF	P27352	380

IntAct

10 interactions, top by confidence:

A	B	Type	Score
GKN2	TMEM237	psi-mi:“MI:0915”(physical association)	0.560
FAM209A	GKN2	psi-mi:“MI:0915”(physical association)	0.560
ADAM19	TSC22D2	psi-mi:“MI:0914”(association)	0.350
GKN2	BCHE	psi-mi:“MI:0914”(association)	0.350
HOXB8	IMPDH1	psi-mi:“MI:0914”(association)	0.350
GKN2	TMEM237	psi-mi:“MI:0915”(physical association)	0.000
GKN2	FAM209A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (7): GKN2 (Two-hybrid), GKN2 (Two-hybrid), P4HB (Affinity Capture-MS), BCHE (Affinity Capture-MS), GKN2 (Affinity Capture-MS), GKN2 (Affinity Capture-MS), TUBB7P (Affinity Capture-MS)

ESM2 similar proteins: A2VDN0, A5A6H8, B5DFM7, E9Q9F6, O18638, O42204, O43736, O88393, O89051, P0DP43, P21841, P26342, P58239, Q03167, Q06890, Q06AV4, Q14CH0, Q29TV8, Q3T0P7, Q4R540, Q52N47, Q5NVC3, Q5PQL7, Q5R876, Q5SC59, Q5SC60, Q5SY80, Q5XIE8, Q60HC1, Q61500, Q6AYE5, Q6GPK2, Q6P7C7, Q6P995, Q6W3E5, Q71SY6, Q802A9, Q86XM0, Q86XP6, Q8BGN6

Diamond homologs: Q29TV8, Q86XP6, Q9CQS6, P15783, D2XPP7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

547 predictions. Top by Δscore:

Variant	Effect	Δscore
2:68946456:AGAGC:A	acceptor_gain	1.0000
2:68946457:GAGC:G	acceptor_gain	1.0000
2:68946458:AGC:A	acceptor_gain	1.0000
2:68946458:AGCC:A	acceptor_loss	1.0000
2:68946459:GC:G	acceptor_gain	1.0000
2:68946460:CC:C	acceptor_gain	1.0000
2:68946461:C:CC	acceptor_gain	1.0000
2:68946467:C:CT	acceptor_gain	1.0000
2:68946468:G:T	acceptor_gain	1.0000
2:68946469:G:C	acceptor_gain	1.0000
2:68946469:G:GC	acceptor_gain	1.0000
2:68946471:A:AC	acceptor_gain	1.0000
2:68946471:A:C	acceptor_gain	1.0000
2:68946475:C:CT	acceptor_gain	1.0000
2:68946476:A:T	acceptor_gain	1.0000
2:68950120:GCTTA:G	donor_loss	1.0000
2:68950121:CTTA:C	donor_loss	1.0000
2:68950122:TTA:T	donor_loss	1.0000
2:68950123:TA:T	donor_loss	1.0000
2:68950124:A:AC	donor_gain	1.0000
2:68950125:C:CC	donor_gain	1.0000
2:68950125:CA:C	donor_gain	1.0000
2:68950125:CAT:C	donor_gain	1.0000
2:68950125:CATG:C	donor_gain	1.0000
2:68950125:CATGT:C	donor_gain	1.0000
2:68950162:T:TA	donor_gain	1.0000
2:68950259:AAAAC:A	acceptor_gain	1.0000
2:68950261:AACC:A	acceptor_loss	1.0000
2:68950262:AC:A	acceptor_gain	1.0000
2:68950263:CC:C	acceptor_gain	1.0000

AlphaMissense

1214 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:68946348:C:G	C143S	0.980
2:68946349:A:T	C143S	0.980
2:68947247:G:T	A72E	0.969
2:68946348:C:T	C143Y	0.956
2:68946349:A:G	C143R	0.956
2:68947221:A:G	C81R	0.956
2:68947219:G:C	C81W	0.954
2:68946347:G:C	C143W	0.952
2:68947220:C:G	C81S	0.949
2:68947221:A:T	C81S	0.949
2:68950152:A:G	S60P	0.945
2:68946425:C:A	W117C	0.942
2:68946425:C:G	W117C	0.942
2:68945387:C:G	C179S	0.939
2:68945388:A:T	C179S	0.939
2:68947220:C:T	C81Y	0.937
2:68947248:C:G	A72P	0.937
2:68950185:C:G	A49P	0.932
2:68946348:C:A	C143F	0.922
2:68950184:G:T	A49D	0.920
2:68945429:C:G	C165S	0.917
2:68945430:A:T	C165S	0.917
2:68947216:A:C	F82L	0.917
2:68947216:A:T	F82L	0.917
2:68947218:A:G	F82L	0.917
2:68947224:C:G	A80P	0.916
2:68946331:A:C	Y149D	0.911
2:68947220:C:A	C81F	0.908
2:68945388:A:G	C179R	0.907
2:68945387:C:T	C179Y	0.903

dbSNP variants (sampled 300 via entrez): RS1000012455 (2:68953456 G>A,T), RS1000528390 (2:68949479 G>A), RS1001014289 (2:68954537 T>C), RS1001044519 (2:68949731 T>C), RS1001204874 (2:68946810 G>A,T), RS1001718385 (2:68947213 G>C), RS1001802029 (2:68952503 C>T), RS1002463083 (2:68953446 G>A), RS1002590879 (2:68946415 T>C), RS1002608208 (2:68948156 G>C), RS1002643174 (2:68946181 C>T), RS1002719402 (2:68947652 G>A), RS1002794623 (2:68952055 G>A,C), RS1002879157 (2:68945283 G>A,T), RS1002993628 (2:68945734 C>A)

Disease associations

OMIM: gene MIM:618589 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
pentanal	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
Aldehydes	increases expression	1
Camptothecin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Silicon Dioxide	increases expression	1

Clinical trials (associated diseases)

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