TFF2

Summary

TFF2 (trefoil factor 2, HGNC:11756) is a protein-coding gene on chromosome 21q22.3, encoding Trefoil factor 2 (Q03403). Inhibits gastrointestinal motility and gastric acid secretion.

Members of the trefoil family are characterized by having at least one copy of the trefoil motif, a 40-amino acid domain that contains three conserved disulfides. They are stable secretory proteins expressed in gastrointestinal mucosa. Their functions are not defined, but they may protect the mucosa from insults, stabilize the mucus layer and affect healing of the epithelium. The encoded protein inhibits gastric acid secretion. This gene and two other related trefoil family member genes are found in a cluster on chromosome 21.

Source: NCBI Gene 7032 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 21 total
• MANE Select transcript: NM_005423

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11756
Approved symbol	TFF2
Name	trefoil factor 2
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000160181
Ensembl biotype	protein_coding
OMIM	182590
Entrez	7032

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000291526, ENST00000463771, ENST00000475297

RefSeq mRNA: 1 — MANE Select: NM_005423 NM_005423

CCDS: CCDS13684

Canonical transcript exons

ENST00000291526 — 4 exons

Exon	Start	End
ENSE00001139218	42350879	42350994
ENSE00001266989	42346357	42346546
ENSE00003487843	42347486	42347632
ENSE00003593184	42349881	42350030

Expression profiles

Bgee: expression breadth ubiquitous, 157 present calls, max score 99.56.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 8.0419 / max 10576.1369, expressed in 61 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190608	7.9790	48
190610	0.0397	13
190609	0.0232	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	99.56	gold quality
mucosa of stomach	UBERON:0001199	99.54	gold quality
pylorus	UBERON:0001166	96.84	gold quality
gall bladder	UBERON:0002110	93.91	gold quality
body of stomach	UBERON:0001161	92.40	gold quality
stomach	UBERON:0000945	92.28	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.20	gold quality
duodenum	UBERON:0002114	89.41	gold quality
fundus of stomach	UBERON:0001160	85.92	gold quality
epithelial cell of pancreas	CL:0000083	84.59	silver quality
islet of Langerhans	UBERON:0000006	83.30	gold quality
cardia of stomach	UBERON:0001162	82.83	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.61	silver quality
ileal mucosa	UBERON:0000331	77.87	silver quality
left lobe of thyroid gland	UBERON:0001120	73.09	gold quality
pancreas	UBERON:0001264	72.01	gold quality
right lobe of thyroid gland	UBERON:0001119	71.89	gold quality
rectum	UBERON:0001052	71.43	gold quality
thyroid gland	UBERON:0002046	71.36	gold quality
body of pancreas	UBERON:0001150	66.58	gold quality
endometrium epithelium	UBERON:0004811	65.84	gold quality
paraflocculus	UBERON:0005351	63.04	gold quality
Brodmann (1909) area 10	UBERON:0013541	62.88	gold quality
frontal pole	UBERON:0002795	62.41	gold quality
middle frontal gyrus	UBERON:0002702	61.45	gold quality
right lobe of liver	UBERON:0001114	61.24	gold quality
lower esophagus mucosa	UBERON:0035834	60.21	gold quality
right coronary artery	UBERON:0001625	59.73	gold quality
right uterine tube	UBERON:0001302	59.63	gold quality
endocervix	UBERON:0000458	59.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8495	yes	8996.19
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA6, MYC, PPARG, SP3, TP53, USF1

miRNA regulators (miRDB)

22 targeting TFF2, 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-9-5P	100.00	72.28	2361
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-8060	98.61	66.93	1187
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-4662B	98.33	66.37	1163
HSA-MIR-4647	98.30	66.41	1139
HSA-MIR-876-5P	97.99	68.49	1345
HSA-MIR-3928-3P	97.61	66.53	1096
HSA-MIR-8069	97.05	66.79	718
HSA-MIR-3167	96.81	67.09	1236

Literature-anchored findings (GeneRIF, showing 40)

• autoinduction of promoter requires an upstream cis-acting element (PMID:12054609)
• Transcripts not detectable in conjunctiva. Review. (PMID:12613926)
• expression of TFF2 and Helicobacter pylori infection in carcinogenesis of gastric mucosa (PMID:12717829)
• The results suggest that TFF2 expression may play a role in gastric cancer invasion and could be a useful target for therapeutic intervention. (PMID:13679442)
• PPARgamma mediates NSAIDs-induced up-regulation of TFF2 expression in gastric epithelial cells. (PMID:14759512)
• TFF2 and its putative receptor, DMBT1, were expressed non-specifically in biliary epithelial cells of the damaged small bile ducts, suggesting a cytoprotective role in biliary pathophysiology. (PMID:15101998)
• increased TFF1 and 2 concentrations found in serum from inflammatory bowel disease patients (PMID:15115253)
• TFF2 could play a role in mammary gland tumorigenesis. (PMID:15177880)
• TFF2 is expressed in normal and malignant breast epithelial cells and it stimulates the migration of breast cancer cells. (PMID:15177883)
• Epidermal growth factor and trefoil factor family 2 synergistically trigger chemotaxis on BEAS-2B cells via different signaling cascades (PMID:15256384)
• The group of trefoil factor peptides (TFF1-3) are part of the protective mechanism operating in the intestinal mucosa and play a fundamental role in epithelial protection, repair, and restitution. (PMID:15578191)
• Demonstration that TFF2 rhythm is impaired in cohorts of individuals known to suffer gastric symptoms suggests that interventions to restore the normal TFF2 rhythm in those with poor mucosal protection could reduce morbidity. (PMID:15984970)
• TFF1, TFF2, TFF3 and MUC5AC may have roles in pathogenesis of pterygium goblet cells (PMID:16142316)
• TFF2 staining was detected in large, diffuse tumors and in tumors with lymph node metastasis and had a significant correlation with the number of microvessels. (PMID:16166422)
• human pancreatic polypeptide inhibits TFF2 secretion in a diurnal rhythm (PMID:16359755)
• reduced expression of TFF1 and TFF2 in precancerous conditions and gastric cancer may be associated with the proliferation and malignant transformation of gastric mucosa (PMID:16718800)
• Co-localization of TFF2 with gland mucous cell mucin suggests a physical interaction between TFF2 and gland mucous cell mucin. The TFF2 trapped in the adherent mucins may be responsible for mucosal defense, healing, and repair. (PMID:16786324)
• D21S1893-D21S1890 region may harbor candidate genes especially TFF (TFF1, TFF2, and TFF3) and serine protease family, which might be involved in tumor invasion and metastasis contributing to poor survival. (PMID:16830362)
• PPARgamma may be involved in the gastric mucosal defense through regulating TFF2 expression (PMID:17118693)
• Gastrin regulates TFF2 transcription through a GC-rich DNA-binding site and a protein kinase dependent pathway. (PMID:17332476)
• The TFF1-GKN2 heterodimer and TFF2 differ characteristically by their binding to gastric mucins. (PMID:17982272)
• CXCR4 as a bona fide signaling receptor for TFF2 and suggest a mechanism through which TFF2 may modulate immune and tumorigenic responses in vivo. (PMID:19064997)
• circulating TFFs are not candidate markers of trisomy 21 in first-trimester pregnancies (PMID:19172695)
• The researchers found evidence that H. pylori-associated CAG has a negative effect on the expression of TFF2 in the gastric antrum and may be associated with H. pylori-induced gastric mucosal damage. (PMID:19344006)
• p53 induces cell apoptosis and inhibits cell migration in part by downregulating TFF2 expression through an AP-1-like site, suggesting that TFF2 may be an important downstream target of p53. (PMID:19541923)
• TFF1, TFF2, and TFF3 expression were localized systematically in surgical specimens from the urinary tract. (PMID:20063012)
• TFF2 negatively regulates preneoplastic progression and subsequent tumor development in the stomach, a role that is subverted by promoter methylation during H pylori infection (PMID:20801119)
• TFF1, TFF2, and PDX1 were expressed only in lobular endocervical glandular hyperplasia. (PMID:21228366)
• Data show that frog TFF2 activates protease-activated receptor (PAR) 1 to induce human platelet aggregation, and suggest that human TFF2 promotes cell migration via PAR4. (PMID:21461878)
• TFF2 is mitogenic in cholangiocarcinoma via EGFR/MAPK activation. (PMID:21472131)
• Report a novel TFF2 splice variant (EX2TFF2) which correlates with longer overall survival time in cholangiocarcinoma. (PMID:22159958)
• Report TFF2 expression in normal/diseased pancreas and suggest role in tumor cell migration. (PMID:22286382)
• TFF2 messenger RNA expression is significantly increased in nasal mucosal brushings during asthma exacerbations in children. (PMID:22329990)
• Human gastric TFF2 peptide contains an N-linked fucosylated N,N’-diacetyllactosediamine (LacdiNAc) oligosaccharide (PMID:22997242)
• this study indicated that Sp3 was a major regulator of TFF2 expression. (PMID:23000412)
• Significantly higher levels of TFF2 were in patients with Multiple Organ Dysfunction Syndrome. (PMID:23628371)
• There is an association between TFF2 and TFF3 polymorphisms and risk of atrophic gastritis and gastric cancer in Chinese people. (PMID:23933418)
• Human TTF2 is a lectin that binds alpha-GlcNAc-capped mucin 6 g with antibiotic activity against Helicobacter pylori. (PMID:25124036)
• The structural features of the N-linked N,N’-di-N-acetyllactosediamine-inducing determinant on human TFF2 are discussed. (PMID:25210040)
• protease-activated receptor 4 and Trefoil factor 2 are expressed in human colorectal cancer (PMID:25876034)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tff2	ENSMUSG00000024028
rattus_norvegicus	Tff2	ENSRNOG00000001162

Paralogs (2): TFF3 (ENSG00000160180), TFF1 (ENSG00000160182)

Protein

Protein identifiers

Trefoil factor 2 — Q03403 (reviewed: Q03403)

Alternative names: Spasmolysin, Spasmolytic polypeptide

All UniProt accessions (1): Q03403

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits gastrointestinal motility and gastric acid secretion. Could function as a structural component of gastric mucus, possibly by stabilizing glycoproteins in the mucus gel through interactions with carbohydrate side chains.

Subcellular location. Secreted.

Tissue specificity. Stomach.

RefSeq proteins (1): NP_005414* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000519	P_trefoil_dom	Domain
IPR017957	P_trefoil_CS	Conserved_site
IPR017994	P_trefoil_chordata	Family
IPR044913	P_trefoil_dom_sf	Homologous_superfamily

Pfam: PF00088

UniProt features (14 total): disulfide bond 7, sequence conflict 2, domain 2, signal peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q03403-F1	93.35	0.79

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 (7): 101–118, 29–127, 31–58, 42–57, 52–69, 81–107, 91–106

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 120 (showing top): GOBP_DIGESTION, MODULE_92, GOBP_ACID_SECRETION, GOBP_RESPONSE_TO_PEPTIDE, MODULE_45, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GOBP_NEGATIVE_REGULATION_OF_SECRETION, GOBP_MAINTENANCE_OF_GASTROINTESTINAL_EPITHELIUM, GOBP_SECRETION, GOBP_DIGESTIVE_SYSTEM_PROCESS, GOBP_REGULATION_OF_DIGESTIVE_SYSTEM_PROCESS, GOBP_REGULATION_OF_SYSTEM_PROCESS

GO Biological Process (3): maintenance of gastrointestinal epithelium (GO:0030277), negative regulation of gastric acid secretion (GO:0060455), chemokine-mediated signaling pathway (GO:0070098)

GO Molecular Function (2): CXCR4 chemokine receptor binding (GO:0031723), protein binding (GO:0005515)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
epithelial structure maintenance	1
digestive system process	1
gastric acid secretion	1
negative regulation of secretion	1
regulation of gastric acid secretion	1
negative regulation of digestive system process	1
G protein-coupled receptor signaling pathway	1
cytokine-mediated signaling pathway	1
cellular response to chemokine	1
CXCR chemokine receptor binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

967 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TFF2	MUC6	Q6W4X9	885
TFF2	CXCR4	P30991	817
TFF2	MUC5AC	P98088	807
TFF2	GKN2	Q86XP6	753
TFF2	GAST	P01350	724
TFF2	CBLIF	P27352	633
TFF2	BHLHA15	Q7RTS1	593
TFF2	MUC2	Q02817	581
TFF2	ATR	Q13535	580
TFF2	IDS	P22304	548
TFF2	GKN1	Q9NS71	541
TFF2	REG4	Q9BYZ8	540
TFF2	ATP4B	P51164	520
TFF2	PGC	P20142	511
TFF2	TFF3	Q07654	505

IntAct

64 interactions, top by confidence:

A	B	Type	Score
DDX3X	TFF2	psi-mi:“MI:0915”(physical association)	0.560
TFF2	DNM2	psi-mi:“MI:0915”(physical association)	0.560
TFF2		psi-mi:“MI:0915”(physical association)	0.560
ELAVL2	TFF2	psi-mi:“MI:0915”(physical association)	0.560
DNAJB1	TFF2	psi-mi:“MI:0915”(physical association)	0.560
	TFF2	psi-mi:“MI:0915”(physical association)	0.560
TAF7	TFF2	psi-mi:“MI:0915”(physical association)	0.560
PDLIM5	TFF2	psi-mi:“MI:0915”(physical association)	0.560
SNRPG	TFF2	psi-mi:“MI:0915”(physical association)	0.560
ZHX2	TFF2	psi-mi:“MI:0915”(physical association)	0.560
PMP22	TFF2	psi-mi:“MI:0915”(physical association)	0.560
TUBB	TFF2	psi-mi:“MI:0915”(physical association)	0.560
HTT	TFF2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (4): TFF2 (PCA), TFF2 (Affinity Capture-MS), TFF2 (Affinity Capture-MS), TFF2 (Reconstituted Complex)

ESM2 similar proteins: A8YXX7, B4X8D9, O46655, O75711, O76095, O77049, O88745, O88823, O88824, P01186, P01359, P04155, P08163, P08833, P0CW02, P18406, P21743, P21744, P22934, P24593, P24594, P25118, P35455, P47876, P47879, P55773, Q03191, Q03403, Q05717, Q07079, Q07654, Q08423, Q16663, Q28985, Q29183, Q62395, Q63467, Q66IA6, Q6DGP8, Q6Q484

Diamond homologs: A8YXX7, B4X8D9, P01359, P04155, P10667, P17437, Q00222, Q00223, Q03191, Q03403, Q03404, Q05049, Q07654, Q08423, Q09030, Q29183, Q62395, Q63467, Q863B4, Q863J2, Q863T4, B3EWZ5, B3EWZ6, Q9MYM4, P10253, Q5R7A9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	16
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

513 predictions. Top by Δscore:

Variant	Effect	Δscore
21:42347631:CT:C	acceptor_gain	1.0000
21:42350877:A:AC	donor_gain	1.0000
21:42350878:C:CC	donor_gain	1.0000
21:42347637:C:CT	acceptor_gain	0.9900
21:42350867:T:A	donor_gain	0.9900
21:42350878:CA:C	donor_gain	0.9900
21:42350878:CAG:C	donor_gain	0.9900
21:42350878:CAGG:C	donor_gain	0.9900
21:42350878:CAGGG:C	donor_gain	0.9900
21:42350892:C:CA	donor_gain	0.9900
21:42350893:C:A	donor_gain	0.9900
21:42347633:C:CC	acceptor_gain	0.9800
21:42350873:ACTT:A	donor_loss	0.9800
21:42350875:TTA:T	donor_loss	0.9800
21:42350876:T:TG	donor_loss	0.9800
21:42350877:A:T	donor_loss	0.9800
21:42350878:C:CA	donor_loss	0.9800
21:42350908:AG:A	donor_gain	0.9800
21:42350908:AGC:A	donor_gain	0.9800
21:42350908:AGCC:A	donor_gain	0.9800
21:42350872:CACT:C	donor_loss	0.9700
21:42347632:TCTG:T	acceptor_loss	0.9600
21:42347634:T:A	acceptor_loss	0.9600
21:42347637:C:T	acceptor_gain	0.9600
21:42347638:A:C	acceptor_gain	0.9600
21:42350889:A:AC	donor_gain	0.9600
21:42350890:C:CC	donor_gain	0.9600
21:42350909:G:C	donor_gain	0.9600
21:42347638:A:AC	acceptor_gain	0.9300
21:42350873:A:AC	donor_gain	0.9300

AlphaMissense

850 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:42349955:C:G	C52S	0.992
21:42349956:A:T	C52S	0.992
21:42349900:G:C	F70L	0.990
21:42349900:G:T	F70L	0.990
21:42349902:A:G	F70L	0.990
21:42349904:C:G	C69S	0.990
21:42349905:A:T	C69S	0.990
21:42347509:C:G	C118S	0.989
21:42347510:A:T	C118S	0.989
21:42347505:G:C	F119L	0.988
21:42347505:G:T	F119L	0.988
21:42347507:A:G	F119L	0.988
21:42349933:G:C	F59L	0.986
21:42349933:G:T	F59L	0.986
21:42349935:A:G	F59L	0.986
21:42349954:A:C	C52W	0.986
21:42347538:G:C	F108L	0.983
21:42347538:G:T	F108L	0.983
21:42347540:A:G	F108L	0.983
21:42349993:C:A	R39S	0.983
21:42349993:C:G	R39S	0.983
21:42347590:C:G	C91S	0.982
21:42347591:A:T	C91S	0.982
21:42349901:A:C	F70C	0.979
21:42349905:A:G	C69R	0.979
21:42349903:A:C	C69W	0.978
21:42349955:C:A	C52F	0.977
21:42347508:G:C	C118W	0.976
21:42347510:A:G	C118R	0.976
21:42347560:C:G	C101S	0.976

dbSNP variants (sampled 300 via entrez): RS1000395550 (21:42348275 A>G), RS1002532139 (21:42348965 A>T), RS1003734794 (21:42346202 A>G), RS1003843111 (21:42347979 G>A), RS1004425985 (21:42352829 G>A,C), RS1005449802 (21:42348131 C>A,G), RS1006301394 (21:42349055 C>G), RS1007662790 (21:42350166 A>G), RS1007695080 (21:42349653 G>C,T), RS1008194174 (21:42346757 C>T), RS1008361246 (21:42351493 C>A,T), RS1008716420 (21:42346852 A>G), RS1008811262 (21:42350444 G>A), RS1009245752 (21:42347080 G>A,C,T), RS1009674050 (21:42347457 CCAGA>C)

Disease associations

OMIM: gene MIM:182590 | 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

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects binding, increases reaction, increases expression	2
Tamoxifen	affects binding, increases reaction, decreases expression, increases expression	2
Valproic Acid	affects cotreatment, increases expression, increases methylation	2
deoxynivalenol	affects expression, affects reaction, decreases secretion	1
o,p’-DDT	decreases expression	1
SB 203580	affects expression, affects reaction	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	affects expression, affects reaction	1
entinostat	decreases expression	1
belinostat	decreases expression	1
NSC 689534	increases expression, affects binding	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	increases reaction, decreases expression, affects binding	1
Adenine	affects reaction, affects expression	1
Ascorbic Acid	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Copper	affects binding, increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Quercetin	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Isotretinoin	decreases expression	1
Sodium Selenite	decreases expression	1

Clinical trials (associated diseases)

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