Trefoil factor 3

Trefoil factor 3 is a protein that in humans is encoded by the TFF3 gene.^[5][6][7]

TFF3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1E9T, 1PE3
Identifiers
Aliases	TFF3, ITF, P1B, TFI, trefoil factor 3
External IDs	OMIM: 600633; MGI: 104638; HomoloGene: 2427; GeneCards: TFF3; OMA:TFF3 - orthologs
Gene location (Human) Chr. Chromosome 21 (human)[1] Band 21q22.3 Start 42,311,667 bp[1] End 42,315,409 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17 A3.3|17 15.8 cM Start 31,344,280 bp[2] End 31,348,620 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of transverse colon mucosa of ileum left lobe of thyroid gland pancreatic ductal cell right lobe of thyroid gland rectum mucosa of sigmoid colon right uterine tube olfactory zone of nasal mucosa trachea Top expressed in crypt of lieberkuhn of small intestine ileum left colon duodenum intestinal villus epithelium of small intestine Paneth cell Ileal epithelium migratory enteric neural crest cell jejunum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding molecular function Cellular component cytoplasm extracellular space extracellular region secretory granule Biological process wound healing regulation of glucose metabolic process maintenance of gastrointestinal epithelium Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7033 21786 Ensembl ENSG00000160180 ENSMUSG00000024029 UniProt Q07654 Q62395 RefSeq (mRNA) NM_003226 NM_011575 RefSeq (protein) NP_003217 NP_035705 Location (UCSC) Chr 21: 42.31 – 42.32 Mb Chr 17: 31.34 – 31.35 Mb PubMed search [3] [4]
Wikidata
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Function

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 disulfide bonds. They are stable secretory proteins expressed in gastrointestinal mucosa. Their functions are diverse, including protection of the mucosa, thickening of the mucus, and increasing epithelial healing rates. This gene is a marker of columnar epithelium and is expressed in a variety of tissues including goblet cells of the intestines and colon. This gene and two other related trefoil family member genes are found in a cluster on chromosome 21.^[7]

Glycan binding

All three human trefoil factors are lectins that interact specifically with the disaccharide GlcNAc-α-1,4-Gal.^[8] This disaccharide is an unusual glycotope that is only known to exist on the large, heavily glycosylated, mucins in the mucosa. By cross-linking mucins through the bivalent binding of this glycotope, the trefoil factors are then able to reversible modulate the thickness and viscosity of the mucus.^[8]

In breast milk

Trefoil factors (TFF) are secretory products of mucin producing cells. They play a key role in the maintenance of the surface integrity of oral mucosa and enhance healing of the gastrointestinal mucosa by a process called restitution. TFF comprises the gastric peptides (TFF1), spasmolytic peptide (TFF2), and the intestinal trefoil factor (TFF3, this protein). They have an important and necessary role in epithelial restitution within the gastrointestinal tract. Significant amounts of TFF are present in human milk. Evidence has been presented that TFF3 isolated from milk strongly correlates with downregulation of IL-6 and IL-8 in human intestinal epithelial cells. On the other hand, TFF3 activated the epithelial cells in culture to produce beta-defensin 2 (hBD2) and beta defensins 4 (hBD4). These findings suggest that TFF can activate intestinal epithelial cells and could actively participate in the immune system of breastfed babies by inducing the production of peptides related to innate defence, such as defensins.^[9]

Activation of PAR-2 receptors

Two main mechanisms have been described for the activation of PAR-2: (A) by specific cleavage that unmask the receptor-activating peptide sequence present in the extracellular N-terminal domain of each PAR, leading to cell signaling via interaction of the exposed tethered ligand with the body of the receptor itself; and (B) by synthetic peptides, such as SLIGKV, that bind to the receptor, mimicking the actions of agonist proteases.^[10] During lactation, TFF3 secreted in human milk may activate intestinal epithelial cells through PAR-2 receptors, which in turn induces hBD2 and hBD4 expression and cytokine regulation.^[10]

Clinical significance

Using TFF3 as a marker of columnar epithelium, a process using an ingestible oesophageal sampling device (Cytosponge) coupled with immunocytochemistry for trefoil factor 3 to improve the accuracy and acceptability of the detection/screening of Barrett's oesophagus has been developed.^[11] However the clinical utility of such a test may be limited by frequent staining of TFF3 in gastric cardia and subsequent risk of false positives.^[12]