The Tumor Suppressor TFF1 Occurs in Different Forms and Interacts with Multiple Partners in the Human Gastric Mucus Barrier: Indications for Diverse Protective Functions

• Published in: International journal of molecular sciences 2020-04, Vol.21 (7), p.2508
• Main Authors: Heuer, Jörn, Heuer, Franziska, Stürmer, René, Harder, Sönke, Schlüter, Hartmut, Braga Emidio, Nayara, Muttenthaler, Markus, Jechorek, Dörthe, Meyer, Frank, Hoffmann, Werner
• Format: Article
• Language: English
• Subjects: Adenoma; Carcinoma; Carrier Proteins - metabolism; Cell adhesion & migration; Cell Adhesion Molecules - metabolism; Cysteine - metabolism; Disulfide bonds; Fc receptors; FCGBP; Gastric cancer; Gastric mucosa; Gastric Mucosa - metabolism; gastrokine; Humans; Hydrogen peroxide; Immunoglobulin G; inflammation; Mucin; Mucin-6 - metabolism; Mucus; Oxidative stress; Peptides; Polyethylene glycol; Protein Binding; Protein Multimerization; Proteins; Pyloric Antrum - metabolism; reactive oxygen species; Residues; Trefoil factor; trefoil factor, TFF1; Trefoil Factor-1 - chemistry; Trefoil Factor-1 - metabolism; Tumor suppressor genes; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21072508

TFF1 is a protective peptide of the Trefoil Factor Family (TFF), which is co-secreted with the mucin MUC5AC, gastrokine 2 (GKN2), and IgG Fc binding protein (FCGBP) from gastric surface mucous cells. -deficient mice obligatorily develop antropyloric adenoma and about 30% progress to carcinomas, indicating that Tff1 is a tumor suppressor. As a hallmark, TFF1 contains seven cysteine residues with three disulfide bonds stabilizing the conserved TFF domain. Here, we systematically investigated the molecular forms of TFF1 in the human gastric mucosa. TFF1 mainly occurs in an unusual monomeric form, but also as a homodimer. Furthermore, minor amounts of TFF1 form heterodimers with GKN2, FCGBP, and an unknown partner protein, respectively. TFF1 also binds to the mucin MUC6 in vitro, as shown by overlay assays with synthetic I-labeled TFF1 homodimer. The dominant presence of a monomeric form with a free thiol group at Cys-58 is in agreement with previous studies in and mouse. Cys-58 is likely highly reactive due to flanking acid residues (PPEEEC EF) and might act as a scavenger for extracellular reactive oxygen/nitrogen species protecting the gastric mucosa from damage by oxidative stress, e.g., H O generated by dual oxidase (DUOX).