Trefoil Factor Family (TFF) Peptides

Trefoil factor family (TFF) peptides mainly consist of characteristic TFF domains, which contain about 40 amino acid residues, including 6 conserved cysteine residues. TFF peptides possess a single (mammalian TFF1 and TFF3), two (mammalian TFF2, Xenopus laevis xP2) or four TFF domains (X. laevis xP4). They exhibit lectin activities and are characteristic exocrine products of the mucous epithelia. Here, they play different roles for mucosal protection and the innate immune defense: TFF1 is a gastric tumor suppressor; TFF2 builds a lectin complex with the mucin MUC6, physically stabilizing the inner gastric mucus layer; and TFF3 forms a disulfide-linked heterodimer with IgG Fc binding protein (FCGBP), probably preventing the infiltration of microorganisms. Minor amounts of TFF peptides are endocrine products of the immune and nervous systems. Pathologically, TFF peptides are linked to inflammation. There are increasing indications that TFF peptides can antagonize cytokine receptors, such as receptors for IL-1β, IL-6, and TNFα (thereby acting as anti-inflammatory peptides). TFF peptides can probably also activate a variety of receptors, such as CXCR4. The TFF domain is a unique shuffled module which is also present in a number of mosaic proteins, such as zona pellucida proteins, sugar degrading enzymes and frog skin mucins. Here, their function seems to be defined by a lectin activity, which might even allow a role in fertilization.

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Trefoil Factor Family (TFF) Peptides and Their Diverse Molecular Functions in Mucus Barrier Protection and More: Changing the Paradigm

International Journal of Molecular Sciences ◽

10.3390/ijms21124535 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4535 ◽

Cited By ~ 2

Author(s):

Werner Hoffmann

Keyword(s):

Thiol Group ◽

Suppressor Gene ◽

Immune Defense ◽

Trefoil Factor ◽

Gastric Mucus ◽

Free Thiol Group ◽

Trefoil Factor Family ◽

Molecular Functions ◽

Mucus Barrier ◽

Tff Peptides

Trefoil factor family peptides (TFF1, TFF2, TFF3) are typically co-secreted together with mucins. Tff1 represents a gastric tumor suppressor gene in mice. TFFs are also synthesized in minute amounts in the immune and central nervous systems. In mucous epithelia, they support rapid repair by enhancing cell migration (“restitution”) via their weak chemotactic and anti-apoptotic effects. For a long time, as a paradigm, this was considered as their major biological function. Within recent years, the formation of disulfide-linked heterodimers was documented for TFF1 and TFF3, e.g., with gastrokine-2 and IgG Fc binding protein (FCGBP). Furthermore, lectin activities were recognized as enabling binding to a lipopolysaccharide of Helicobacter pylori (TFF1, TFF3) or to a carbohydrate moiety of the mucin MUC6 (TFF2). Only recently, gastric TFF1 was demonstrated to occur predominantly in monomeric forms with an unusual free thiol group. Thus, a new picture emerged, pointing to diverse molecular functions for TFFs. Monomeric TFF1 might protect the gastric mucosa as a scavenger for extracellular reactive oxygen/nitrogen species. Whereas, the TFF2/MUC6 complex stabilizes the inner layer of the gastric mucus. In contrast, the TFF3–FCGBP heterodimer (and also TFF1–FCGBP) are likely part of the innate immune defense of mucous epithelia, preventing the infiltration of microorganisms.

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Trefoil Factor Family (TFF) Peptides and their Different Roles in the Mucosal Innate Immune Defense and More: An Update

Current Medicinal Chemistry ◽

10.2174/0929867328666210215114140 ◽

2021 ◽

Vol 28 ◽

Author(s):

Werner Hoffmann

Keyword(s):

Cysteine Residue ◽

Immune Defense ◽

Innate Immune ◽

Molecular Forms ◽

Trefoil Factor ◽

Gastric Mucus ◽

Innate Immune Defense ◽

Trefoil Factor Family

: Mucous epithelia are protected by complex mucus barrier layers, which are part of the innate immune defense. Trefoil factor family peptides TFF1, TFF2, and TFF3 have lectin activities and are predominantly co-secreted together with mucins from these epithelia. TFF1 and TFF2 are mainly expressed in the gastric mucosa; whereas TFF3 is rather widely secreted from most mucous epithelia and their glands. TFF1 and TFF3 consist of a single TFF domain and an additional free 7th cysteine residue; whereas TFF2 contains two TFF domains. Systematic analyses of the molecular forms of TFFs gave new insights into their diverse molecular functions. TFF1 mainly exists as a monomer with an unusual free thiol group and only minor amounts form a disulfide linked homodimer as well as heterodimers with gastrokine-2 and IgG-Fc-binding protein (FCGBP). TFF3 mainly forms a heterodimer with FCGBP in vivo, but binds also Deleted in Malignant Brain Tumors/gp340 (DMBT1gp340) in vitro. In contrast, TFF2 binds as a lectin to a conserved O-linked carbohydrate moiety of the mucin MUC6. Both FCGBP and DMBT1gp340 are secreted from most mucous epithelia and their glands and are involved in mucosal innate immunity. Thus, a new picture emerged pointing to functions of TFF3-FCGBP (and TFF1-FCGBP) for mucosal innate immune defense, e.g. supporting the clearing of microorganisms. Such a function could be well be supported by DMBT1gp340. In contrast, the TFF2/MUC6 complex probably stabilizes physically the inner adherent gastric mucus layer. Furthermore, there are indications that TFF3-FCGBP might play also a role in blood vessels.

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ChemInform Abstract: Trefoil Factor Family (TFF) Peptides and Chemokine Receptors: A Promising Relationship.

ChemInform ◽

10.1002/chin.201009242 ◽

2010 ◽

Vol 41 (9) ◽

Author(s):

Werner Hoffmann

Keyword(s):

Chemokine Receptors ◽

Trefoil Factor ◽

Trefoil Factor Family ◽

Tff Peptides

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Salivary Trefoil Factor Family (TFF) Peptides and Their Roles in Oral and Esophageal Protection: Therapeutic Potential

International Journal of Molecular Sciences ◽

10.3390/ijms222212221 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12221

Author(s):

Werner Hoffmann

Keyword(s):

Wound Healing ◽

Therapeutic Potential ◽

Artificial Saliva ◽

Human Saliva ◽

Immune Defense ◽

Protective Effects ◽

Trefoil Factor Family ◽

Tff Peptides ◽

Antimicrobial Barrier

Human saliva is a complex body fluid with more than 3000 different identified proteins. Besides rheological and lubricating properties, saliva supports wound healing and acts as an antimicrobial barrier. TFF peptides are secreted from the mucous acini of the major and minor salivary glands and are typical constituents of normal saliva; TFF3 being the predominant peptide compared with TFF1 and TFF2. Only TFF3 is easily detectable by Western blotting. It occurs in two forms, a disulfide-linked homodimer (Mr: 13k) and a high-molecular-mass heterodimer with IgG Fc binding protein (FCGBP). TFF peptides are secretory lectins known for their protective effects in mucous epithelia; the TFF3 dimer probably has wound-healing properties due to its weak motogenic effect. There are multiple indications that FCGBP and TFF3-FCGBP play a key role in the innate immune defense of mucous epithelia. In addition, homodimeric TFF3 interacts in vitro with the salivary agglutinin DMBT1gp340. Here, the protective roles of TFF peptides, FCGBP, and DMBT1gp340 in saliva are discussed. TFF peptides are also used to reduce radiotherapy- or chemotherapy-induced oral mucositis. Thus, TFF peptides, FCGBP, and DMBT1gp340 are promising candidates for better formulations of artificial saliva, particularly improving wound healing and antimicrobial effects even in the esophagus.

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Trefoil factor family peptides – friends or foes?

BioMolecular Concepts ◽

10.1515/bmc-2015-0020 ◽

2015 ◽

Vol 6 (5-6) ◽

pp. 343-359 ◽

Cited By ~ 17

Author(s):

Maike Busch ◽

Nicole Dünker

Keyword(s):

Cancer Research ◽

Tumor Suppressors ◽

Current Knowledge ◽

Tumor Biology ◽

Epigenetic Mechanisms ◽

Trefoil Factor ◽

Protective Function ◽

Trefoil Factor Family ◽

Tff Peptides

AbstractTrefoil factor family (TFF) peptides are a group of molecules bearing a characteristic three-loop trefoil domain. They are mainly secreted in mucous epithelia together with mucins but are also synthesized in the nervous system. For many years, TFF peptides were only known for their wound healing and protective function, e.g. in epithelial protection and restitution. However, experimental evidence has emerged supporting a pivotal role of TFF peptides in oncogenic transformation, tumorigenesis and metastasis. Deregulated expression of TFF peptides at the gene and protein level is obviously implicated in numerous cancers, and opposing functions as oncogenes and tumor suppressors have been described. With regard to the regulation of TFF expression, epigenetic mechanisms as well as the involvement of various miRNAs are new, promising aspects in the field of cancer research. This review will summarize current knowledge about the expression and regulation of TFF peptides and the involvement of TFF peptides in tumor biology and cancerogenesis.

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