Mechanisms of regulatory peptide action in the gastrointestinal tract: trefoil peptides.

The trefoil peptide family is comprised of three small peptides (designated pS2, SP, and ITF) exhibiting a unique motif of three intrachain loops formed by disulfide bonds. These highly protease-resistant peptides are secreted onto the mucosal surface by goblet cells or their equivalents. Most importantly, these factors protect epithelium from injury and promote repair through restitution after injury has occurred. Targeted deletion of the gene encoding ITF results in exquisite sensitivity to colonic injury by standard agents (e.g., dextran sodium sulfate) due to an inability to repair the epithelium. Studies have led to insight into the intracellular responses to trefoil peptides, including ras-dependent MAP kinase activation and activation of epidermal growth factor receptor. Among other effects, activation of these pathways is associated with redistribution of E-cadherin from the cell surface to intracellular domains, where it is complexed with catenins, and phosphorylation of akt, inactivating this kinase associated with apoptosis. In addition, trefoil peptides appear to block both p53 dependent and p53 independent apoptosis through pathways associated with activation of EGFR and P13 kinase. These observations suggest that trefoil peptides elicit a coordinated cellular response enabling cell migration without triggering the programmed cell death response usually precipitated by cell detachment from a stationary anchored state.