Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

Abstract

The secreted trefoil factor family 2 (TFF2) protein contributes to the protection of the gastrointestinal mucosa from injury by strengthening and stabilizing mucin gels, stimulating epithelial restitution, and restraining the associated inflammation. Although trefoil factors have been shown to activate signaling pathways, no cell surface receptor has been directly linked to trefoil peptide signaling. Here we demonstrate the ability of TFF2 peptide to activate signaling via the CXCR4 chemokine receptor in cancer cell lines. We found that both mouse and human TFF2 proteins (at ϳ0.5 M) activate Ca 2؉ signaling in lymphoblastic Jurkat cells that could be abrogated by receptor desensitization (with SDF-1␣) or pretreatment with the specific antagonist AMD3100 or an anti-CXCR4 antibody. TFF2 pretreatment of Jurkat cells decreased Ca 2؉ rise and chemotactic response to SDF-1␣. In addition, the CXCR4-negative gastric epithelial cell line AGS became highly responsive to TFF2 treatment upon expression of the CXCR4 receptor. TFF2-induced activation of mitogen-activated protein kinases in gastric and pancreatic cancer cells, KATO III and AsPC-1, respectively, was also dependent on the presence of the CXCR4 receptor. Finally we demonstrate a distinct proliferative effect of TFF2 protein on an AGS gastric cancer cell line that expresses CXCR4. Overall these data identify CXCR4 as a bona fide signaling receptor for TFF2 and suggest a mechanism through which TFF2 may modulate immune and tumorigenic responses in vivo.

Trefoil Factor 2 Requires Na/H Exchanger 2 Activity to Enhance Mouse Gastric Epithelial Repair

“…All of the currently available results indicate TFFs, especially the endogenous gastric TFF2, accelerate gastric epithelial restitution (4). The downstream effectors of TFFs have been elusive, although it has recently been shown that TFF2 activates calcium-dependent signaling and ERK1/2 phosphorylation via the CXCR4 receptor, providing the first validation of a TFF receptor (5). As discussed in a recent review, the expanding information about signaling events stimulated by TFFs is broadening understanding of how restituting cells loosen contacts with neighboring cells, enhance their resistance to apoptosis, and initiate migration across a wound (3).…”

TFF2, a MUC6-binding lectin stabilizing the gastric mucus barrier and more (Review)

“…However, all attempts have so far failed to convincingly demonstrate a typical transmembrane receptor for TFF2. Currently, TFF2 is considered a low affinity ligand for the chemokine receptor CXCR4 (40,41). Furthermore, integrin β1 as well as a large transmembrane glycoprotein with similarity to CRP-Ductin/ DMBT1/gp-340/hensin have been identified as TFF2 binding proteins in the porcine stomach (42).…”

Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization

“…CXCL12 also has an additional receptor, CXCR7, 45 which is believed to act as a decoy receptor to sequester the ligand; 46,47 however, CXCR7 does not appear to have a major role in hematopoiesis. 48 Additionally, there are several low-affinity ligands of CXCR4, such as trefoil factor 2 49 and defensin 50 but their significance in hematopoiesis is unclear. There is considerable evidence showing that CXCR4 signaling provides a key retention signal for HSPCs in the bone marrow.…”