Secreted trefoil factor 2 activates the CXCR4 receptor in epithelial and lymphocytic cancer cell lines.
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 approximately 0.5 microm) activate Ca2+ signaling in lymphoblastic Jurkat cells that could be abrogated by receptor desensitization (with SDF-1alpha) or pretreatment with the specific antagonist AMD3100 or an anti-CXCR4 antibody. TFF2 pretreatment of Jurkat cells decreased Ca2+ rise and chemotactic response to SDF-1alpha. 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.
Dubeykovskaya
Zinaida
Z
Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
Dubeykovskiy
Alexander
A
Solal-Cohen
Joel
J
Wang
Timothy C
TC
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001596:Benzylamines; D020013:Calcium Signaling / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D000080027:Cyclams; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009077:Mucins / Q000378:metabolism* / Q000494:pharmacology; D009124:Muscle Proteins / Q000378:metabolism* / Q000494:pharmacology; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000819:agonists / Q000378:metabolism* / Q000494:pharmacology; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000819:agonists / Q000378:metabolism*; D000071164:Trefoil Factor-2
D019380:Anti-HIV Agents; D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D009077:Mucins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D010455:Peptides; D019718:Receptors, CXCR4; C000604007:TFF2 protein, human; C481546:TFF2 protein, mouse; D000071164:Trefoil Factor-2; D020928:Mitogen-Activated Protein Kinases; C088327:plerixafor