Intracellular Signaling Triggered by Formyl-Peptide Receptors in Nonphagocytic Cells

Formyl-peptide receptors (FPR) are expressed in several cell types including phagocytic leukocytes, and a wide variety of agonists of FPR and of its FPRL1 variant have been identified. These ligands interact with their specific receptors on the cellular membrane, and activate specific biological functions through a G-protein-coupled pathway. In nonphagocytic cells, agonist/FPR binding also induces transactivation of the constitutive membrane receptors PDGF-R, EGF-R and uPAR that in turn trigger specific, characteristic intracellular signal transduction pathways. The second messengers resulting from the interaction between ligands and formyl-peptide receptors act on various intracellular kinases (mitogen-activated protein kinases, protein kinases C and B, Jun kinase and some tyrosine kinases). Activation of NADPH oxidase expressed in nonphagocytic cells, and phosphorylation and nuclear translocation of regulatory transcriptional factors may be the downstream targets of this signaling cascade. The activated signal transduction pathways also lead to various biochemical cellular responses that can contribute to cell proliferation, and can protect against cell death and the malignant behavior of several human cancer cell lines. Dissection of the signaling cascade triggered by different agonists will shed light on the role of FPRs in nonphagocytic cells in both human physiology and diseases.