Genomes and Genes
formyl peptide receptors
Summary: A family of G-protein-coupled receptors that was originally identified by its ability to bind N-formyl peptides such as N-FORMYLMETHIONINE LEUCYL-PHENYLALANINE. Since N-formyl peptides are found in MITOCHONDRIA and BACTERIA, this class of receptors is believed to play a role in mediating cellular responses to cellular damage and bacterial invasion. However, non-formylated peptide ligands have also been found for this receptor class.
- Tokay T, Hachem R, Masmoudi Kouki O, Gandolfo P, Desrues L, Leprince J, et al. Beta-amyloid peptide stimulates endozepine release in cultured rat astrocytes through activation of N-formyl peptide receptors. Glia. 2008;56:1380-9 pubmed publisher..Taken together, these data demonstrate for the first time that Abeta(25-35) stimulates endozepine release from rat astrocytes through a FPR receptor positively coupled to PKA and PKC. ..
- Gripentrog J, Mills J, Saari G, Miettinen H. Variable responses of formyl peptide receptor haplotypes toward bacterial peptides. Immunogenetics. 2008;60:83-93 pubmed publisher..We also investigated whether certain FPR haplotypes are associated with rheumatoid arthritis (RA) by sequencing FPR1 from 148 Caucasian individuals. The results suggested that FPR haplotypes do not significantly contribute toward RA. ..
- Betten A -, Bylund J, Christophe T, Cristophe T, Boulay F, Romero A, et al. A proinflammatory peptide from Helicobacter pylori activates monocytes to induce lymphocyte dysfunction and apoptosis. J Clin Invest. 2001;108:1221-8 pubmed..These novel mechanisms may be subject to local, histaminergic regulation in the gastric mucosa. ..
- Rabiet M, Huet E, Boulay F. Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR. Eur J Immunol. 2005;35:2486-95 pubmed..We identified novel mitochondrial host-derived agonists for human N-formyl-peptide receptors that might play a role in inflammatory or degenerative processes linked to their stimulation. ..
- Le Y, Oppenheim J, Wang J. Pleiotropic roles of formyl peptide receptors. Cytokine Growth Factor Rev. 2001;12:91-105 pubmed..These new findings have greatly expanded the functional scope of the formyl peptide receptors and call for more in-depth investigation of the role of these receptors in pathophysiological conditions.
- Glogauer M, Hartwig J, Stossel T. Two pathways through Cdc42 couple the N-formyl receptor to actin nucleation in permeabilized human neutrophils. J Cell Biol. 2000;150:785-96 pubmed..Since maximal inhibition of the Arp2/3 pathway leaves an N17Rac inhibitable alternate pathway intact, we conclude that this alternate involves phosphoinositide-mediated uncapping of actin filament barbed ends. ..
- Sun R, Iribarren P, Zhang N, Zhou Y, Gong W, Cho E, et al. Identification of neutrophil granule protein cathepsin G as a novel chemotactic agonist for the G protein-coupled formyl peptide receptor. J Immunol. 2004;173:428-36 pubmed..Thus, our studies identify CaG as a novel, host-derived chemotactic agonist for FPR and expand the functional scope of this receptor in inflammatory and immune responses. ..
- Mills J, Miettinen H, Cummings D, Jesaitis A. Characterization of the binding site on the formyl peptide receptor using three receptor mutants and analogs of Met-Leu-Phe and Met-Met-Trp-Leu-Leu. J Biol Chem. 2000;275:39012-7 pubmed
- Loor F, Tiberghien F, Wenandy T, Didier A, Traber R. Cyclosporins: structure-activity relationships for the inhibition of the human FPR1 formylpeptide receptor. J Med Chem. 2002;45:4613-28 pubmed..Moreover, because the conformations of the N(10)-desmethylated cyclosporins widely differ from the CsH one, they probably bind to different pharmacophores on the FPR molecules. ..
- Migeotte I, Riboldi E, Franssen J, Gregoire F, Loison C, Wittamer V, et al. Identification and characterization of an endogenous chemotactic ligand specific for FPRL2. J Exp Med. 2005;201:83-93 pubmed..Therefore, F2L appears as a new natural chemoattractant peptide for DCs and monocytes, and the first potent and specific agonist of FPRL2. ..
- Bennett T, Foutz T, Gurevich V, Sklar L, Prossnitz E. Partial phosphorylation of the N-formyl peptide receptor inhibits G protein association independent of arrestin binding. J Biol Chem. 2001;276:49195-203 pubmed..We therefore propose that phosphorylation alone may be sufficient to desensitize the FPR in vivo, raising the possibility that for certain G protein-coupled receptors, desensitization may not be the primary function of arrestin. ..
- Kirpotina L, Khlebnikov A, Schepetkin I, Ye R, Rabiet M, Jutila M, et al. Identification of novel small-molecule agonists for human formyl peptide receptors and pharmacophore models of their recognition. Mol Pharmacol. 2010;77:159-70 pubmed publisher..These studies further demonstrate that agonists of FPR1/FPR2 include compounds with wide chemical diversity and that analysis of such compounds can enhance our understanding of their ligand/receptor interaction. ..
- Chiang N, Gronert K, Clish C, O Brien J, Freeman M, Serhan C. Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion. J Clin Invest. 1999;104:309-16 pubmed..Moreover, LXA4 and ATL counter BLTR-amplified networks, revealing a novel protective role for LX and ATL in stress responses that has applications in perioperative medicine. ..
- Southgate E, He R, Gao J, Murphy P, Nanamori M, Ye R. Identification of formyl peptides from Listeria monocytogenes and Staphylococcus aureus as potent chemoattractants for mouse neutrophils. J Immunol. 2008;181:1429-37 pubmed..aureus are approximately 100-fold more potent than fMLF in activating mouse neutrophils. The ability of mFPR1 to detect bacterially derived formyl peptides indicates that this important host defense mechanism is conserved in mice. ..
- Bylund J, Samuelsson M, Collins L, Karlsson A. NADPH-oxidase activation in murine neutrophils via formyl peptide receptors. Exp Cell Res. 2003;282:70-7 pubmed..Finally, we show that a synthetic hexapeptide, WKYMVM, is a more potent stimulus than fMLF for murine neutrophils and that these two agonists probably act via nonidentical high-affinity receptors. ..
- Haas P, de Haas C, Kleibeuker W, Poppelier M, Van Kessel K, Kruijtzer J, et al. N-terminal residues of the chemotaxis inhibitory protein of Staphylococcus aureus are essential for blocking formylated peptide receptor but not C5a receptor. J Immunol. 2004;173:5704-11 pubmed..4 +/- 7.7 nM) could be an important new tool to further stimulate the fundamental research on the mechanisms underlying the FPR and its role in disease processes. ..
- Gauthier J, Fortin A, Bergeron Y, Dumas M, Champagne M, Bergeron M. Differential contribution of bacterial N-formyl-methionyl-leucyl- phenylalanine and host-derived CXC chemokines to neutrophil infiltration into pulmonary alveoli during murine pneumococcal pneumonia. Infect Immun. 2007;75:5361-7 pubmed..Our results suggest that fMLP and chemokines play important roles in pneumococcal pneumonia and that these roles vary according to bacterial and host genetic backgrounds, implying redundancy among chemoattractant molecules...
- Huang J, Hu J, Bian X, Chen K, Gong W, Dunlop N, et al. Transactivation of the epidermal growth factor receptor by formylpeptide receptor exacerbates the malignant behavior of human glioblastoma cells. Cancer Res. 2007;67:5906-13 pubmed..Thus, targeting both receptors may yield antiglioblastoma agents superior to those targeting one of them. ..
- Bylund J, Pellmé S, Fu H, Mellqvist U, Hellstrand K, Karlsson A, et al. Cytochalasin B triggers a novel pertussis toxin sensitive pathway in TNF-alpha primed neutrophils. BMC Cell Biol. 2004;5:21 pubmed..The receptor uncoupling results in respiratory burst activity when signals generated by reactivated formyl peptide receptors trigger the NADPH-oxidase to produce superoxide anions...
- Kim S, Kim Y, Lee H, Kim Y, Jeon S, Baek S, et al. The agonists of formyl peptide receptors prevent development of severe sepsis after microbial infection. J Immunol. 2010;185:4302-10 pubmed publisher..In this paper, we report that the administration of peptide agonists of formyl peptide receptors, including Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm), protected against death by enhanced bactericidal activity ..
- Hartt J, Barish G, Murphy P, Gao J. N-formylpeptides induce two distinct concentration optima for mouse neutrophil chemotaxis by differential interaction with two N-formylpeptide receptor (FPR) subtypes. Molecular characterization of FPR2, a second mouse neutrophil FPR. J Exp Med. 1999;190:741-7 pubmed
- Bylund J, Björstad A, Granfeldt D, Karlsson A, Woschnagg C, Dahlgren C. Reactivation of formyl peptide receptors triggers the neutrophil NADPH-oxidase but not a transient rise in intracellular calcium. J Biol Chem. 2003;278:30578-86 pubmed..We show that the deactivated formyl peptide receptors (FPRs) can be reactivated/resensitized by the cytoskeleton-disrupting drug cytochalasin B...
- Stenfeldt A, Karlsson J, Wenneras C, Bylund J, Fu H, Dahlgren C. Cyclosporin H, Boc-MLF and Boc-FLFLF are antagonists that preferentially inhibit activity triggered through the formyl peptide receptor. Inflammation. 2007;30:224-9 pubmed..Lately, a great number of agonists for various formyl peptide receptors have been identified using a selection of antagonists...
- Migeotte I, Communi D, Parmentier M. Formyl peptide receptors: a promiscuous subfamily of G protein-coupled receptors controlling immune responses. Cytokine Growth Factor Rev. 2006;17:501-19 pubmed..Newly developed tools will allow to study further this family of receptors. ..
- Yao X, Ping Y, Chen J, Xu C, Chen D, Zhang R, et al. Glioblastoma stem cells produce vascular endothelial growth factor by activation of a G-protein coupled formylpeptide receptor FPR. J Pathol. 2008;215:369-76 pubmed publisher..Our results indicate that FPR expressed by human GSCs may play an important role in glioma angiogenesis. ..
- Hauser C, Sursal T, Rodriguez E, Appleton P, Zhang Q, Itagaki K. Mitochondrial damage associated molecular patterns from femoral reamings activate neutrophils through formyl peptide receptors and P44/42 MAP kinase. J Orthop Trauma. 2010;24:534-8 pubmed publisher..MTD then activates PMN. Release of damage signals like MTD from FFx may underlie activation of the cytokine cascades known to be associated with fracture fixation and lung injury. ..
- Wang Z, Ye R. Characterization of two new members of the formyl peptide receptor gene family from 129S6 mice. Gene. 2002;299:57-63 pubmedb>Formyl peptide receptors are G-protein-coupled, seven-transmembrane domain receptors originally identified in leukocytes...
- Yang D, Chen Q, Gertz B, He R, Phulsuksombati M, Ye R, et al. Human dendritic cells express functional formyl peptide receptor-like-2 (FPRL2) throughout maturation. J Leukoc Biol. 2002;72:598-607 pubmed
- Czapiga M, Gao J, Kirk A, Lekstrom Himes J. Human platelets exhibit chemotaxis using functional N-formyl peptide receptors. Exp Hematol. 2005;33:73-84 pubmed..Given their myeloid lineage, we hypothesized that platelets express functional N-formyl peptide receptors and respond to the bacterially derived chemotactic peptide N-formyl peptide with gradient-driven ..
- Cilibrizzi A, Quinn M, Kirpotina L, Schepetkin I, Holderness J, Ye R, et al. 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones: a novel class of small-molecule agonists for formyl peptide receptors. J Med Chem. 2009;52:5044-57 pubmed publisher..Agonists were able to activate intracellular calcium mobilization and chemotaxis in human neutrophils. The most potent chemotactic agent (EC(50) = 0.6 microM) was the mixed FPR/FPRL1 agonist 14h. ..
- Rabiet M, Huet E, Boulay F. The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview. Biochimie. 2007;89:1089-106 pubmed..Although FPR, FPRL1 and C5aR trigger similar biological functions and undergo a rapid chemoattractant-mediated phosphorylation, they appear to be differentially regulated and experience different intracellular fates. ..
- Elagoz A, Henderson D, Babu P, Salter S, Grahames C, Bowers L, et al. A truncated form of CKbeta8-1 is a potent agonist for human formyl peptide-receptor-like 1 receptor. Br J Pharmacol. 2004;141:37-46 pubmed..These interactions were shown to be via FPRL-1 by specific blockade of PMNs activation in the presence of an FPRL-1 antibody. ..
- Bae Y, Lee H, Jo E, Kim J, Kang H, Ye R, et al. Identification of peptides that antagonize formyl peptide receptor-like 1-mediated signaling. J Immunol. 2004;173:607-14 pubmed..WRW(4) is the first specific FPRL1 antagonist and is expected to be useful in the study of FPRL1 signaling and in the development of drugs against FPRL1-related diseases. ..
- Magalhaes M, Zhu F, Sarantis H, Gray Owen S, Ellen R, Glogauer M. Expression and translocation of fluorescent-tagged p21-activated kinase-binding domain and PH domain of protein kinase B during murine neutrophil chemotaxis. J Leukoc Biol. 2007;82:559-66 pubmed..The visualization and analysis of transfected fluorescent markers in primary neutrophils are a powerful technique to monitor chemotaxis signaling pathways in real time. ..
- Le Y, Wetzel M, Shen W, Gong W, Rogers T, Henderson E, et al. Desensitization of chemokine receptor CCR5 in dendritic cells at the early stage of differentiation by activation of formyl peptide receptors. Clin Immunol. 2001;99:365-72 pubmedChemokine receptors are subjected to heterologous desensitization by activation of formyl peptide receptors. We investigated the cross-talk between formyl peptide receptors and the chemokine receptor CCR5 in human monocyte-differentiated ..
- Zhou Y, Bian X, Le Y, Gong W, Hu J, Zhang X, et al. Formylpeptide receptor FPR and the rapid growth of malignant human gliomas. J Natl Cancer Inst. 2005;97:823-35 pubmed..Thus, FPR may represent a molecular target for the development of novel antiglioma therapeutics. ..
- Fillion I, Ouellet N, Simard M, Bergeron Y, Sato S, Bergeron M. Role of chemokines and formyl peptides in pneumococcal pneumonia-induced monocyte/macrophage recruitment. J Immunol. 2001;166:7353-61 pubmed..These data demonstrate that a complex chemokine network is activated in response to pulmonary pneumococcal infection, and also suggest an important role for fMLP receptor in monocyte/macrophage recruitment in that model. ..
- Perretti M, Chiang N, La M, Fierro I, Marullo S, Getting S, et al. Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor. Nat Med. 2002;8:1296-302 pubmed
- Gavins F, Yona S, Kamal A, Flower R, Perretti M. Leukocyte antiadhesive actions of annexin 1: ALXR- and FPR-related anti-inflammatory mechanisms. Blood. 2003;101:4140-7 pubmed..The present findings demonstrate that endogenous regulatory autocoids such as lipoxin A(4) and annexin 1-derived peptides function to disengage adherent cells during cell-cell interactions. ..
- Kuhns D, Nelson E, Alvord W, Gallin J. Fibrinogen induces IL-8 synthesis in human neutrophils stimulated with formyl-methionyl-leucyl-phenylalanine or leukotriene B(4). J Immunol. 2001;167:2869-78 pubmed..The data indicate that fibrinogen can function not only as a substrate in the clotting cascade, but also as an important effector during the evolution of the innate immune response. ..
- Liberles S, Horowitz L, Kuang D, CONTOS J, Wilson K, Siltberg Liberles J, et al. Formyl peptide receptors are candidate chemosensory receptors in the vomeronasal organ. Proc Natl Acad Sci U S A. 2009;106:9842-7 pubmed publisher..Given the presence of formylated peptides in bacteria and mitochondria, possible roles for VNO FPRs include the assessment of conspecifics or other species based on variations in normal bacterial flora or mitochondrial proteins. ..
- Kam A, Liu A, Wong Y. Formyl peptide-receptor like-1 requires lipid raft and extracellular signal-regulated protein kinase to activate inhibitor-kappa B kinase in human U87 astrocytoma cells. J Neurochem. 2007;103:1553-66 pubmed..Taken together, these results demonstrate that FPRL-1 is capable of activating NFkappaB signaling through IKK phosphorylation and this may serve as a useful therapeutical target for FPRL-1-related diseases. ..
- Seifert R, Wenzel Seifert K. Defective Gi protein coupling in two formyl peptide receptor mutants associated with localized juvenile periodontitis. J Biol Chem. 2001;276:42043-9 pubmed..The severe functional defects in FPR-F110S and FPR-C126W contrast with the discrete clinical symptoms associated with these mutations, indicating that loss of FPR function in host defense is, for the most part, readily compensated. ..
- Rondepierre F, Bouchon B, Papon J, Bonnet Duquennoy M, Kintossou R, Moins N, et al. Proteomic studies of B16 lines: involvement of annexin A1 in melanoma dissemination. Biochim Biophys Acta. 2009;1794:61-9 pubmed publisher..We further demonstrated that the presence of several formyl peptide receptors (FPR1, FPRrs1 and 2) revealed by qRT-PCR, played a role in B16 invasion: incubation of B16Bl6 cells with ..
- Postma B, Poppelier M, van Galen J, Prossnitz E, Van Strijp J, de Haas C, et al. Chemotaxis inhibitory protein of Staphylococcus aureus binds specifically to the C5a and formylated peptide receptor. J Immunol. 2004;172:6994-7001 pubmed..This selectivity and high-affinity binding with potent antagonistic effects makes CHIPS a promising lead for the development of new anti-inflammatory compounds for diseases in which damage by neutrophils plays a key role. ..
- Deng X, Ueda H, Su S, Gong W, Dunlop N, Gao J, et al. A synthetic peptide derived from human immunodeficiency virus type 1 gp120 downregulates the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes by activating the 7-transmembrane G-protein-coupled receptor FPRL1/LXA4R. Blood. 1999;94:1165-73 pubmed..This may explain, at least in part, the initial activation of innate immune responses in HIV-1-infected patients followed by immune suppression. ..
- John C, Sahni V, Mehet D, Morris J, Christian H, Perretti M, et al. Formyl peptide receptors and the regulation of ACTH secretion: targets for annexin A1, lipoxins, and bacterial peptides. FASEB J. 2007;21:1037-46 pubmedThe N-formyl peptide receptors (FPRs) are a family of G-protein coupled receptors that respond to proinflammatory N-formylated bacterial peptides (e.g...
- Lee H, Kim M, Park K, Bae Y, Yun J, Park J, et al. Serum amyloid A stimulates matrix-metalloproteinase-9 upregulation via formyl peptide receptor like-1-mediated signaling in human monocytic cells. Biochem Biophys Res Commun. 2005;330:989-98 pubmed..Taken together, we suggest that SAA plays a role in the modulation of inflammatory and immune responses via FPRL1, by inducing MMP-9 upregulation in human monocytic cells. ..
- Seifert R, Wenzel Seifert K. The human formyl peptide receptor as model system for constitutively active G-protein-coupled receptors. Life Sci. 2003;73:2263-80 pubmed..Moreover, N-glycosylation of the N-terminus seems to be important for constitutive FPR activity. Finally, we discuss some future directions of research. ..
- Viswanathan A, Painter R, Lanson N, Wang G. Functional expression of N-formyl peptide receptors in human bone marrow-derived mesenchymal stem cells. Stem Cells. 2007;25:1263-9 pubmed..Therefore, the N-formyl peptide receptors present in MSCs may play an important role in signaling stem cell adhesion, migration, and homing to ..
- Pieretti S, Di Giannuario A, De Felice M, Perretti M, Cirino G. Stimulus-dependent specificity for annexin 1 inhibition of the inflammatory nociceptive response: the involvement of the receptor for formylated peptides. Pain. 2004;109:52-63 pubmed..These results indicate that exogenously administered Anxa1 can peripherally and centrally inhibit the nociceptive transmission associated with inflammatory processes through a mechanism that involves formyl peptide receptors.
- Babbin B, Lee W, Parkos C, Winfree L, Akyildiz A, Perretti M, et al. Annexin I regulates SKCO-15 cell invasion by signaling through formyl peptide receptors. J Biol Chem. 2006;281:19588-99 pubmed..extracellular AnxA1 has been shown to regulate leukocyte migratory events through interactions with n-formyl peptide receptors (nFPRs), we examined the expression of FPR-1, FPRL-1, and FPRL-2 in SKCO-15 cells by reverse ..
- Betten A, Dahlgren C, Hermodsson S, Hellstrand K. Histamine inhibits neutrophil NADPH oxidase activity triggered by the lipoxin A4 receptor-specific peptide agonist Trp-Lys-Tyr-Met-Val-Met. Scand J Immunol. 2003;58:321-6 pubmed..Our data suggest that histamine downregulates FPRL1- and FPR-induced NADPH oxidase activity upstream of protein kinase C (PKC) and downstream of the separation of the peptide-induced signal into granule secretion and oxidase activation. ..