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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Review FPR1 (formyl peptide receptor 1) Jian Huang, Ji Ming Wang High Altitude Military Medical College, Third Military Medical University, Chongqing, 400038, China (JH), Laboratory of Molecular Immunoregulation, Cancer and inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA (JMW) Published in Atlas Database: June 2012 Online updated version : http://AtlasGeneticsOncology.org/Genes/FPR1ID44328ch19q13.html DOI : 10.4267/2042/48359 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology as lung epithelial cells and hepatocytes. These findings suggest that FPR1 is involved in a broader spectrum of pathophysiologic processes. Identity Other names: FMLP, FPR HGNC (Hugo): FPR1 Location: 19q13.41 Description DNA/RNA Transcription Size: 6127 bases. All three genes, FPR1, FPR2 and FPR3, are clustered on chromosome 19q13.3. FPR1 is encoded by a 6 kb single copy gene. The open reading frame is intronless but the 5' untranslated region resides in three exons. The start sites for transcription and translation are separated by approximately 5 kb. The FPR1 gene contains three Alu repeats, one in each intron and a third in the 3' flanking region. The proposed promoter contains a nonconsensus TATA box and an inverted CCAAT element. Note FPR1 is a G protein-coupled receptor (GPCR), originally identified in phagocytic leukocytes, which mediates cell chemotaxis and activation in response to the bacterial chemotactic peptide N-formyl-methionylleucyl-phenylalanine (fMLF). A number of host-derived chemotactic agonists of FPR1 have been identified, including formyl peptides potentially released by mitochondria of ruptured cells, Annexin I produced by activated epithelia, and a neutrophil granule protein, cathepsin G. In addition, functional FPR1 has been detected in cells of nonhematopoietic origin, such Pseudogene No known pseudogenes. This gene is located in formylpeptide receptor gene cluster region including FPR1, FPR2 and FPR3 on chromosome 19p. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12) 889 FPR1 (formyl peptide receptor 1) Huang J, Wang JM Predicted transmembrane disposition of the human FPR1. al., 2001). The 11 Ser and Thr residues in the cytoplasmic tail are potential phosphorylation sites for GRK2 and GRK3 (Prossnitz et al., 1995). CHO, carbohydrate, marks the identified and potential (in parenthesis) sites for N-glycosylation. The predicted disulfide bond between Cys98 and Cys176 is marked with double-line (=). Protein Note FPR1 gene encodes a putative 350 aminoacid protein with seven transmembrane segments, three extra- and two intra-cellular loops. Description Expression The protein sequence of the FPR-98 isoform (Leu110, Ala346) is shown (Boulay et al.,1990; Ye et al., 2009). The transmembrane domains (TMs) are predicted based on hydrophobicity of the amino acid sequence and on similarities to the rhodopsin structure. The amino acids that form the boundaries of the transmembrane domains are numbered. One-letter amino acid code is used. The square blocks in reverce color represent positions at which amino acid substitutions result from polymorphisms, including amino acids 11 (Ile/Thr), 47 (Val/Ala), 101 (Leu/Val), 190 (Arg/Trp), 192 (Asn/Lys) and 346 (Ala/Glu). The circle blocks in reverse color indicate amino acids with known functions as follows. Arg84, Lys85, and Asp284 are critical for high-affinity binding of fMLF (Mills et al., 1998; Quehenberger et al., 1997). Asp122, Arg123, and Cys124 are the signature sequence for G protein interaction (DRY in many GPCRs). NPMLY in the TM7 are known signature sequence (NPXXY) for receptor internalization (Gripentrog et al., 2000; He et Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12) FPR1 has been detected in phagocytic leukocytes, hepatocytes, dendritic cells, astrocytes, microglia cells, and the tunica media of coronary arteries. Becker et al. showed that FPR1 or an antigenically similar receptor is located in a number of human tissues and organs, including secretory cells in the thyroid, adrenals and other glands, the liver, the central nervous system, and neurons in the autonomic nervous system. FPR1 is also expressed in neutrophils of non-human primates and rodents. Localisation Cell membrane. Function Agonist binding to FPR1 elicits a cascade of signal transduction pathways that involve phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinases (MAPK), and the transcription factors nuclear factorκB and hypoxic inducible factor-1α (HIF-1α). 890 FPR1 (formyl peptide receptor 1) Huang J, Wang JM Amino acid sequence of FPR-WT and localization of the F110S and C126W mutations (Seifert et al., 2001). Shown is the twodimensional structure of FPR-WT (isoform 26) (27). Amino acids are given in one-letter code. The FPR N terminus (top) faces the extracellular space; the FPR C terminus (bottom) faces the cytosol. The transmembrane domains are included in the boxed area. Extracellular consensus sites for N-glycosylation are shown (Y). The positions of the F110S and C126W mutations are indicated (•). There is a disulfide bridge between the first and second extracellular loops. Note that the consensus sites for N-glycosylation are not altered in FPR-F110S and FPR-C126W. Because of its expression in cells of the immune system and its interaction with bacterial chemotactic peptides, this receptor was thought to participate in host defense against microbial infection. In addition, FPR1 expressed in highly malignant human glioblastoma promotes tumor progression. Prognosis FPR1 protein staining was detected in 11 of 14 grade III anaplastic astrocytoma specimens and six of six grade IV glioblastoma multiforme specimens. Microvessels and necrotic tumor cells were readily visible among FPR1-positive intact tumor cells. In contrast, only two of 13 less aggressive grade II astrocytoma specimens showed positive FPR staining. Thus, FPR expression appears to be associated with a majority of poorly differentiated primary human gliomas of grades III and IV. Cytogenetics Highly malignant human glioblastoma and anaplastic astrocytoma specimens were stained positively for FPR1. FPR1 was expressed selectively in glioma cell lines with a more highly malignant phenotype. FPR expressed in glioblastoma cell lines mediates cell chemotaxis, proliferation and production of an angiogenic factor, vascular endothelial growth factor (VEGF), in response to agonists released by necrotic tumor cells. Furthermore, FPR in glioblastoma cells activates the receptor for epidermal growth factor (EGFR) by increasing the Homology In primates, the sequence of FPR1 is highly conserved. Rabbit and mouse FPR1 share 78 and 76% identity with human FPR1 respectively. Mutations Two loss of funtion mutations (F110S and C126W) that correlate with localized juvenile periodontitis. The F110S mutation resides in the third transmembrane domain, whereas the C126W mutation resides in the second intracellular loop. Implicated in Glioblastoma Note Promoting glioblastoma progression. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12) 891 FPR1 (formyl peptide receptor 1) Huang J, Wang JM The role of FPR in glioblastoma progression. FPR on glioblastoma cells is activated by agonists released by necrotic tumor cells. The signaling cascade coupled to FPR in tumor cells activates PI3 kinase, MAPKs, PLC, PLD, Akt/Bcl2 and transcription factors such as NFκB, STAT3 and HIF-1α, to enhance cell chemotaxis, growth and release of angiogenic factors. The FPR function in glioblastoma cells is partially mediated by EGFR through a Src-kinase dependent transactivation pathway (Huang et al., 2008). Quehenberger O, Pan ZK, Prossnitz ER, Cavanagh SL, Cochrane CG, Ye RD. Identification of an N-formyl peptide receptor ligand binding domain by a gain-of-function approach. Biochem Biophys Res Commun. 1997 Sep 18;238(2):377-81 phosphorylation of a selected tyrosine residue in the intracellular tail of EGFR. Thus, FPR hijacked by human glioblastoma cells exploits the function of EGFR to promote rapid tumor progression. Becker EL, Forouhar FA, Grunnet ML, Boulay F, Tardif M, Bormann BJ, Sodja D, Ye RD, Woska JR Jr, Murphy PM. Broad immunocytochemical localization of the formylpeptide receptor in human organs, tissues, and cells. Cell Tissue Res. 1998 Apr;292(1):129-35 Inflammation Note Mediating neutrophil accumulation at the sites of injury. Mills JS, Miettinen HM, Barnidge D, Vlases MJ, Wimer-Mackin S, Dratz EA, Sunner J, Jesaitis AJ. Identification of a ligand binding site in the human neutrophil formyl peptide receptor using a site-specific fluorescent photoaffinity label and mass spectrometry. J Biol Chem. 1998 Apr 24;273(17):10428-35 Antibacteria host defense Note Mediating host resistance against Listeria infection. Gao JL, Lee EJ, Murphy PM. Impaired antibacterial host defense in mice lacking the N-formylpeptide receptor. J Exp Med. 1999 Feb 15;189(4):657-62 References Boulay F, Tardif M, Brouchon L, Vignais P. Synthesis and use of a novel N-formyl peptide derivative to isolate a human Nformyl peptide receptor cDNA. Biochem Biophys Res Commun. 1990 May 16;168(3):1103-9 Gripentrog JM, Jesaitis AJ, Miettinen HM. A single amino acid substitution (N297A) in the conserved NPXXY sequence of the human N-formyl peptide receptor results in inhibition of desensitization and endocytosis, and a dose-dependent shift in p42/44 mitogen-activated protein kinase activation and chemotaxis. Biochem J. 2000 Dec 1;352 Pt 2:399-407 Prossnitz ER, Kim CM, Benovic JL, Ye RD. Phosphorylation of the N-formyl peptide receptor carboxyl terminus by the G protein-coupled receptor kinase, GRK2. J Biol Chem. 1995 Jan 20;270(3):1130-7 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12) 892 FPR1 (formyl peptide receptor 1) Huang J, Wang JM He R, Browning DD, Ye RD. Differential roles of the NPXXY motif in formyl peptide receptor signaling. J Immunol. 2001 Mar 15;166(6):4099-105 behavior of human glioblastoma cells. Cancer Res. 2007 Jun 15;67(12):5906-13 Huang J, Chen K, Gong W, Zhou Y, Le Y, Bian X, Wang JM. Receptor "hijacking" by malignant glioma cells: a tactic for tumor progression. Cancer Lett. 2008 Aug 28;267(2):254-61 Seifert R, Wenzel-Seifert K. Defective Gi protein coupling in two formyl peptide receptor mutants associated with localized juvenile periodontitis. J Biol Chem. 2001 Nov 9;276(45):420439 Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM. International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol Rev. 2009 Jun;61(2):119-61 Le Y, Murphy PM, Wang JM. Formyl-peptide receptors revisited. Trends Immunol. 2002 Nov;23(11):541-8 Zhou Y, Bian X, Le Y, Gong W, Hu J, Zhang X, Wang L, Iribarren P, Salcedo R, Howard OM, Farrar W, Wang JM. Formylpeptide receptor FPR and the rapid growth of malignant human gliomas. J Natl Cancer Inst. 2005 Jun 1;97(11):823-35 This article should be referenced as such: Huang J, Wang JM. FPR1 (formyl peptide receptor 1). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12):889-893. Huang J, Hu J, Bian X, Chen K, Gong W, Dunlop NM, Howard OM, Wang JM. Transactivation of the epidermal growth factor receptor by formylpeptide receptor exacerbates the malignant Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12) 893