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FPR1 (formyl peptide receptor 1)

Written2012-06Jian Huang, Ji Ming Wang
High Altitude Military Medical College, Third Military Medical University, Chongqing, 400038, China (JH); Laboratory of Molecular Immunoregulation, Cancer, inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA (JMW)

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)FPR
FMLP
Other alias
HGNC (Hugo) FPR1
LocusID (NCBI) 2357
Atlas_Id 44328
Location 19q13.41  [Link to chromosome band 19q13]
Location_base_pair Starts at 51745770 and ends at 51751897 bp from pter ( according to hg19-Feb_2009)  [Mapping FPR1.png]

DNA/RNA

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-methionyl-leucyl-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 as lung epithelial cells and hepatocytes. These findings suggest that FPR1 is involved in a broader spectrum of pathophysiologic processes.
 
  This gene is located in formylpeptide receptor gene cluster region including FPR1, FPR2 and FPR3 on chromosome 19p.
Description Size: 6127 bases.
Transcription 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.
Pseudogene No known pseudogenes.

Protein

Note FPR1 gene encodes a putative 350 aminoacid protein with seven transmembrane segments, three extra- and two intra-cellular loops.
 
  Predicted transmembrane disposition of the human FPR1.
Description 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 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 (=).
Expression 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 factor-κB and hypoxic inducible factor-1α (HIF-1α). 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.
Homology In primates, the sequence of FPR1 is highly conserved. Rabbit and mouse FPR1 share 78 and 76% identity with human FPR1 respectively.

Mutations

Note 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.
 
  Amino acid sequence of FPR-WT and localization of the F110S and C126W mutations (Seifert et al., 2001). Shown is the two-dimensional 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.

Implicated in

Note
  
Entity Glioblastoma
Note Promoting glioblastoma 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 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.
 
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).
  
  
Entity Inflammation
Note Mediating neutrophil accumulation at the sites of injury.
  
  
Entity Antibacteria host defense
Note Mediating host resistance against Listeria infection.
  

Bibliography

Broad immunocytochemical localization of the formylpeptide receptor in human organs, tissues, and cells.
Becker EL, Forouhar FA, Grunnet ML, Boulay F, Tardif M, Bormann BJ, Sodja D, Ye RD, Woska JR Jr, Murphy PM.
Cell Tissue Res. 1998 Apr;292(1):129-35.
PMID 9506920
 
Synthesis and use of a novel N-formyl peptide derivative to isolate a human N-formyl peptide receptor cDNA.
Boulay F, Tardif M, Brouchon L, Vignais P.
Biochem Biophys Res Commun. 1990 May 16;168(3):1103-9.
PMID 2161213
 
Impaired antibacterial host defense in mice lacking the N-formylpeptide receptor.
Gao JL, Lee EJ, Murphy PM.
J Exp Med. 1999 Feb 15;189(4):657-62.
PMID 9989980
 
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.
Gripentrog JM, Jesaitis AJ, Miettinen HM.
Biochem J. 2000 Dec 1;352 Pt 2:399-407.
PMID 11085933
 
Differential roles of the NPXXY motif in formyl peptide receptor signaling.
He R, Browning DD, Ye RD.
J Immunol. 2001 Mar 15;166(6):4099-105.
PMID 11238659
 
Receptor "hijacking" by malignant glioma cells: a tactic for tumor progression.
Huang J, Chen K, Gong W, Zhou Y, Le Y, Bian X, Wang JM.
Cancer Lett. 2008 Aug 28;267(2):254-61. Epub 2008 Apr 22.
PMID 18433988
 
Transactivation of the epidermal growth factor receptor by formylpeptide receptor exacerbates the malignant behavior of human glioblastoma cells.
Huang J, Hu J, Bian X, Chen K, Gong W, Dunlop NM, Howard OM, Wang JM.
Cancer Res. 2007 Jun 15;67(12):5906-13.
PMID 17575160
 
Formyl-peptide receptors revisited.
Le Y, Murphy PM, Wang JM.
Trends Immunol. 2002 Nov;23(11):541-8.
PMID 12401407
 
Identification of a ligand binding site in the human neutrophil formyl peptide receptor using a site-specific fluorescent photoaffinity label and mass spectrometry.
Mills JS, Miettinen HM, Barnidge D, Vlases MJ, Wimer-Mackin S, Dratz EA, Sunner J, Jesaitis AJ.
J Biol Chem. 1998 Apr 24;273(17):10428-35.
PMID 9553101
 
Phosphorylation of the N-formyl peptide receptor carboxyl terminus by the G protein-coupled receptor kinase, GRK2.
Prossnitz ER, Kim CM, Benovic JL, Ye RD.
J Biol Chem. 1995 Jan 20;270(3):1130-7.
PMID 7836371
 
Identification of an N-formyl peptide receptor ligand binding domain by a gain-of-function approach.
Quehenberger O, Pan ZK, Prossnitz ER, Cavanagh SL, Cochrane CG, Ye RD.
Biochem Biophys Res Commun. 1997 Sep 18;238(2):377-81.
PMID 9299516
 
Defective Gi protein coupling in two formyl peptide receptor mutants associated with localized juvenile periodontitis.
Seifert R, Wenzel-Seifert K.
J Biol Chem. 2001 Nov 9;276(45):42043-9. Epub 2001 Sep 14.
PMID 11559706
 
International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family.
Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM.
Pharmacol Rev. 2009 Jun;61(2):119-61. Epub 2009 Jun 4.
PMID 19498085
 
Formylpeptide receptor FPR and the rapid growth of malignant human gliomas.
Zhou Y, Bian X, Le Y, Gong W, Hu J, Zhang X, Wang L, Iribarren P, Salcedo R, Howard OM, Farrar W, Wang JM.
J Natl Cancer Inst. 2005 Jun 1;97(11):823-35.
PMID 15928303
 

Citation

This paper should be referenced as such :
Huang, J ; Wang, JM
FPR1 (formyl peptide receptor 1)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(12):889-893.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/FPR1ID44328ch19q13.html


External links

Nomenclature
HGNC (Hugo)FPR1   3826
LRG (Locus Reference Genomic)LRG_146
Cards
AtlasFPR1ID44328ch19q13
Entrez_Gene (NCBI)FPR1  2357  formyl peptide receptor 1
AliasesFMLP; FPR
GeneCards (Weizmann)FPR1
Ensembl hg19 (Hinxton)ENSG00000171051 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000171051 [Gene_View]  chr19:51745770-51751897 [Contig_View]  FPR1 [Vega]
ICGC DataPortalENSG00000171051
TCGA cBioPortalFPR1
AceView (NCBI)FPR1
Genatlas (Paris)FPR1
WikiGenes2357
SOURCE (Princeton)FPR1
Genetics Home Reference (NIH)FPR1
Genomic and cartography
GoldenPath hg38 (UCSC)FPR1  -     chr19:51745770-51751897 -  19q13.41   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)FPR1  -     19q13.41   [Description]    (hg19-Feb_2009)
EnsemblFPR1 - 19q13.41 [CytoView hg19]  FPR1 - 19q13.41 [CytoView hg38]
Mapping of homologs : NCBIFPR1 [Mapview hg19]  FPR1 [Mapview hg38]
OMIM136537   
Gene and transcription
Genbank (Entrez)AK314935 BC005315 BQ016000 BT007429 CB993626
RefSeq transcript (Entrez)NM_001193306 NM_002029
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)FPR1
Cluster EST : UnigeneHs.753 [ NCBI ]
CGAP (NCI)Hs.753
Alternative Splicing GalleryENSG00000171051
Gene ExpressionFPR1 [ NCBI-GEO ]   FPR1 [ EBI - ARRAY_EXPRESS ]   FPR1 [ SEEK ]   FPR1 [ MEM ]
Gene Expression Viewer (FireBrowse)FPR1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2357
GTEX Portal (Tissue expression)FPR1
Protein : pattern, domain, 3D structure
UniProt/SwissProtP21462   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP21462  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP21462
Splice isoforms : SwissVarP21462
PhosPhoSitePlusP21462
Domaine pattern : Prosite (Expaxy)G_PROTEIN_RECEP_F1_1 (PS00237)    G_PROTEIN_RECEP_F1_2 (PS50262)   
Domains : Interpro (EBI)Formyl_pep_1_rcpt    Formyl_rcpt-rel    GPCR_Rhodpsn    GPCR_Rhodpsn_7TM   
Domain families : Pfam (Sanger)7tm_1 (PF00001)   
Domain families : Pfam (NCBI)pfam00001   
Conserved Domain (NCBI)FPR1
DMDM Disease mutations2357
Blocks (Seattle)FPR1
SuperfamilyP21462
Human Protein AtlasENSG00000171051
Peptide AtlasP21462
HPRD00646
IPIIPI00328644   
Protein Interaction databases
DIP (DOE-UCLA)P21462
IntAct (EBI)P21462
FunCoupENSG00000171051
BioGRIDFPR1
STRING (EMBL)FPR1
ZODIACFPR1
Ontologies - Pathways
QuickGOP21462
Ontology : AmiGOactivation of MAPK activity  complement receptor mediated signaling pathway  complement receptor activity  N-formyl peptide receptor activity  protein binding  plasma membrane  integral component of plasma membrane  chemotaxis  inflammatory response  signal transduction  G-protein coupled receptor signaling pathway  adenylate cyclase-modulating G-protein coupled receptor signaling pathway  phospholipase C-activating G-protein coupled receptor signaling pathway  positive regulation of cytosolic calcium ion concentration  nitric oxide mediated signal transduction  integral component of membrane  secretory granule membrane  azurophil granule membrane  neutrophil degranulation  RAGE receptor binding  leukocyte migration  cell chemotaxis  ficolin-1-rich granule membrane  
Ontology : EGO-EBIactivation of MAPK activity  complement receptor mediated signaling pathway  complement receptor activity  N-formyl peptide receptor activity  protein binding  plasma membrane  integral component of plasma membrane  chemotaxis  inflammatory response  signal transduction  G-protein coupled receptor signaling pathway  adenylate cyclase-modulating G-protein coupled receptor signaling pathway  phospholipase C-activating G-protein coupled receptor signaling pathway  positive regulation of cytosolic calcium ion concentration  nitric oxide mediated signal transduction  integral component of membrane  secretory granule membrane  azurophil granule membrane  neutrophil degranulation  RAGE receptor binding  leukocyte migration  cell chemotaxis  ficolin-1-rich granule membrane  
Pathways : BIOCARTAfMLP induced chemokine gene expression in HMC-1 cells [Genes]   
Pathways : KEGGRap1 signaling pathway    Neuroactive ligand-receptor interaction    Staphylococcus aureus infection   
REACTOMEP21462 [protein]
REACTOME PathwaysR-HSA-6798695 [pathway]   
NDEx NetworkFPR1
Atlas of Cancer Signalling NetworkFPR1
Wikipedia pathwaysFPR1
Orthology - Evolution
OrthoDB2357
GeneTree (enSembl)ENSG00000171051
Phylogenetic Trees/Animal Genes : TreeFamFPR1
HOVERGENP21462
HOGENOMP21462
Homologs : HomoloGeneFPR1
Homology/Alignments : Family Browser (UCSC)FPR1
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerFPR1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FPR1
dbVarFPR1
ClinVarFPR1
1000_GenomesFPR1 
Exome Variant ServerFPR1
ExAC (Exome Aggregation Consortium)FPR1 (select the gene name)
Genetic variants : HAPMAP2357
Genomic Variants (DGV)FPR1 [DGVbeta]
DECIPHERFPR1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisFPR1 
Mutations
ICGC Data PortalFPR1 
TCGA Data PortalFPR1 
Broad Tumor PortalFPR1
OASIS PortalFPR1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICFPR1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDFPR1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
BioMutasearch FPR1
DgiDB (Drug Gene Interaction Database)FPR1
DoCM (Curated mutations)FPR1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)FPR1 (select a term)
intoGenFPR1
NCG5 (London)FPR1
Cancer3DFPR1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM136537   
Orphanet23535   
MedgenFPR1
Genetic Testing Registry FPR1
NextProtP21462 [Medical]
TSGene2357
GENETestsFPR1
Target ValidationFPR1
Huge Navigator FPR1 [HugePedia]
snp3D : Map Gene to Disease2357
BioCentury BCIQFPR1
ClinGenFPR1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2357
Chemical/Pharm GKB GenePA28244
Clinical trialFPR1
Miscellaneous
canSAR (ICR)FPR1 (select the gene name)
Probes
Litterature
PubMed105 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineFPR1
EVEXFPR1
GoPubMedFPR1
iHOPFPR1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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