Download Gene Section FPR1 (formyl peptide receptor 1) Atlas of Genetics and Cytogenetics

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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