Alternative titles; symbols
HGNC Approved Gene Symbol: PTAFR
Cytogenetic location: 1p35.3 Genomic coordinates (GRCh38): 1:28,147,166-28,193,856 (from NCBI)
Platelet-activating factor receptor is a G protein-coupled receptor that binds platelet-activating factor (PAF), a phospholipid (1-0-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) that has been implicated as a mediator in diverse pathologic processes, such as allergy, asthma, septic shock, arterial thrombosis, and inflammatory processes (summary by Iovino et al., 2013).
By PCR using primers based on the sequence of guinea pig PAF receptor to amplify guinea pig genomic DNA, followed by screening of a human genomic library, Seyfried et al. (1992) isolated the human PTAFR gene. They determined that the PAF receptor appears to be a member of the G protein-coupled family of receptors and exhibits significant similarity to many members of this family.
Using either a conserved rhodopsin-type receptor sequence or the sequence of guinea pig PAF receptor as probe to screen cDNA libraries of hematopoietic origin, Ye et al. (1991), Nakamura et al. (1991), and Kunz et al. (1992) cloned the cDNA for human PAF receptor. Human PTAFR shares about 82% identity with the guinea pig PAF receptor. Kunz et al. (1992) determined that the deduced 342-amino acid protein contains 7 putative transmembrane domains interspersed with polar peptide segments, characteristic of rhodopsin-type G protein-dependent receptors. PTAFR has 2 N-glycosylation sites, but unlike other rhodopsin family members, there is no N-glycosylation site in the N-terminal segment. Transfection of PTAFR into COS-7 cells resulted in expression of the receptor with an extracellular N terminus.
Nakamura et al. (1991) determined that the calculated molecular mass of the PTAFR protein is about 39.2 kD. Northern blot analysis detected abundant expression of an approximately 3.8-kb PTAFR transcript in leukocytes, with less expression in undifferentiated eosinophilic or erythroleukemia cell lines. Ye et al. (1991) detected a 4.0-kb PTAFR transcript in placenta and lung, but not in heart, brain, liver, skeletal muscle, kidney, or pancreas. Differentiated HL-60 granulocytes also expressed PTAFR, but undifferentiated cells did not.
Nakamura et al. (1991) recorded an electrophysiologic response in injected Xenopus oocytes following PTAFR expression, and observed that transfected COS-7 cells showed ligand binding with pharmacologic properties of the PAF receptor. Activation of the PAF receptor yielded inositol 1,4,5-trisphosphate production in both COS-7 cells and oocytes. Injection of a nonhydrolyzable GTP analog into oocytes inhibited PAF-induced chloride ion currents, indicating that PAF stimulates phosphoinositide turnover via G protein(s). The level of PTAFR mRNA increased in an eosinophilic leukemia cell line treated with granulocyte-macrophage colony stimulating factor (138960), IL5 (147850), and n-butyrate.
Ye et al. (1991) demonstrated that stably transfected mouse fibroblasts expressing human PTAFR responded to subnanomolar PAF stimulation with calcium mobilization, which could be inhibited by a PAF antagonist. Calcium mobilization was PAF-dose-dependent and appeared to result from an increase in the intracellular level of free calcium, since addition of EGTA did not alter the calcium response.
Kunz et al. (1992) found that expression of PTAFR in a myeloid cell line decreased following differentiation induced with dibutyryl-cAMP. They demonstrated uptake of PAF by PTAFR-transfected COS-7 cells, and the uptake was blocked by a PAF receptor antagonist.
Cundell et al. (1995) found that the mechanism of Streptococcus pneumoniae attachment differed between activated and resting cells, and that PTAFR is utilized to gain entry into activated cells. PAF and the pneumococcal cell wall share phosphorylcholine as a determinant of proinflammatory activity. Attachment of bacterial phosphorylcholine to PTAFR enhanced adherence, which was coupled to invasion of endothelial, epithelial, and PTAFR-transfected COS-7 cells. This progression was arrested in vitro and in vivo by PTAFR-specific antagonists. PAF interaction with PTAFR resulted in activation of phospholipase C (see 604114), but pneumococcal interaction with PTAFR did not. Cundell et al. (1995) concluded that the binding of bacterial phosphorylcholine to PTAFR in the absence of signal transduction subverts receptor internalization to allow cell invasion.
By transduction of PTAFR into a PTAFR-negative epidermal cell line, Marques et al. (2002) demonstrated that PTAFR activation stimulates ERK (601795) and p38 (600289) MAP kinases, but not the JNK (601158) MAP kinase. PTAFR activation also stimulated ERK-dependent cell proliferation. ERK activation by PTAFR required the cleavage of membrane-bound heparin-binding EGF (126150) by matrix metalloproteinases (see 600754) and the subsequent activation of the EGF receptor (131550). However, activation of p38 by PTAFR occurred through a distinct pathway.
Lukashova et al. (2001) found that PAF induced rapid tyrosine phosphorylation of TYK2 (176941) in 2 human monocytic cell lines and in COS-7 cells transfected with PTAFR and TYK2 cDNAs. TYK2 coimmunoprecipitated and colocalized with PTAFR independent of ligand binding. Deletion mutation analysis indicated that the N terminus of TYK2 bound PTAFR. Activation of TYK2 was followed by a time-dependent 2- to 4-fold increase in the level of tyrosine phosphorylation of STAT1 (600555), STAT2 (600556), and STAT3 (102582), and a sustained 2.5-fold increase in STAT5 (see 601511) tyrosine phosphorylation. STAT1 and STAT3 translocated to the nucleus following PAF stimulation, and their translocation was dependent on TYK2 in transiently-transfected COS-7 cells. In the presence of TYK2, PAF induced activation of PTAFR promoter-1 in a reporter assay. TYK2 activation and signaling by PAF was independent of G proteins.
Seyfried et al. (1992) determined that the PTAFR coding sequence contains no introns.
Chase et al. (1993) found evidence for at least 1 intron in the 5-prime untranslated region of the PTAFR gene.
By analysis of rodent/human somatic cell hybrids, Seyfried et al. (1992) concluded that the PTAFR gene is located on human chromosome 1. Chase et al. (1996) used fluorescence in situ hybridization to localize PTAFR to 1p35-p34.3. By Southern blot analysis, Kunz et al. (1992) determined that GPR135 is a single-copy gene.
Chase, P. B., Halonen, M., Regan, J. W. Cloning of a human platelet-activating factor receptor gene: evidence for an intron in the 5-prime-untranslated region. Am. J. Resp. Cell Molec. Biol. 8: 240-244, 1993. [PubMed: 8383507] [Full Text: https://doi.org/10.1165/ajrcmb/8.3.240]
Chase, P. B., Yang, J.-M., Thompson, F. H., Halonen, M., Regan, J. W. Regional mapping of the human platelet-activating factor receptor gene (PTAFR) to 1p35-p34.3 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 72: 205-207, 1996. [PubMed: 8978777] [Full Text: https://doi.org/10.1159/000134190]
Cundell, D. R., Gerard, N. P., Gerard, C., Idanpaan-Heikkila, I., Tuomanen, E. I. Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature 377: 435-438, 1995. [PubMed: 7566121] [Full Text: https://doi.org/10.1038/377435a0]
Iovino, F., Brouwer, M. C., van de Beek, D., Molema, G., Bijlsma, J. J. E. Signalling or binding: the role of the platelet-activating factor receptor in invasive pneumococcal disease. Cell. Microbiol. 15: 870-881, 2013. [PubMed: 23444839] [Full Text: https://doi.org/10.1111/cmi.12129]
Kunz, D., Gerard, N. P., Gerard, C. The human leukocyte platelet-activating factor receptor: cDNA cloning, cell surface expression, and construction of a novel epitope-bearing analog. J. Biol. Chem. 267: 9101-9106, 1992. [PubMed: 1374385]
Lukashova, V., Asselin, C., Krolewski, J. J., Rola-Pleszczynski, M., Stankova, J. G-protein-independent activation of Tyk2 by the platelet-activating factor receptor. J. Biol. Chem. 276: 24113-24121, 2001. [PubMed: 11309383] [Full Text: https://doi.org/10.1074/jbc.M100720200]
Marques, S. A., Dy, L. C., Southall, M. D., Yi, Q., Smietana, E., Kapur, R., Marques, M., Travers, J. B., Spandau, D. F. The platelet-activating factor receptor activates the extracellular signal-regulated kinase mitogen-activated protein kinase and induces proliferation of epidermal cells through an epidermal growth factor-receptor-dependent pathway. J. Pharm. Exp. Ther. 300: 1026-1035, 2002. [PubMed: 11861812] [Full Text: https://doi.org/10.1124/jpet.300.3.1026]
Nakamura, M., Honda, Z., Izumi, T., Sakanaka, C., Mutoh, H., Minami, M., Bito, H., Seyama, Y., Matsumoto, T., Noma, M., Shimizu, T. Molecular cloning and expression of platelet-activating factor receptor from human leukocytes. J. Biol. Chem. 266: 20400-20405, 1991. [PubMed: 1657923]
Seyfried, C. E., Schweickart, V. L., Godiska, R., Gray, P. W. The human platelet-activating factor receptor gene (PTAFR) contains no introns and maps to chromosome 1. Genomics 13: 832-834, 1992. [PubMed: 1322356] [Full Text: https://doi.org/10.1016/0888-7543(92)90162-l]
Ye, R. D., Prossnitz, E. R., Zou, A., Cochrane, C. G. Characterization of a human cDNA that encodes a functional receptor for platelet activating factor. Biochem. Biophys. Res. Commun. 180: 105-111, 1991. [PubMed: 1656963] [Full Text: https://doi.org/10.1016/s0006-291x(05)81261-6]