Alternative titles; symbols
HGNC Approved Gene Symbol: F2R
Cytogenetic location: 5q13.3 Genomic coordinates (GRCh38): 5:76,716,126-76,735,770 (from NCBI)
Coughlin et al. (1992) reviewed the cloning and characterization of a platelet thrombin (176930) receptor (Vu et al., 1991). The thrombin receptor is structurally related to other members of the 7-transmembrane receptor family and has been isolated from diverse cell types. It is intimately involved in the regulation of the thrombotic response.
Riewald et al. (2002) demonstrated that activated protein C (612283) uses the endothelial cell protein C receptor (EPCR; 600646) as a coreceptor for cleavage of protease-activated receptor-1 (PAR1) on endothelial cells. Gene profiling demonstrated that PAR1 signaling could account for all activated protein C-induced protective genes, including the immunomodulatory monocyte chemoattractant protein-1 (MCP1; 158105), which was selectively induced by activation of PAR1, but not PAR2 (600933). Thus, Riewald et al. (2002) concluded that the prototypical thrombin receptor is the target for EPCR-dependent APC signaling, suggesting a role for this receptor cascade in protection from sepsis.
Boire et al. (2005) found that expression of PAR1 was both required and sufficient to promote growth and invasion of breast carcinoma cells in a xenograft mouse model. Matrix metalloprotease-1 (MMP1; 120353) acted as a protease agonist of PAR1, cleaving the receptor at the proper site to generate PAR1-dependent Ca(2+) signals and migration. MMP1 activity was derived from fibroblasts and was absent from the breast cancer cells. These results demonstrated that MMP1 in the stromal-tumor microenvironment can alter the behavior of cancer cells through PAR1 to promote cell migration and invasion.
Pepducins are lipid-conjugated, membrane-tethered, cell-penetrating peptides that act as agonists or antagonists of their cognate receptor. Kaneider et al. (2007) found that pepducin antagonists and agonists based on the third intracellular loop of PAR1 had substantial beneficial or harmful effects on survival, vascular integrity, and disseminated intravascular coagulation in mice depending on the stage of sepsis. The effects of the pepducins were lost in Par1-deficient mice. RNA interference-mediated suppression of PAR2 expression in human endothelial cells showed that the protective effects of PAR1 activation required PAR2. Transactivation of PAR2 signaling by PAR1 was enhanced by endotoxin-dependent recruitment of PAR1-PAR2 complexes to the endothelial cell surface. Kaneider et al. (2007) proposed that therapeutics that selectively activate PAR1-PAR2 complexes may be beneficial in the treatment of sepsis.
Niessen et al. (2008) demonstrated that PAR1 signaling sustains a lethal inflammatory response that can be interrupted by inhibition of either thrombin or PAR1 signaling. The sphingosine 1-phosphate (S1P) axis is a downstream component of PAR1 signaling, and by combining chemical and genetic probes for S1P receptor-3 (S1P3; 601965) Niessen et al. (2008) showed a critical role for dendritic cell PAR1-S1P3 crosstalk in regulating amplification of inflammation in sepsis syndrome. Conversely, dendritic cells sustain escalated systemic coagulation and are the primary hub at which coagulation and inflammation intersect within the lymphatic compartment. Loss of dendritic cell PAR1-S1P3 signaling sequestered dendritic cells and inflammation into draining lymph nodes, and attenuated dissemination of interleukin-1-beta (147720) to the lungs. Thus, Niessen et al. (2008) concluded that activation of dendritic cells by coagulation in the lymphatics emerged as a theretofore unknown mechanism that promotes systemic inflammation and lethality in decompensated innate immune responses.
Using data from a genomewide association study, Chu et al. (2014) identified MIR190A (615845) as the only microRNA gene within a region of chromosome 15q containing SNPs associated with breast cancer lymph node metastasis. Overexpression of MIR190A in breast cancer cells inhibited cell migration and invasiveness. Database analysis revealed several putative MIR190A targets, including PAR1, a metastasis-promoting protein. Transfection and inhibitor studies revealed that expression of MIR190A was negatively correlated with that of PAR1 and that MIR190A downregulated PAR1 protein content.
Schmidt et al. (1996) characterized the TR gene by isolating overlapping clones from a genomic library. Genomic analysis confirmed that the TR gene is of limited complexity, spanning approximately 27 kb and containing 2 exons separated by a large intron of approximately 22 kb. The larger second exon contains the majority of the coding sequence and the thrombin (176930) cleavage site. A predominant transcription initiation site 351 bp upstream from the initiator methionine was identified in both human umbilical vein endothelial and erythroleukemia cells. Schmidt et al. (1996) demonstrated that the TR promoter is TATA-less, although nucleic acid motifs potentially involved in transcriptional gene regulation are evident and include a GATA motif, octamer enhancer sequences, AP-2-like sites, and Sp1 sites. The 7-transmembrane segment thrombin receptor represents the prototype of a novel class of proteolytically cleaved receptors that mediate signaling events by functional coupling to G proteins.
Crystal Structure
Zhang et al. (2012) reported the 2.2-angstrom resolution crystal structure of human PAR1 bound to vorapaxar, a PAR1 antagonist. The structure reveals an unusual mode of drug binding that explains how a small molecule binds virtually irreversibly to inhibit receptor activation by the tethered ligand of PAR1. In contrast to deep, solvent-exposed binding pockets observed in other peptide-activated G protein-coupled receptors, the vorapaxar-binding pocket is superficial but has little surface exposed to the aqueous solvent.
Using PCR analyses of a human/rodent hybrid cell mapping panel, Bahou et al. (1993) assigned the TR gene to chromosome 5. By fluorescence in situ hybridization, they refined the localization to 5q13, confirming its presence as a single locus in the human genome. Poirier et al. (1996) mapped the Cf2r gene to mouse chromosome 13 by studies of an interspecific backcross.
Utilizing 2 distinct radiation hybrid mapping panels with different levels of resolution, Schmidt et al. (1997) demonstrated that this gene, sometimes referred to as PAR1, and the proteinase activated receptor-2 gene (600933) are tightly linked. Physical mapping using yeast artificial chromosomes and inversion field gel electrophoresis demonstrated that they are maximally separated by 90 kb.
Griffin et al. (2001) reported a role for Par1, a protease-activated G protein-coupled receptor for thrombin (176930), in embryonic development. Approximately one-half of Par1 -/- embryos died at midgestation with bleeding from multiple sites. Par1 is expressed in endothelial cells, and a Par1 transgene driven by an endothelial-specific promoter prevented death of Par1 -/- embryos. Griffin et al. (2001) concluded that the coagulation cascade and PAR1 modulate endothelial cell function in developing blood vessels and that thrombin's actions on endothelial cells, rather than on platelets, mesenchymal cells, or fibrinogen (see 134820), contribute to vascular development and hemostasis in the mouse embryo.
Vergnolle et al. (2004) found that PAR1 was overexpressed in the colon of patients with inflammatory bowel disease (IBD). In mice, intracolonic administration of Par1 agonists led to an inflammatory reaction characterized by edema and granulocyte infiltration. Par1 activation exacerbated and prolonged inflammation in a mouse model of IBD, whereas Par1 antagonism significantly decreased the mortality and severity of colonic inflammation. Experimental colitis development was strongly attenuated in Par1-null mice compared to wildtype mice. Vergnolle et al. (2004) suggested that PAR1 inhibition might be beneficial in the context of IBD and other chronic intestinal inflammatory disorders. The authors retracted the paper because a published figure was mistakenly reproduced from a previous publication; however, the senior author emphasized that this did not diminish the validity of work contributed by coauthors of the paper.
Guo et al. (2004) found that activated protein C protected mouse cortical neurons from NMDA- and staurosporine-induced apoptosis in vitro and in vivo. APC administration blocked nuclear translocation of apoptosis-inducing factor (AIF; 300169) and caspase-3 (CASP3; 600636) activation in response to NMDA and caspase-8 (CASP8; 601763) activation in response to staurosporine. Further studies with antibodies and mutant proteins showed that APC did not change the structure of or block NMDA receptors, that the APC active serine protease site was necessary for the effect, and that both PAR1 and PAR3 (601919) were required for APC-mediated neuronal protection.
Reinhardt et al. (2012) showed that the gut microbiota promotes tissue factor (TF; 134390) glycosylation associated with localization of TF on the cell surface, the activation of coagulation proteases, and phosphorylation of the TF cytoplasmic domain in the small intestine. Anti-Tf treatment of colonized germ-free mice decreased microbiota-induced vascular remodeling and expression of the proangiogenic factor angiopoietin-1 (ANG1; 601667) in the small intestine. Mice with a genetic deletion of the Tf cytoplasmic domain or with hypomorphic Tf alleles had a decreased intestinal vessel density. Coagulation proteases downstream of Tf activate protease-activated receptor (PAR) signaling implicated in angiogenesis. Vessel density and phosphorylation of the cytoplasmic domain of Tf were decreased in small intestine from Par1-deficient but not Par2 (600933)-deficient mice, and inhibition of thrombin showed that thrombin-Par1 signaling was upstream of Tf phosphorylation. Reinhardt et al. (2012) concluded that the microbiota-induced extravascular TF-PAR1 signaling loop is a novel pathway in vascular remodeling in the small intestine.
Bahou, W. F., Nierman, W. C., Durkin, A. S., Potter, C. L., Demetrick, D. J. Chromosomal assignment of the human thrombin receptor gene: localization to region q13 of chromosome 5. Blood 82: 1532-1537, 1993. [PubMed: 8395910]
Boire, A., Covic, L., Agarwal, A., Jacques, S., Sherifi, S., Kuliopulos, A. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120: 303-131, 2005. [PubMed: 15707890] [Full Text: https://doi.org/10.1016/j.cell.2004.12.018]
Chu, H.-W., Cheng, C.-W., Chou, W.-C., Hu, L.-Y., Wang, H.-W., Hsiung, C.-N., Hsu, H.-M., Wu, P.-E., Hou, M.-F., Shen, C.-Y., Yu, J.-C. A novel estrogen receptor-microRNA 190a-PAR-1-pathway regulates breast cancer progression, a finding initially suggested by genome-wide analysis of loci associated with lymph-node metastasis. Hum. Molec. Genet. 23: 355-367, 2014. [PubMed: 24009311] [Full Text: https://doi.org/10.1093/hmg/ddt426]
Coughlin, S. R., Vu, T.-K. H., Hung, D. T., Wheaton, V. I. Characterization of a functional thrombin receptor: issues and opportunities. J. Clin. Invest. 89: 351-355, 1992. [PubMed: 1310691] [Full Text: https://doi.org/10.1172/JCI115592]
Griffin, C. T., Srinivasan, Y., Zheng, Y.-W., Huang, W., Coughlin, S. R. A role for thrombin receptor signaling in endothelial cells during embryonic development. Science 293: 1666-1670, 2001. [PubMed: 11533492] [Full Text: https://doi.org/10.1126/science.1061259]
Guo, H., Liu, D., Gelbard, H., Cheng, T., Insalaco, R., Fernandez, J. A., Griffin, J. H., Zlokovic, B. V. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 41: 563-572, 2004. [PubMed: 14980205] [Full Text: https://doi.org/10.1016/s0896-6273(04)00019-4]
Kaneider, N. C., Leger, A. J., Agarwal, A., Nguyen, N., Perides, G., Derian, C., Covic, L., Kuliopulos, A. 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. Nature Immun. 8: 1303-1312, 2007. [PubMed: 17965715] [Full Text: https://doi.org/10.1038/ni1525]
Niessen, F., Schaffner, F., Furlan-Freguia, C., Pawlinski, R., Bhattacharjee, G., Chun, J., Derian, C. K., Andrade-Gordon, P., Rosen, H., Ruf, W. Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature 452: 654-658, 2008. [PubMed: 18305483] [Full Text: https://doi.org/10.1038/nature06663]
Poirier, C., O'Brien, E. P., Bueno Brunialti, A. L., Chambard, J.-C., Swank, R. T., Guenet, J.-L. The gene encoding the thrombin receptor (Cf2r) maps to mouse chromosome 13. Mammalian Genome 7: 322, 1996. [PubMed: 8661713] [Full Text: https://doi.org/10.1007/BF03035441]
Reinhardt, C., Bergentall, M., Greiner, T. U., Schaffner, F., Ostergren-Lunden, G., Petersen, L. C., Ruf, W., Backhed, F. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 483: 627-631, 2012. [PubMed: 22407318] [Full Text: https://doi.org/10.1038/nature10893]
Riewald, M., Petrovan, R. J., Donner, A., Mueller, B. M., Ruf, W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296: 1880-1882, 2002. [PubMed: 12052963] [Full Text: https://doi.org/10.1126/science.1071699]
Schmidt, V. A., Nierman, W. C., Feldblyum, T. V., Maglott, D. R., Bahou, W. F. The human thrombin receptor and proteinase activated receptor-2 genes are tightly linked on chromosome 5q13. Brit. J. Haemat. 97: 523-529, 1997. [PubMed: 9207393] [Full Text: https://doi.org/10.1046/j.1365-2141.1997.922907.x]
Schmidt, V. A., Vitale, E., Bahou, W. F. Genomic cloning and characterization of the human thrombin receptor gene: structural similarity to the proteinase activated receptor-2 gene. J. Biol. Chem. 271: 9307-9312, 1996. [PubMed: 8621593]
Vergnolle, N., Cellars, L., Mencarelli, A., Rizzo, G., Swaminathan, S., Beck, P., Steinhoff, M., Andrade-Gordon, P., Bunnett, N. W., Hollenberg, M. D., Wallace, J. L., Cirino, G., Fiorucci, S. A role for proteinase-activated receptor-1 in inflammatory bowel diseases. J. Clin. Invest. 114: 1444-1456, 2004. Note: Retraction: J. Clin. Invest. 116: 2056 only, 2006. [PubMed: 15545995] [Full Text: https://doi.org/10.1172/JCI21689]
Vu, T.-K. H., Hung, D. T., Wheaton, V. I., Coughlin, S. R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64: 1057-1068, 1991. [PubMed: 1672265] [Full Text: https://doi.org/10.1016/0092-8674(91)90261-v]
Zhang, C., Srinivasan, Y., Arlow, D. H., Fung, J. J., Palmer, D., Zheng, Y., Green H. F., Pandey, A., Dror, R. O., Shaw, D. E., Weis, W. I., Coughlin, S. R., Kobilka, B. K. High-resolution crystal structure of human protease-activated receptor 1. Nature 492: 387-392, 2012. [PubMed: 23222541] [Full Text: https://doi.org/10.1038/nature11701]