Affinage

F2RL3

Proteinase-activated receptor 4 · UniProt Q96RI0

Length
385 aa
Mass
41.1 kDa
Annotated
2026-04-28
100 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

F2RL3 encodes PAR4, a G protein-coupled receptor activated by proteolytic cleavage of its N-terminal exodomain by thrombin (and other serine proteases such as MASP-1 and Der p3), generating a tethered ligand that engages a binding site formed by TM3 and TM7, with ECL3 serving as a gatekeeper (PMID:32575122, PMID:17595115, PMID:19667088). Unlike PAR1, PAR4 does not require GPIbα as a cofactor for thrombin activation and signals primarily through Gq-coupled sustained Ca²⁺ mobilization, Rho-kinase–dependent myosin light chain phosphorylation, and a receptor-associated nSMase/ceramide–p38 MAPK–NF-κB axis, producing prolonged platelet activation, microparticle generation, and thrombin generation (PMID:10820018, PMID:23307185, PMID:23065519, PMID:12871418). PAR4 forms homodimers via TM4 hydrophobic residues required for efficient calcium signaling, and heterodimerizes with P2Y12 (through TM4 LGL194-196) to enable arrestin-2 recruitment and sustained Akt signaling, while PAR2 heterodimerization relieves β-COP1-mediated ER retention and promotes surface delivery (PMID:22318735, PMID:24723492, PMID:22411985). Platelet-specific PAR4 deletion demonstrates that PAR4 is essential for stable arterial and venous thrombus formation and hemostatic plug stability in vivo, and epigenetic regulation of F2RL3 expression via smoking-induced DNA hypomethylation modulates PAR4-dependent platelet reactivity (PMID:34689407, PMID:35012325).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Establishing that PAR4 generates a functionally distinct, slower and more sustained Ca²⁺ signal than PAR1 in human platelets resolved how two thrombin receptors produce non-redundant temporal signaling patterns, with PAR4 being more effective at driving secondary ADP-dependent autocrine signals.

    Evidence PAR-selective peptide ligands and calcium imaging in human platelets

    PMID:10820018

    Open questions at the time
    • Mechanism for prolonged Ca²⁺ kinetics not structurally explained
    • Relative contribution of PAR4 vs PAR1 to in vivo hemostasis not yet tested
  2. 2000 High

    Demonstrating that mouse PAR3 does not signal itself but serves as a cofactor presenting thrombin to PAR4 revealed the first example of a GPCR acting as a non-signaling co-receptor, explaining how PAR4 is activated at low thrombin concentrations in mouse platelets.

    Evidence PAR3 knockout mice combined with heterologous expression and thrombin binding inhibition

    PMID:10766244

    Open questions at the time
    • Whether human PAR3 plays an analogous cofactor role for human PAR4 not established
    • Structural basis for cofactor mechanism unknown at this point
  3. 2003 Medium

    Showing that GPIbα is required as a cofactor for PAR1 but not PAR4 activation by thrombin distinguished the two receptors' cofactor dependencies and established PAR4 as the thrombin receptor that functions independently of the GPIb-IX-V complex.

    Evidence GPIbα-blocking antibodies, P2Y1/P2Y12 antagonists, PAR1 desensitization in human platelets

    PMID:12871418

    Open questions at the time
    • How PAR4 achieves sufficient thrombin cleavage without GPIbα cofactor not structurally explained
    • Single lab study
  4. 2006 High

    Revealing that PAR4 signals platelet aggregation through Ca²⁺ mobilization synergistic with P2Y12 receptor activation—and that dual blockade of both abolishes PAR4-induced aggregation—defined the signaling codependency distinguishing PAR4 from PAR1 downstream pathways.

    Evidence Selective PAR agonist peptides, P2Y12 inhibitors, calcium imaging, and aggregometry in human platelets

    PMID:16837456

    Open questions at the time
    • Physical basis for PAR4-P2Y12 cooperation not yet determined
    • Whether this codependency operates identically in vivo unclear
  5. 2007 High

    Crystal structures of thrombin–PAR3 and thrombin–PAR4 exodomain complexes provided the atomic-level explanation for the PAR3 cofactor mechanism: cleaved PAR3 occupies exosite I to allosterically widen the active site for PAR4 engagement, while kinetic mutagenesis identified Pro-46 as critical for PAR4 cleavage efficiency.

    Evidence X-ray crystallography at 2.0–3.5 Å; recombinant exodomain cleavage kinetics with site-directed mutagenesis

    PMID:17595115 PMID:17606903

    Open questions at the time
    • Full-length PAR4 structure not available
    • How exodomain cleavage triggers transmembrane conformational change not resolved
  6. 2007 High

    Demonstrating that PAR1 but not PAR4 couples to Gi/o–PI3K signaling in platelets established that the two thrombin receptors engage fundamentally different G-protein repertoires, explaining PAR4's reliance on Gq-driven pathways.

    Evidence Pertussis toxin, PI3K inhibitors, integrin activation assays in human platelets

    PMID:17303701

    Open questions at the time
    • Whether PAR4 engages G12/13 directly not systematically tested
    • Mechanism for receptor-selective G-protein coupling unknown
  7. 2010 High

    Identifying arrestin-2 as a PAR4-selective signaling adaptor that recruits PI3K and is required for Akt activation and in vivo thrombus stability established a non-canonical signaling branch specific to PAR4.

    Evidence Co-immunoprecipitation, arrestin-2 knockout platelets, ferric chloride thrombosis model in mice

    PMID:21106537

    Open questions at the time
    • Direct arrestin-2–PAR4 binding site not mapped
    • Temporal dynamics of arrestin recruitment to PAR4 not resolved
  8. 2012 High

    Discovery that PAR4 homodimerizes via TM4 hydrophobic residues, that nSMase constitutively associates with PAR4 to generate ceramide upon activation, and that PAR2 heterodimerization relieves β-COP1-mediated ER retention collectively defined a multi-layered regulatory architecture unique to PAR4.

    Evidence BiFC, BRET, co-IP, mutagenesis of TM4 and RXR retention motif, LC-MS/MS ceramide quantification in human platelets and HEK293 cells

    PMID:22318735 PMID:22411985 PMID:23065519

    Open questions at the time
    • Stoichiometry of nSMase–PAR4 complex unknown
    • Whether PAR2–PAR4 heterodimerization occurs in platelets in vivo not tested
    • Structural basis of TM4 dimer interface at atomic resolution lacking
  9. 2013 High

    Identification of PC-TP as a PAR4-specific signaling mediator and the natural Ala120Thr variant (rs773902) as a gain-of-function PAR4 polymorphism revealed lipid-dependent and genetic modulators of PAR4 platelet reactivity with clinical significance.

    Evidence PC-TP inhibition/siRNA in platelets and megakaryocytes; QTL analysis and transfected cell IP3/calcium/aggregation assays for rs773902

    PMID:24216752 PMID:25293779

    Open questions at the time
    • Mechanism by which PC-TP specifically supports PAR4 but not PAR1 signaling unknown
    • Structural consequence of Ala120Thr in TM2 not determined
  10. 2014 High

    Mapping the PAR4–P2Y12 heterodimer interface to TM4 residues LGL194-196 and showing this interaction is required for agonist-dependent arrestin recruitment provided the molecular basis for the PAR4–P2Y12 signaling codependency observed earlier.

    Evidence BRET, TM4 chimeric mutants, calcium flux assays in HEK293T cells

    PMID:24723492

    Open questions at the time
    • Whether TM4-mediated dimerization is dynamic or constitutive not determined
    • In vivo validation of LGL mutant in platelets lacking
  11. 2019 High

    Identification of Asp230 in ECL2 as critical for PAR4 activation and demonstration that biased agonist peptides favoring β-arrestin recruitment over calcium signaling enhance platelet aggregation established that PAR4 supports biased signaling with distinct functional outputs.

    Evidence Peptide library, site-directed mutagenesis, in silico docking, parallel Gαq/calcium and β-arrestin assays, platelet aggregation

    PMID:31892516

    Open questions at the time
    • Structural basis of biased agonism at PAR4 not visualized
    • In vivo consequence of biased PAR4 signaling untested
  12. 2020 High

    H/D exchange and mutagenesis mapped the PAR4 tethered-ligand binding site to TM3/TM7 with ECL3 as a gatekeeper, while GRK5 was identified as a kinase regulating PAR4-mediated platelet reactivity, and PAR4 was linked to NLRP3 inflammasome activation in diabetic cardiomyopathy.

    Evidence HDX-MS with mutagenesis and signaling assays; GWAS with iPSC-megakaryocyte enhancer assays; PAR4 knockout mice on high-fat diet with human cardiac fibroblasts

    PMID:31912235 PMID:32575122 PMID:32649856

    Open questions at the time
    • Full receptor activation model integrating tethered ligand engagement with G-protein coupling absent
    • Whether GRK5 directly phosphorylates PAR4 C-terminus not shown
    • Whether PAR4 inflammasome role is platelet-dependent or fibroblast-autonomous in vivo unclear
  13. 2021 High

    Platelet-specific conditional PAR4 deletion proved that PAR4 in platelets is essential for stable arterial and venous thrombus formation and hemostatic plug stability, distinguishing PAR4's role in thrombus consolidation from initial plug formation.

    Evidence PAR4fl/fl;PF4Cre+ conditional knockout mice, FeCl3 arterial and saphenous vein laser injury models

    PMID:34689407

    Open questions at the time
    • Relative contribution of PAR4 vs PAR1 in human thrombus stability not genetically tested
    • Whether pharmacological PAR4 inhibition recapitulates genetic deletion phenotype in primates unknown
  14. 2022 Medium

    Demonstrating that smoking-induced hypomethylation of F2RL3 exon 2 increases PAR4 mRNA expression and platelet reactivity established an epigenetic mechanism controlling PAR4 levels with implications for smoking-related thrombotic risk.

    Evidence Cohort methylation–platelet reactivity analysis, cigarette smoke extract treatment with methylation/mRNA quantification, luciferase reporters

    PMID:35012325

    Open questions at the time
    • Whether methylation changes are reversible upon smoking cessation not tested longitudinally
    • Transcription factors mediating methylation-sensitive F2RL3 expression not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length active-state structure of PAR4 bound to its tethered ligand and G-protein, the complete phosphorylation code for GRK5/arrestin regulation, and the in vivo therapeutic window for selective PAR4 antagonism in humans remain unresolved.
  • No full-length PAR4 structure available
  • GRK5 phosphorylation sites on PAR4 not mapped
  • No human clinical data on selective PAR4 antagonism

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 7
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-109582 Hemostasis 4 R-HSA-168256 Immune System 3
Partners
ARRB1F2RF2RL1GRK5P2RY12PCTPSMPD3YWHAZ
Complex memberships
PAR4 homodimerPAR4–P2Y12 heterodimerPAR4–PAR2 heterodimer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Mouse PAR3 (mPAR3) does not itself mediate transmembrane signaling but functions as a cofactor that presents thrombin to mPAR4, facilitating cleavage and activation of mPAR4 by thrombin at low thrombin concentrations. Heterologous expression systems, PAR3 knockout mice, inhibition of thrombin binding to mPAR3 Nature High 10766244
2000 PAR4 generates a slower, prolonged Ca2+ response compared to PAR1's rapid spike after thrombin activation of human platelets, and PAR4 activation is more effective than PAR1 in mounting secondary autocrine Ca2+ signals from secreted ADP; PAR4 activation requires prior PAR1 activation for full ADP response. PAR-specific peptide ligands and anti-PAR1 reagents, calcium imaging in human platelets Biochemistry High 10820018
2007 Crystal structures of murine thrombin bound to extracellular fragments of PAR3 and PAR4 revealed that cleaved PAR3 occupies exosite I of thrombin and allosterically widens access to the active site, while PAR4 engages the primary specificity pocket and active site directly; this structural basis explains how PAR3 acts as a cofactor promoting PAR4 cleavage. X-ray crystallography at 2.0 Å (PAR3 complex) and 3.5 Å (PAR4 complex) Proceedings of the National Academy of Sciences of the United States of America High 17606903
2007 Active-site mutagenesis of PAR4 exodomain identified that the P2 position proline (Pro-46) is critical for thrombin cleavage kinetics: PAR4-P46A mutation markedly lowered kcat and kcat/Km ~35-fold. PAR4 exodomains act as competitive inhibitors of thrombin, unlike PAR1 exodomains which are noncompetitive inhibitors. Recombinant exodomain cleavage assays, kinetic analysis (Km, kcat), site-directed mutagenesis Biochemistry High 17595115
2006 PAR4, but not PAR1, signals platelet aggregation through Ca2+ mobilization and synergistic P2Y12 receptor activation at high agonist concentrations; dual inhibition of P2Y12 and calcium mobilization completely inhibits PAR4-induced aggregation but not PAR1-mediated aggregation. Selective PAR agonist peptides, P2Y12 inhibitors, calcium imaging, aggregometry in human platelets The Journal of biological chemistry High 16837456
2007 PAR1, but not PAR4, directly couples to Gi/o in human platelets to activate phosphoinositide-3 kinase (PI3K), which regulates integrin αIIbβ3 activation and platelet aggregation; PI3K inhibitors eliminate PAR1-mediated but not PAR4-mediated signaling. PI3K inhibitors, Gi/o pertussis toxin studies, aggregometry, integrin activation assays in human platelets Molecular pharmacology High 17303701
2012 PAR4 homodimerizes through hydrophobic residues in transmembrane helix 4; mutations disrupting dimer formation reduce PAR4-mediated calcium mobilization, linking dimerization to receptor signaling. Bimolecular fluorescence complementation, BRET assays, rho-PAR4 chimeras and point mutants, calcium signaling assays The Journal of biological chemistry High 22318735
2012 PAR4 is largely retained in the endoplasmic reticulum via an arginine-based (RXR) ER retention sequence in intracellular loop 2 binding to β-COP1; PAR2 heterodimerization disrupts β-COP1 binding, facilitates interaction with chaperone 14-3-3ζ, and promotes plasma membrane delivery and enhanced PAR4 signaling. Intermolecular FRET, co-immunoprecipitation, site-directed mutagenesis of RXR motif, subcellular fractionation, glycosylation analysis The Journal of biological chemistry High 22411985
2010 Arrestin-2 associates with the p85 PI3Kα/β subunit in thrombin-stimulated platelets and is recruited to PAR4 (but not PAR1) in a P2Y1- and P2Y12-dependent manner; PAR4-dependent Akt phosphorylation and fibrinogen binding are reduced in arrestin-2 knockout platelets, and arrestin-2 knockout mice show reduced thrombosis in vivo. Co-immunoprecipitation, arrestin-2 knockout platelets, ferric chloride thrombosis model in mice The Journal of biological chemistry High 21106537
2014 PAR4 and P2Y12 directly interact through PAR4 transmembrane domain 4 residues LGL194-196; this PAR4-P2Y12 dimerization is required for agonist-dependent P2Y12-dependent arrestin recruitment to PAR4 and sustained Akt signaling. PAR4 also forms homodimers that regulate Gq-coupled calcium responses. BRET in HEK293T cells, transmembrane domain chimeric mutant PAR4SFT, calcium flux assays Molecular pharmacology High 24723492
2009 MASP-1 (complement lectin pathway protease) directly cleaves and activates PAR4 on human endothelial cells, triggering Ca2+ signaling, NF-κB, and p38 MAPK pathways; MASP-2 had no such effect, and PAR4 agonist peptide mimicked the response. Synthetic peptide substrates for PAR selectivity, PAR4 agonist peptide, MASP-1/2 treatment of HUVECs, mRNA quantification, membrane PAR4 depletion assay Journal of immunology Medium 19667088
2013 PAR4 stimulation leads to stronger and more sustained myosin light chain phosphorylation (via Rho-kinase) compared to PAR1, resulting in greater factor V secretion, more microparticle generation, and higher peak thrombin generation from platelet membranes. PAR-selective activating peptides, Rho-kinase inhibitors, flow cytometry, thrombin generation assay, Western blotting in human platelets Molecular pharmacology Medium 23307185
2012 Neutral sphingomyelinase (nSMase) is directly associated with PAR4 (but not PAR1) in resting human platelets; PAR4 activation by thrombin or PAR4-AP increases C24:0-ceramide levels via nSMase, which then activates p38 MAPK-NF-κB signaling to promote platelet activation. Immunoprecipitation, LC-MS/MS ceramide quantification, flow cytometry, aggregometry, PAR-selective agonist peptides Haematologica Medium 23065519
2019 Asp230 in extracellular loop 2 is critical for PAR4 activation by both agonist peptide and the tethered ligand; peptides that cannot activate calcium signaling fail to cause platelet aggregation, while peptides with enhanced β-arrestin recruitment but equal calcium signaling trigger greater platelet aggregation — demonstrating biased signaling through PAR4. Peptide library screening, site-directed mutagenesis, in silico docking, Gαq/11-coupled calcium assay, β-arrestin recruitment assay, MAPK activation, platelet aggregation The Journal of biological chemistry High 31892516
2020 Hydrogen/deuterium exchange identified the PAR4 ligand binding site as composed of TM3 and TM7 domains; computational modeling predicted an interaction between Gly48 of the tethered ligand and Thr153 in TM3; mutation of Thr153 significantly decreased PAR4 signaling. Extracellular loop 3 (ECL3) serves as a gatekeeper for tethered ligand-LBS interaction, with Pro310 rigidity in ECL3 being essential for PAR4 activation. Hydrogen/deuterium exchange mass spectrometry, computational modeling, site-directed mutagenesis, signaling assays Blood High 32575122
2013 The F2RL3 SNP rs773902 (Ala120Thr in transmembrane domain 2) alters PAR4 function: the Thr120 variant generates greater inositol 1,4,5-trisphosphate, higher PAR4-induced platelet aggregation and Ca2+ flux compared to Ala120; a second variant Phe296Val abolishes the enhanced signaling of Thr120. Quantitative trait locus analysis, transfected cell IP3 generation assay, platelet aggregation and Ca2+ flux measurements Blood High 25293779
2013 Phosphatidylcholine transfer protein (PC-TP) specifically mediates PAR4- but not PAR1-mediated platelet activation; PC-TP inhibition or depletion blocks PAR4-mediated aggregation in platelets and megakaryocytic cell lines, and miR-376c negatively regulates PC-TP expression to modulate PAR4 reactivity. PC-TP inhibition/siRNA knockdown, platelet aggregation and calcium mobilization, miR-376c transfection in megakaryocytes Nature medicine High 24216752
2020 GRK5 (G protein-coupled receptor kinase 5) promotes platelet activation specifically via PAR4 receptor signaling; disruption of platelet GRK5 expression is associated with enhanced PAR4-mediated platelet reactivity through a GATA1-driven megakaryocyte enhancer mechanism. GWAS, iPSC-derived megakaryocyte experiments, allele-specific enhancer assays, platelet reactivity measurements American journal of human genetics Medium 32649856
2020 PAR4 drives canonical NLRP3 inflammasome signaling in diabetic hearts: PAR4 genetic deletion prevents diet-induced cleavage of caspase-1, IL-1β, and gasdermin D; in human cardiac fibroblasts under high glucose, PAR4 upregulation mediates thrombin-induced IL-1β transcription and secretion via caspase-1. PAR4 global knockout mice, high glucose cardiac fibroblast model, Western blotting for caspase-1/IL-1β/GSDMD cleavage, human atrial appendage samples Basic research in cardiology Medium 31912235
2021 Platelet-specific PAR4 deletion (PAR4fl/fl;PF4Cre+) demonstrates that PAR4 signaling in platelets is critical for arterial and venous thrombosis and hemostatic plug stability in mice; platelet PAR4 contributes specifically to plug stability independently of initial plug formation. Megakaryocyte/platelet-specific conditional knockout mice, FeCl3 arterial thrombosis, saphenous vein laser injury model Journal of thrombosis and haemostasis High 34689407
2001 Thrombin-induced endostatin release from rat platelets is mediated via PAR4; the PAR4-selective antagonist trans-cinnamoyl-YPGKF-NH2 prevents endostatin release induced by thrombin or PAR4-specific agonist, and this release occurs via an ADP-independent mechanism. PAR4 agonist peptides, selective PAR4 antagonist, immunoprecipitation/Western blot, ADP scavenger apyrase experiments in rat platelets British journal of pharmacology Medium 11606309
2011 Subthreshold PAR4 activation rapidly abrogates PAR1 signaling desensitization by reconstituting PKC signaling-dependent ADP release from dense granules and fibrinogen release from α-granules, thereby restoring PAR1-mediated platelet aggregation through Gαi signaling. PAR-selective hexapeptide agonists, PAR1 desensitization protocol, granule secretion assays, PKC inhibitors, Gαi signaling mimetics The Biochemical journal Medium 21391917
2022 Smoking-induced DNA hypomethylation at F2RL3 exon 2 region increases PAR4 (F2RL3) mRNA expression and is associated with enhanced PAR4-stimulated platelet reactivity; reporter assays suggest the exon 2 region controls F2RL3 gene expression. Cohort methylation-platelet reactivity analysis, in vitro cigarette smoke extract exposure with DNA methylation and mRNA quantification, luciferase reporter assays Circulation research Medium 35012325
2011 Human TFF2 (trefoil factor 2) activates PAR4 to promote epithelial cell migration; PAR4 depletion by siRNA largely inhibits hTFF2-stimulated migration of HT-29 cells, and PAR4 expression in PAR4-negative cell lines restores hTFF2-induced ERK1/2 phosphorylation and migration. siRNA knockdown of PAR4, PAR4 reconstitution in PAR4-negative cell lines, ERK1/2 phosphorylation assay, cell migration assay Cellular and molecular life sciences Medium 21461878
2018 The house dust mite allergen Der p3 activates PAR4 receptors to stimulate store-operated Ca2+ entry through Orai1/STIM1 channels in mast cells; Ca2+ influx is more tightly coupled to the PAR4 pathway than PAR2, and Der p3-PAR4 signaling drives mast cell migration. PAR4 siRNA knockdown, selective PAR agonist peptides, Orai1/STIM1 channel pharmacology, calcium imaging, mast cell migration assay Molecular cell Medium 29677491
2003 In thrombin-induced human platelet activation, glycoprotein Ibα (GPIbα) is required as a cofactor for PAR1 but not PAR4 activation at physiological thrombin concentrations; ADP secretion via P2Y1 and P2Y12 amplifies PAR1-coupled but not PAR4-coupled platelet responses. GPIbα-blocking antibodies, selective P2Y1/P2Y12 antagonists, PAR1 desensitization/selective antagonists, platelet aggregation and calcium mobilization Journal of thrombosis and haemostasis Medium 12871418

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 PAR3 is a cofactor for PAR4 activation by thrombin. Nature 446 10766244
1996 The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Cell 325 8797824
2002 Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells. Journal of immunology (Baltimore, Md. : 1950) 315 11907122
2000 Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. Biochemistry 243 10820018
2009 The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell 192 19632185
2013 Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nature medicine 179 24216752
1997 Expression and function of the leucine zipper protein Par-4 in apoptosis. Molecular and cellular biology 165 9199316
2005 Direct binding to ceramide activates protein kinase Czeta before the formation of a pro-apoptotic complex with PAR-4 in differentiating stem cells. The Journal of biological chemistry 128 15901738
2017 Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding. Science translational medicine 117 28053157
2005 Binding and phosphorylation of par-4 by akt is essential for cancer cell survival. Molecular cell 113 16209943
2009 Complement protease MASP-1 activates human endothelial cells: PAR4 activation is a link between complement and endothelial function. Journal of immunology (Baltimore, Md. : 1950) 108 19667088
2014 Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race. Blood 106 25293779
2005 Par-4 links dopamine signaling and depression. Cell 106 16051151
2003 Apoptosis by Par-4 in cancer and neurodegenerative diseases. Experimental cell research 101 12565819
2013 F2RL3 methylation as a biomarker of current and lifetime smoking exposures. Environmental health perspectives 100 24273234
2003 Regulation of cell death in mitotic neural progenitor cells by asymmetric distribution of prostate apoptosis response 4 (PAR-4) and simultaneous elevation of endogenous ceramide. The Journal of cell biology 100 12885759
1999 The downregulation of the pro-apoptotic protein Par-4 is critical for Ras-induced survival and tumor progression. The EMBO journal 100 10562548
2006 PAR4, but not PAR1, signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation. The Journal of biological chemistry 94 16837456
1999 Decreased expression of the pro-apoptotic protein Par-4 in renal cell carcinoma. Oncogene 91 10022126
2017 PAR4 (Protease-Activated Receptor 4) Antagonism With BMS-986120 Inhibits Human Ex Vivo Thrombus Formation. Arteriosclerosis, thrombosis, and vascular biology 90 29269513
1992 par-4, a gene required for cytoplasmic localization and determination of specific cell types in Caenorhabditis elegans embryogenesis. Genetics 90 1582558
2005 Phosphorylation of Par-4 by protein kinase A is critical for apoptosis. Molecular and cellular biology 89 15657440
2014 F2RL3 methylation in blood DNA is a strong predictor of mortality. International journal of epidemiology 77 24510982
2020 Thrombin receptor PAR4 drives canonical NLRP3 inflammasome signaling in the heart. Basic research in cardiology 76 31912235
2005 Ras-mediated loss of the pro-apoptotic response protein Par-4 is mediated by DNA hypermethylation through Raf-independent and Raf-dependent signaling cascades in epithelial cells. The Journal of biological chemistry 74 15831492
2005 Tumour-suppression activity of the proapoptotic regulator Par4. EMBO reports 73 15877079
2010 Cancer-selective apoptotic effects of extracellular and intracellular Par-4. Oncogene 67 20440265
2007 PAR1, but not PAR4, activates human platelets through a Gi/o/phosphoinositide-3 kinase signaling axis. Molecular pharmacology 67 17303701
2009 Of the atypical PKCs, Par-4 and p62: recent understandings of the biology and pathology of a PB1-dominated complex. Cell death and differentiation 66 19713972
2008 MEX-5 asymmetry in one-cell C. elegans embryos requires PAR-4- and PAR-1-dependent phosphorylation. Development (Cambridge, England) 66 18842813
2007 Crystal structures of murine thrombin in complex with the extracellular fragments of murine protease-activated receptors PAR3 and PAR4. Proceedings of the National Academy of Sciences of the United States of America 66 17606903
2014 The microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4. Journal of cell science 64 25472717
1997 Immunohistochemical analysis of the proapoptotic protein Par-4 in normal rat tissues. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 57 9269897
2007 Interaction of thrombin with PAR1 and PAR4 at the thrombin cleavage site. Biochemistry 56 17595115
2008 Par-4 inhibits Akt and suppresses Ras-induced lung tumorigenesis. The EMBO journal 54 18650932
2010 Deficiency of PAR4 attenuates cerebral ischemia/reperfusion injury in mice. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 53 20087365
2002 Par-4, a pro-apoptotic gene, inhibits radiation-induced NF kappa B activity and Bcl-2 expression leading to induction of radiosensitivity in human prostate cancer cells PC-3. Cancer biology & therapy 53 12170775
2016 TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells. Cancer biology & therapy 52 27830973
2013 Protease-activated receptor (PAR) 1 and PAR4 differentially regulate factor V expression from human platelets. Molecular pharmacology 52 23307185
2003 Genetic inactivation of Par4 results in hyperactivation of NF-kappaB and impairment of JNK and p38. EMBO reports 50 12634851
2014 Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival. Cell death and differentiation 49 24992930
2010 The roles and mechanisms of PAR4 and P2Y12/phosphatidylinositol 3-kinase pathway in maintaining thrombin-induced platelet aggregation. British journal of pharmacology 48 20880402
2001 Thrombin-induced platelet endostatin release is blocked by a proteinase activated receptor-4 (PAR4) antagonist. British journal of pharmacology 48 11606309
1999 Par-4: an emerging pivotal player in neuronal apoptosis and neurodegenerative disorders. Journal of molecular neuroscience : MN 48 10691289
2004 Evidence for the presence of functional protease activated receptor 4 (PAR4) in the rat colon. Gut 45 14724155
2017 Protease-Activated Receptor PAR-4: An Inducible Switch between Thrombosis and Vascular Inflammation? Thrombosis and haemostasis 44 29044290
2010 Arrestin-2 differentially regulates PAR4 and ADP receptor signaling in platelets. The Journal of biological chemistry 44 21106537
2006 Comparison of the effects of PAR1 antagonists, PAR4 antagonists, and their combinations on thrombin-induced human platelet activation. European journal of pharmacology 44 16890935
2008 Chemoprevention of pancreatic cancer: characterization of Par-4 and its modulation by 3,3' diindolylmethane (DIM). Pharmaceutical research 43 18427961
2017 miR-17-3P regulates the proliferation and survival of colon cancer cells by targeting Par4. Molecular medicine reports 42 29115593
2014 The physical association of the P2Y12 receptor with PAR4 regulates arrestin-mediated Akt activation. Molecular pharmacology 41 24723492
2012 Platelet protease-activated receptor (PAR)4, but not PAR1, associated with neutral sphingomyelinase responsible for thrombin-stimulated ceramide-NF-κB signaling in human platelets. Haematologica 41 23065519
2012 Novel role for proteinase-activated receptor 2 (PAR2) in membrane trafficking of proteinase-activated receptor 4 (PAR4). The Journal of biological chemistry 40 22411985
2009 Proteinase-activated receptor-4 (PAR4) activation leads to sensitization of rat joint primary afferents via a bradykinin B2 receptor-dependent mechanism. Journal of neurophysiology 40 19889854
2010 UNC-6 and UNC-40 promote dendritic growth through PAR-4 in Caenorhabditis elegans neurons. Nature neuroscience 37 21186357
2003 Regulation of mature T lymphocyte proliferation and differentiation by Par-4. The EMBO journal 37 12970181
2018 DNA methylation of the cancer-related genes F2RL3 and AHRR is associated with occupational exposure to polycyclic aromatic hydrocarbons. Carcinogenesis 36 29722794
2003 Synergistic effects of chemotherapeutic drugs in lymphoma cells are associated with down-regulation of inhibitor of apoptosis proteins (IAPs), prostate-apoptosis-response-gene 4 (Par-4), death-associated protein (Daxx) and with enforced caspase activation. Biochemical pharmacology 36 12948851
2016 Contributions of Protease-Activated Receptors PAR1 and PAR4 to Thrombin-Induced GPIIbIIIa Activation in Human Platelets. Molecular pharmacology 35 27784794
2018 Protease-Activated Receptor 4 (PAR4): A Promising Target for Antiplatelet Therapy. International journal of molecular sciences 34 29443899
2011 Stress-induced depressive behaviors are correlated with Par-4 and DRD2 expression in rat striatum. Behavioural brain research 34 21596067
2018 Epigenetic silencing of tumor suppressor Par-4 promotes chemoresistance in recurrent breast cancer. The Journal of clinical investigation 33 30148456
2013 A novel long non-coding RNA T-ALL-R-LncR1 knockdown and Par-4 cooperate to induce cellular apoptosis in T-cell acute lymphoblastic leukemia cells. Leukemia & lymphoma 32 23906015
2008 Maternal Par4 and platelets contribute to defective placenta formation in mouse embryos lacking thrombomodulin. Blood 32 18490515
1998 Apoptosis mediated by a novel leucine zipper protein Par-4. Apoptosis : an international journal on programmed cell death 32 14646502
2020 A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling. American journal of human genetics 31 32649856
2011 Activation of protease-activated receptor (PAR) 1 by frog trefoil factor (TFF) 2 and PAR4 by human TFF2. Cellular and molecular life sciences : CMLS 31 21461878
2005 Regulation of cancer cell survival by Par-4. Annals of the New York Academy of Sciences 31 16382046
2003 Thrombin-induced platelet PAR4 activation: role of glycoprotein Ib and ADP. Journal of thrombosis and haemostasis : JTH 31 12871418
2016 miR-107 Promotes Proliferation and Inhibits Apoptosis of Colon Cancer Cells by Targeting Prostate Apoptosis Response-4 (Par4). Oncology research 30 27938501
2015 PAR-4 and anillin regulate myosin to coordinate spindle and furrow position during asymmetric division. The Journal of cell biology 30 26416962
2012 Mapping human protease-activated receptor 4 (PAR4) homodimer interface to transmembrane helix 4. The Journal of biological chemistry 30 22318735
2015 PAR1-stimulated platelet releasate promotes angiogenic activities of endothelial progenitor cells more potently than PAR4-stimulated platelet releasate. Journal of thrombosis and haemostasis : JTH 29 25495701
2010 Pro-apoptotic Par-4 and dopamine D2 receptor in temporal cortex in schizophrenia, bipolar disorder and major depression. Schizophrenia research 29 20067857
2007 Platelet activation via PAR4 is involved in the initiation of thrombin generation and in clot elasticity development. Thrombosis and haemostasis 29 17334509
2008 Par-4 binds to topoisomerase 1 and attenuates its DNA relaxation activity. Cancer research 28 18676842
2021 Genetic deletion of platelet PAR4 results in reduced thrombosis and impaired hemostatic plug stability. Journal of thrombosis and haemostasis : JTH 27 34689407
2011 Vitamin E forms inhibit IL-13/STAT6-induced eotaxin-3 secretion by up-regulation of PAR4, an endogenous inhibitor of atypical PKC in human lung epithelial cells. The Journal of nutritional biochemistry 27 21764283
2018 The Allergen Der p3 from House Dust Mite Stimulates Store-Operated Ca2+ Channels and Mast Cell Migration through PAR4 Receptors. Molecular cell 26 29677491
2018 A function-blocking PAR4 antibody is markedly antithrombotic in the face of a hyperreactive PAR4 variant. Blood advances 26 29884748
2008 Downregulation of PAR-4, a pro-apoptotic gene, in pancreatic tumors harboring K-ras mutation. International journal of cancer 26 17893871
2020 PAR4 activation involves extracellular loop 3 and transmembrane residue Thr153. Blood 25 32575122
2019 Molecular basis for activation and biased signaling at the thrombin-activated GPCR proteinase activated receptor-4 (PAR4). The Journal of biological chemistry 25 31892516
2011 Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets. The Biochemical journal 25 21391917
2022 Epigenetic Regulation of F2RL3 Associates With Myocardial Infarction and Platelet Function. Circulation research 21 35012325
2005 Activation of PAR4 induces a distinct actin fiber formation via p38 MAPK in human lung endothelial cells. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 21 15923365
2015 Development and characterization of monoclonal antibodies against Protease Activated Receptor 4 (PAR4). Thrombosis research 20 25890453
2013 Antithrombotic effects of PAR1 and PAR4 antagonists evaluated under flow and static conditions. Thrombosis research 20 24268424
2012 The role of thrombin receptors PAR1 and PAR4 for PAI-1 storage, synthesis and secretion by human platelets. Thrombosis research 20 22283974
2015 Stimulation of PAR-1 or PAR-4 promotes similar pattern of VEGF and endostatin release and pro-angiogenic responses mediated by human platelets. Platelets 19 26082997
2007 Protease-activated receptor-1 (PAR1) and PAR2 but not PAR4 mediate relaxations in lower esophageal sphincter. Regulatory peptides 19 17335921
2005 LKB1/PAR4 protein is asymmetrically localized in mouse oocytes and associates with meiotic spindle. Gene expression patterns : GEP 19 15963768
2004 Par-4 inhibits choline uptake by interacting with CHT1 and reducing its incorporation on the plasma membrane. The Journal of biological chemistry 19 15090548
2023 The predominant PAR4 variant in individuals of African ancestry worsens murine and human stroke outcomes. The Journal of clinical investigation 18 37471144
2020 Long non-coding RNA MIR503HG inhibits the proliferation, migration and invasion of colon cancer cells via miR-107/Par4 axis. Experimental cell research 18 32738347
2017 Performance of urine cotinine and hypomethylation of AHRR and F2RL3 as biomarkers for smoking exposure in a population-based cohort. PloS one 18 28453567
2019 Selective Inhibition of PAR4 (Protease-Activated Receptor 4)-Mediated Platelet Activation by a Synthetic Nonanticoagulant Heparin Analog. Arteriosclerosis, thrombosis, and vascular biology 17 30727756
2015 Exposure to welding fumes is associated with hypomethylation of the F2RL3 gene: a cardiovascular disease marker. Occupational and environmental medicine 17 26395445
2014 The relationship between anticancer effect of metformin and the transcriptional regulation of certain genes (CHOP, CAV-1, HO-1, SGK-1 and Par-4) on MCF-7 cell line. European review for medical and pharmacological sciences 17 24943970
2020 Protease activated receptor 4 (PAR4) antagonists: Research progress on small molecules in the field of antiplatelet agents. European journal of medicinal chemistry 16 33049608