Property Summary

NCBI Gene PubMed Count 79
PubMed Score 30.53
PubTator Score 103.13

Knowledge Summary

Patent (31,178)

TINX Plot

  Disease (2)

Expression

  Differential Expression (1)

Disease log2 FC p
lung adenocarcinoma -1.400 1.2e-20

 CSPA Cell Line (1)

MLP Assay (3)

AID Type Active / Inconclusive / Inactive Description
652250 confirmatory 14 / 0 / 177 Discovery of Novel Antagonists of Protease activated receptor 4: Single Point
652253 confirmatory 2 / 0 / 8 Discovery of Novel Antagonists of Protease activated receptor 4: CRC Assay
652261 summary 0 / 0 / 0 ML354 Discovery of Novel Antagonists of Protease activated receptor 4

Gene RIF (62)

PMID Text
27126938 Suppression of PAR4 expression has no significant effect on the proliferation of SW620 cells, but can inhibit the migration of the cells.
26569550 Both GPIbalpha and PAR4 are required for thrombin-induced reactive oxygen species formation in human platelets.
26020638 Bladder PAR activation elicits urothelial MIF release and urothelial MIF receptor signaling at least partly through CXCR4 to result in abdominal hypersensitivity without overt bladder inflammation
25876034 protease-activated receptor 4 and Trefoil factor 2 are expressed in human colorectal cancer
25821117 Findings suggested that F2RL3 methylation is a very strong predictor of lung cancer risk and mortality, particularly at older age.
25664811 The PAR4 expression and activation via intracellular signaling pathways and the role of PAR4 signaling pathways in the development and maintenance of pain.
25293779 Quantitative trait locus analysis identified 3 common single nucleotide polymorphisms in the PAR4 gene (F2RL3) associated with PAR4-induced platelet aggregation. Thr120 was more common in blacks than whites.
25278289 Washed platelets from black volunteers were hyperaggregable in response to PAR4-mediated platelet stimulation compared with whites.
25239438 PAR-4 appears to play a hitherto unsuspected role in diabetic vasculopathy.
25120239 This review summarizes the roles of PAR4 in coagulation and other extracellular protease pathways.
24990072 exosite II is critical for activation of PAR4.
24776597 provide evidence against the hypothesis that PAR-1 and PAR-4 stimulation of platelets trigger differential release of alpha-granules
24723492 PAR4-P2Y12 association supports arrestin-mediated sustained signaling to Akt.
24510982 Lower F2RL3 methylation is a strong predictor of mortality, including all-cause, cardiovascular, cancer and other mortality. Systemic adverse effects of smoking may be mediated by pathways associated with F2RL3 methylation.
24216752 Phosphatidylcholine transfer protein contributes to the racial difference in PAR4-mediated platelet activation.
24097976 PAR1 and PAR4 require allosteric changes induced via receptor cleavage by alpha-thrombin to mediate heterodimer formation
23784669 PAR4 and GPVI-mediated platelet reactivity involves 12-lipoxygenase
23307185 Stimulation of PAR4 on platelets leads to faster and more robust thrombin generation, compared to PAR-1 stimulation.
22511653 The results seem to indicate methylation in F2RL3 to be a potential mediator of the detrimental impact of smoking and mortality in coronary heart disease
22411985 Novel role for proteinase-activated receptor 2 (PAR2) in membrane trafficking of proteinase-activated receptor 4 (PAR4).
22318735 mutations that disrupted dimer formation had reduced calcium mobilization in response to the PAR4 agonist peptide.
22228373 The F2RL3 rs773857 risk allele homozygotes are associated with risk for increased platelet count and hyperactivity.
22151913 PAR4 is down-regulated in the colonic mast cells of post-infectious irritable bowel syndrome.
21649850 PKC inhibition markedly enhances Ca2+ signaling and phosphatidylserine exposure downstream of protease-activated receptor-1 but not protease-activated receptor-4 in human platelets.
21635966 down-regulation of PAR4 expression occurs frequently in gastric cancers and exhibits association with more aggressive gastric cancer
21461878 Data show that frog TFF2 activates protease-activated receptor (PAR) 1 to induce human platelet aggregation, and suggest that human TFF2 promotes cell migration via PAR4.
21391917 The present study elucidates further differences in human platelet PAR signalling regulation and provides evidence for a cross-talk in which PAR4 signalling counteracts mechanisms involved in PAR1 signalling down-regulation.
21164077 High glucose enhances smooth muscle cell responsiveness to thrombin through transcriptional upregulation of PAR-4, mediated via PKC and NFkappaB.
21127289 Protease-activated receptor signaling in platelets activates cytosolic phospholipase A2alpha differently for cyclooxygenase-1 and 12-lipoxygenase catalysis.
20930172 Low concentrations of alpha-thrombin accelerate tissue factor-induced thrombin generation on the surface of vascular smooth muscle cells, and this effect is mediated by PAR-3 and PAR-4.
20807173 Results suggest that lower levels of protease-activated receptors 1 and 4 contribute to the poor thrombin induced aggregation observed with newborn platelets, which can not be compensated by higher levels of GPIbalpha.
20628086 Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator)
20561531 SPSB1 and SPSB4 bind strongly to both Par-4 and VASA peptides.
20230207 Data show that PAR1 and PAR4-activating peptides were as effective as thrombin in inducing annexin V binding in combination with collagen-related peptide in diluted whole blood and platelet rich plasma, but not in washed platelets.
20175118 Thrombin enhances the migration of chondrosarcoma cells by increasing MMP-2 and MMP-13 expression through the PAR/PLC/PKCalpha/c-Src/NF-kappaB signal transduction pathway.
20155436 Human cytomegalovirus induces PARs expression through transcriptional activation in endothelial cells, increasing sensitivity to thrombin.
19913121 Observational study of gene-disease association. (HuGE Navigator)
19667088 Complement protease MASP-1 activates human endothelial cells through PAR4 cleavage
19528350 both Cat-G and PAR(4) play key roles in generating and/or amplifying relapses in ulcerative colitis
19437337 murine platelets are more sensitive to plasmin than human platelets due to differences in the primary sequence of PAR4. In contrast to thrombin-dependent activation of platelets,, mPAR3 inhibits plasmin-induced PAR4 activation.
19058300 These data highlight the role of PAR4 as a new important player in the control of colon tumors and underline the critical role of ErbB-2 transactivation.
19053259 PAR4 uses its anionic cluster to interact with alpha-thrombin. This interaction is important even in the presence of protease-activated receptor 1 (PAR1).
18682394 Coordinate activation of human platelet protease-activated receptor-1 and -4 in response to subnanomolar alpha-thrombin
18480058 PAR4-pretreated platelets, epinephrine caused dense granule secretion, and subsequent signaling from the ATP-gated P2X(1)-receptor and the alpha(2A)-adrenergic receptor induced aggregation.
18427961 Results show the induction of Par-4 by the chemopreventive agent 3,3' diindolylmethane in pancreatic cancer cells in vitro.
18179608 similar to the guinea-pig gallbladder, both PAR(1) and PAR(2) but not PAR(4) mediate muscle contraction in the human gallbladder
17373694 PARs (PAR-1, PAR-2, and PAR-4) are overexpressed in prostate cancer and may serve as potential predictors of recurrence. The data suggest potential role of PARs in autocrine and paracrine mechanisms of prostate cancer.
17323377 cooperative PAR(1)/PAR(4) signaling network that contributes to thrombin-mediated tumor cell migration in hepatocellular carcinoma
16952995 new class of cell-penetrating inhibitors, termed pepducins, that provide insight into previously unidentified roles of PAR1 and PAR4 in protease signaling.
16837456 Data show that at relatively high concentration of agonist, inhibition of the P2Y12 receptor and of calcium mobilization result in complete inhibition of PAR4-induced aggregation, with no effect on either thrombin or PAR1-mediated platelet aggregation.
15203717 beta- and gamma-thrombin selectively activate PAR-4; physiological roles are demonstrated
15099288 results suggest stimulation of both the PAR1 & PAR4 receptors are necessary for thrombin-induced procoagulant activity, & the P2Y(12) receptor, but not the P2Y(1) receptor, is responsible for potentiation of agonist-induced platelet procoagulant activity
15078882 PAR-1 and PAR-4 signal Rap1B activation, the ability of thrombin to activate this GTPase independently of secreted ADP involves costimulation of both receptors as well as binding to GPIb-IX-V.
15045135 evidence that only one of the thrombin platelet receptors, PAR1 or PAR4, is sufficient to induce intracellular signaling leading to the cleavage of the beta3 cytoplasmic domain
14973136 plasmin induces platelet aggregation primarily through slow cleavage of PAR-4; prolonged incubation with plasmin desensitized platelets to further stimulation by thrombin.
14521606 PAR-1 and PAR-4 have roles in activating GPIb translocation into the cytoskeleton in platelets
13678420 Protease-activated receptor-4 exodomains utilize dual prolines and an anionic retention motif for thrombin recognition and cleavage.
12888878 Important role in regulation of thromboxane formation in platelets responding to thrombin through prolonged elevation of [Ca(2+)](i) and activation of phospholipase A(2). Can be activated by relatively low concentrations of thrombin in human platelets.
12871418 PAR4 is activated independently of GPIbalpha and ADP
12008957 The signal from PAR4 stabilizes platelet-platelet aggregate formation in the absence of P2Y12 activation by ADP.
12006403 Activation of platelets via the PAR4 pathway, by treatment with PAR4 agonist peptide AYPGKF, results in thrombin-induced thromboxane production by platelets.
11907122 When expressed in respiratory epithelial cells and cell lines, protease-activated receptor 4 (PAR4)induces the release of IL-6, IL-8, and PGE2.

AA Sequence

MWGRLLLWPLVLGFSLSGGTQTPSVYDESGSTGGGDDSTPSILPAPRGYPGQVCANDSDTLELPDSSRAL      1 - 70
LLGWVPTRLVPALYGLVLVVGLPANGLALWVLATQAPRLPSTMLLMNLAAADLLLALALPPRIAYHLRGQ     71 - 140
RWPFGEAACRLATAALYGHMYGSVLLLAAVSLDRYLALVHPLRARALRGRRLALGLCMAAWLMAAALALP    141 - 210
LTLQRQTFRLARSDRVLCHDALPLDAQASHWQPAFTCLALLGCFLPLLAMLLCYGATLHTLAASGRRYGH    211 - 280
ALRLTAVVLASAVAFFVPSNLLLLLHYSDPSPSAWGNLYGAYVPSLALSTLNSCVDPFIYYYVSAEFRDK    281 - 350
VRAGLFQRSPGDTVASKASAEGGSRGMGTHSSLLQ                                       351 - 385
//

Text Mined References (79)

PMID Year Title
27402844 2016 Protease-activated Receptor-4 Signaling and Trafficking Is Regulated by the Clathrin Adaptor Protein Complex-2 Independent of ?-Arrestins.
27126938 2016 [Downregulation of proteinase activated receptor 4 inhibits migration of SW620 human colorectal cancer cells].
26569550 2015 Thrombin-induced reactive oxygen species generation in platelets: A novel role for protease-activated receptor 4 and GPIb?.
26020638 2015 Macrophage Migration Inhibitory Factor Mediates PAR-Induced Bladder Pain.
25876034 2015 Increased expression of protease-activated receptor 4 and Trefoil factor 2 in human colorectal cancer.
25821117 2015 F2RL3 methylation, lung cancer incidence and mortality.
25664811 2015 New insights into protease-activated receptor 4 signaling pathways in the pathogenesis of inflammation and neuropathic pain: a literature review.
25293779 2014 Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race.
25278289 2014 Mechanism of race-dependent platelet activation through the protease-activated receptor-4 and Gq signaling axis.
25239438 2014 Thrombin receptor protease-activated receptor 4 is a key regulator of exaggerated intimal thickening in diabetes mellitus.
25120239 2015 Protease-activated receptor 4: a critical participator in inflammatory response.
24990072 2014 Thrombin-induced platelet activation via PAR4: pivotal role for exosite II.
24776597 2014 Quantitative proteomics analysis reveals similar release profiles following specific PAR-1 or PAR-4 stimulation of platelets.
24723492 2014 The physical association of the P2Y12 receptor with PAR4 regulates arrestin-mediated Akt activation.
24510982 2014 F2RL3 methylation in blood DNA is a strong predictor of mortality.
24216752 2013 Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c.
24097976 2013 Protease-activated receptor 1 (PAR1) and PAR4 heterodimers are required for PAR1-enhanced cleavage of PAR4 by ?-thrombin.
23784669 2013 12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity.
23307185 2013 Protease-activated receptor (PAR) 1 and PAR4 differentially regulate factor V expression from human platelets.
22511653 2012 Smoking, F2RL3 methylation, and prognosis in stable coronary heart disease.
22411985 2012 Novel role for proteinase-activated receptor 2 (PAR2) in membrane trafficking of proteinase-activated receptor 4 (PAR4).
22318735 2012 Mapping human protease-activated receptor 4 (PAR4) homodimer interface to transmembrane helix 4.
22228373 2012 Polymorphism in the protease-activated receptor-4 gene region associates with platelet activation and perioperative myocardial injury.
22151913 2012 Protease activated receptor 4 status of mast cells in post infectious irritable bowel syndrome.
21649850 2011 PKC inhibition markedly enhances Ca2+ signaling and phosphatidylserine exposure downstream of protease-activated receptor-1 but not protease-activated receptor-4 in human platelets.
21635966 2011 Decreased expression of protease-activated receptor 4 in human gastric cancer.
21461878 2011 Activation of protease-activated receptor (PAR) 1 by frog trefoil factor (TFF) 2 and PAR4 by human TFF2.
21391917 2011 Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets.
21164077 2011 High glucose enhances thrombin responses via protease-activated receptor-4 in human vascular smooth muscle cells.
21127289 2011 Protease-activated receptor signaling in platelets activates cytosolic phospholipase A2? differently for cyclooxygenase-1 and 12-lipoxygenase catalysis.
20930172 2010 Activation of protease-activated receptors 3 and 4 accelerates tissue factor-induced thrombin generation on the surface of vascular smooth muscle cells.
20807173 2010 Newborn platelets: lower levels of protease-activated receptors cause hypoaggregability to thrombin.
20628086 2010 Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.
20561531 2010 Structural basis for Par-4 recognition by the SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4.
20230207 2010 Annexin V binding to platelets is agonist, time and temperature dependent.
20175118 2010 Thrombin enhanced migration and MMPs expression of human chondrosarcoma cells involves PAR receptor signaling pathway.
20155436 2010 Human cytomegalovirus increases HUVEC sensitivity to thrombin and modulates expression of thrombin receptors.
19913121 2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
19667088 2009 Complement protease MASP-1 activates human endothelial cells: PAR4 activation is a link between complement and endothelial function.
19528350 2009 Luminal cathepsin g and protease-activated receptor 4: a duet involved in alterations of the colonic epithelial barrier in ulcerative colitis.
19437337 2009 Regulation of plasmin-induced protease-activated receptor 4 activation in platelets.
19058300 2009 Aberrant expression of proteinase-activated receptor 4 promotes colon cancer cell proliferation through a persistent signaling that involves Src and ErbB-2 kinase.
19053259 2008 Protease-activated receptor 4 uses anionic residues to interact with alpha-thrombin in the absence or presence of protease-activated receptor 1.
18682394 2008 Coordinate activation of human platelet protease-activated receptor-1 and -4 in response to subnanomolar alpha-thrombin.
18480058 2008 The ATP-gated P2X1 receptor plays a pivotal role in activation of aspirin-treated platelets by thrombin and epinephrine.
18427961 2008 Chemoprevention of pancreatic cancer: characterization of Par-4 and its modulation by 3,3' diindolylmethane (DIM).
18179608 2008 Proteinase-activated receptor-1 (PAR(1)) and PAR(2) but not PAR(4) mediate contraction in human and guinea-pig gallbladders.
17373694 2007 Overexpression of protease-activated receptors-1,-2, and-4 (PAR-1, -2, and -4) in prostate cancer.
17323377 2007 Thrombin-mediated hepatocellular carcinoma cell migration: cooperative action via proteinase-activated receptors 1 and 4.
16952995 2006 Protease-activated receptors in cardiovascular diseases.
16837456 2006 PAR4, but not PAR1, signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation.
16102047 2005 Protease-activated receptors in hemostasis, thrombosis and vascular biology.
15489334 2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
15342556 2004 Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions.
15203717 2004 Differential activation and inhibition of human platelet thrombin receptors by structurally distinct alpha-, beta- and gamma-thrombin.
15099288 2004 Role of protease-activated and ADP receptor subtypes in thrombin generation on human platelets.
15078882 2004 Contribution of protease-activated receptors 1 and 4 and glycoprotein Ib-IX-V in the G(i)-independent activation of platelet Rap1B by thrombin.
15045135 2004 Contribution of PAR-1, PAR-4 and GPIbalpha in intracellular signaling leading to the cleavage of the beta3 cytoplasmic domain during thrombin-induced platelet aggregation.
14973136 2004 Plasmin-mediated activation of platelets occurs by cleavage of protease-activated receptor 4.
14521606 2003 Redistribution of glycoprotein Ib within platelets in response to protease-activated receptors 1 and 4: roles of cytoskeleton and calcium.
13678420 2003 Protease-activated receptor-4 uses dual prolines and an anionic retention motif for thrombin recognition and cleavage.
12888878 2003 The role of PAR4 in thrombin-induced thromboxane production in human platelets.
12871418 2003 Thrombin-induced platelet PAR4 activation: role of glycoprotein Ib and ADP.
12732212 2003 PAR-3 is a low-affinity substrate, high affinity effector of thrombin.
12477932 2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.
12008957 2002 Role of the PAR4 thrombin receptor in stabilizing platelet-platelet aggregates as revealed by a patient with Hermansky-Pudlak syndrome.
11907122 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.
11714832 2001 Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2.
10766244 2000 PAR3 is a cofactor for PAR4 activation by thrombin.
10702240 2000 Cathepsin G activates protease-activated receptor-4 in human platelets.
10500152 1999 Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity.
10477691 1999 Dichotomous regulation of myosin phosphorylation and shape change by Rho-kinase and calcium in intact human platelets.
10079109 1999 Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin.
9722561 1998 Gene and locus structure and chromosomal localization of the protease-activated receptor gene family.
9716134 1998 A dual thrombin receptor system for platelet activation.
9618465 1998 Cloning and characterization of human protease-activated receptor 4.
8982657 1996 Direct evidence for two distinct G proteins coupling with thrombin receptors in human neuroblastoma SH-EP cells.
8290554 1994 G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets.
1851174 1991 The G protein coupled to the thromboxane A2 receptor in human platelets is a member of the novel Gq family.