Affinage

F2R

Proteinase-activated receptor 1 · UniProt P25116

Round 2 corrected
Length
425 aa
Mass
47.4 kDa
Annotated
2026-04-28
130 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

F2R (PAR1) is a protease-activated G protein-coupled receptor that transduces extracellular proteolytic signals into diverse intracellular responses governing hemostasis, vascular barrier integrity, inflammation, angiogenesis, and tumor biology. Thrombin cleaves the PAR1 N-terminal exodomain at Arg41 to unmask a tethered peptide ligand (SFLLRN) that self-activates the receptor, coupling to Gq, Gi, and G12/13 to drive platelet aggregation, endothelial permeability changes, RhoA-dependent cytoskeletal remodeling, and NF-κB/MAPK-mediated gene expression (PMID:1672265, PMID:8290554, PMID:11360179). Signaling specificity is determined by the activating protease—MMP-1, MMP-13, and KLK6 cleave PAR1 at noncanonical sites generating biased tethered ligands with distinct G-protein coupling and functional outputs—and by co-receptor context, as EPCR occupancy by APC or protein C switches PAR1 from Gq/G12/13-driven barrier disruption to Gi-dependent barrier protection via sphingosine kinase–S1P1 cross-activation (PMID:19379698, PMID:23086754, PMID:17823308, PMID:15626732). Post-activation fate is governed by BMX kinase-mediated phosphorylation promoting internalization, ADAM17-dependent exodomain shedding limiting surface receptor availability, lysosomal degradation of cleaved receptors, and replenishment from an intracellular Golgi-associated reserve pool (PMID:31910739, PMID:14982936, PMID:7961693).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1991 High

    Identification of PAR1 as the first protease-activated receptor established a fundamentally new GPCR activation paradigm—irreversible proteolytic unmasking of a tethered ligand—resolving how thrombin could signal through a cell-surface receptor.

    Evidence Expression cloning in Xenopus oocytes with site-directed mutagenesis of the thrombin cleavage site and synthetic peptide agonist validation

    PMID:1672265

    Open questions at the time
    • Downstream G-protein coupling partners not yet identified
    • Mechanism of receptor resensitization after irreversible cleavage unknown
    • Whether other proteases could activate PAR1 not addressed
  2. 1994 High

    Defining PAR1's G-protein partners (Gq, G12, G13) and its unconventional trafficking—lysosomal degradation of cleaved receptors plus mobilization of a Golgi-stored reserve pool—explained how cells restore thrombin responsiveness despite irreversible receptor activation.

    Evidence Subtype-specific G-protein coupling assays in platelets; subcellular fractionation and Golgi co-localization in transfected fibroblasts

    PMID:7961693 PMID:8290554

    Open questions at the time
    • Molecular machinery controlling reserve pool translocation undefined
    • Relative contributions of Gq vs G12/13 to specific platelet responses not dissected
  3. 1999 High

    Establishing that PAR1 and PAR4 together account for virtually all thrombin-mediated human platelet activation, and that plasmin can both transiently activate and dominantly desensitize PAR1 by cleaving distal to Arg41, revealed protease-specific regulation of receptor availability.

    Evidence Orthogonal PAR1/PAR4 blocking strategies in human platelet aggregation; kinetic and mutagenesis analysis of plasmin cleavage sites on PAR1 exodomain

    PMID:10079109 PMID:10194379

    Open questions at the time
    • Whether plasmin-PAR1 desensitization is physiologically relevant in vivo not demonstrated
    • Structural basis for differential thrombin vs plasmin exodomain recognition unknown
  4. 2002 High

    Discovery that activated protein C signals through PAR1 in an EPCR-dependent manner to elicit cytoprotective endothelial responses reframed PAR1 as a context-dependent signaling hub whose output depends on co-receptor occupancy, not just protease identity.

    Evidence Cleavage-blocking PAR1 antibodies abolished APC-induced MAP kinase activation and gene induction in HUVECs; microarray profiling

    PMID:12052963

    Open questions at the time
    • Mechanism by which EPCR binding switches PAR1 G-protein coupling not defined
    • Whether APC cleaves PAR1 at a different site than thrombin not resolved
  5. 2004 High

    Identification of ADAM17-mediated PAR1 exodomain shedding as a regulated mechanism to limit surface receptor availability, and demonstration that EPCR-PAR1 barrier protection operates through sphingosine kinase-1 and S1P1, defined two new layers of PAR1 signal regulation.

    Evidence Metalloproteinase inhibitor panel and domain-swap constructs in endothelial cells; siRNA knockdown of SphK1 and S1P1 in dual-chamber barrier assays

    PMID:14982936 PMID:15626732

    Open questions at the time
    • Identity of physiological stimuli for ADAM17-PAR1 shedding in vivo unclear
    • Whether S1P1 cross-activation occurs in non-endothelial PAR1-expressing cells untested
  6. 2005 High

    MMP-1 was identified as a non-thrombin protease agonist of PAR1 that promotes breast cancer invasion in vivo, demonstrating that the tumor microenvironment co-opts PAR1's tethered-ligand mechanism for malignant progression.

    Evidence MMP-1 cleavage site mapping; Ca²⁺ signaling; PAR1-dependent xenograft tumor growth and invasion

    PMID:15707890

    Open questions at the time
    • Whether MMP-1 generates the same or distinct tethered ligand as thrombin not fully resolved
    • Relative contribution of stromal vs autocrine MMP-1 in human tumors unknown
  7. 2007 High

    Mechanistic resolution of how EPCR occupancy redirects PAR1 signaling: protein C/APC Gla domain binding dissociates EPCR from caveolin-1 in lipid rafts, switching PAR1 coupling from Gq/G12/13 to pertussis toxin-sensitive Gi, explaining the paradox of barrier-protective versus barrier-disruptive PAR1 signaling.

    Evidence Lipid raft isolation, EPCR-caveolin-1 co-immunoprecipitation, pertussis toxin blockade, and functional permeability assays in endothelial cells

    PMID:17823308

    Open questions at the time
    • Structural basis of EPCR-PAR1 physical interaction not defined at atomic level
    • Whether lipid raft relocation is necessary or sufficient for G-protein switch untested
  8. 2009 High

    Demonstration that platelet MMP-1 cleaves PAR1 at a cryptic site distinct from thrombin's, preferentially activating RhoA-GTP and MAPK rather than canonical Ca²⁺ signaling, established the concept of protease-specific biased agonism at PAR1 with distinct thrombotic consequences.

    Evidence Cleavage site mapping, Rho-GTP signaling, in vivo thrombosis model with MMP1-PAR1 blockade; zyxin co-IP with PAR1 C-terminus and siRNA-mediated dissection of G-protein-independent cytoskeletal signaling

    PMID:19379698 PMID:19690217

    Open questions at the time
    • Full repertoire of biased signaling outputs from different protease-generated tethered ligands not catalogued
    • Structural basis of biased coupling at the receptor level unknown
  9. 2010 Medium

    PAR1 was found to activate β-catenin stabilization through a Wnt-independent Gα13–Dishevelled axis, expanding its oncogenic repertoire beyond RhoA to include transcriptional reprogramming via Lef/Tcf targets.

    Evidence siRNA-DVL silencing, dominant negative Gα13, Lef/Tcf reporter, Matrigel invasion, and PAR1-transgenic mouse mammary tissue

    PMID:20223821

    Open questions at the time
    • Whether Gα13-DVL axis operates in non-tumor contexts untested
    • Direct physical contacts between Gα13 and DVL not structurally resolved
    • Findings from a single lab
  10. 2012 High

    The 2.2 Å crystal structure of PAR1 bound to vorapaxar revealed an unusually shallow, solvent-occluded orthosteric pocket, explaining the near-irreversible antagonism by vorapaxar and providing an atomic framework for understanding tethered-ligand docking.

    Evidence X-ray crystallography of PAR1–vorapaxar complex at 2.2 Å resolution

    PMID:23222541

    Open questions at the time
    • Structure of activated PAR1 with tethered ligand engaged not available
    • No structure of PAR1 in complex with G proteins
  11. 2018 High

    FVIIa–EPCR engagement was shown to activate anti-inflammatory PAR1 signaling through β-arrestin-1, which blocks TRAF2 recruitment to TNFR1, extending the list of EPCR-dependent PAR1 co-agonists and linking coagulation factor VII to innate immune suppression.

    Evidence PAR1/EPCR/β-arrestin-1 siRNA; TRAF2 co-IP; kinase activation panels; in vivo LPS models in EPCR-overexpressing and EPCR-deficient mice

    PMID:29669778

    Open questions at the time
    • Whether FVIIa cleaves PAR1 at a unique site not mapped
    • Relative physiological importance of FVIIa vs APC as EPCR-PAR1 agonist in vivo unclear
  12. 2019 High

    PAR1 was identified as a mediator of tumor immune evasion: PAR1-deleted pancreatic tumor cells failed to grow in immunocompetent but not immunodeficient hosts, with CD8+ T cell depletion rescuing growth, positioning the TF–thrombin–PAR1 axis as a tumor-intrinsic immune checkpoint.

    Evidence CRISPR PAR1-KO KPC allografts in immunocompetent vs NSG mice; CD8/CD4/NK depletion; TF/prothrombin ASO depletion

    PMID:31048498

    Open questions at the time
    • Mechanism by which PAR1 suppresses CD8+ T cell function not molecularly defined
    • Generalizability beyond pancreatic adenocarcinoma untested
  13. 2020 High

    BMX kinase was identified as a direct PAR1 phosphorylating kinase that promotes receptor internalization and limits thrombin-induced endothelial permeability, with PAR1 antagonism rescuing vascular leak in BMX-deficient sepsis models.

    Evidence BMX-KO mice; CLP sepsis model; ECIS permeability; biochemical PAR1 phosphorylation; PAR1 antagonist rescue in vivo

    PMID:31910739

    Open questions at the time
    • Specific PAR1 phosphorylation sites targeted by BMX not mapped
    • Whether BMX regulates PAR1 in platelets or other cell types unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the activated-state structure of PAR1 with tethered ligand engaged and G-protein bound; the precise molecular basis by which different protease-generated tethered ligands achieve biased coupling to distinct G proteins; and whether intracellular allosteric modulators (parmodulins) can therapeutically separate PAR1's prothrombotic from cytoprotective functions in clinical settings.
  • No activated-state PAR1 structure with tethered ligand or G-protein complex
  • Biased agonism mechanism at atomic resolution unknown
  • Clinical translation of pathway-selective PAR1 modulation unproven

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005764 lysosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-109582 Hemostasis 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-1500931 Cell-Cell communication 3
Partners
BMXDVL1F2GNA13GNAQMMP1PROCRZYX

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 F2R (PAR1) encodes a seven-transmembrane G protein-coupled receptor activated by thrombin through a novel proteolytic mechanism: thrombin cleaves the receptor's N-terminal exodomain at R41, exposing a tethered peptide ligand (beginning with SFLLRN) that binds and activates the receptor in an intramolecular fashion. Uncleavable mutant receptors failed to respond to thrombin but retained responsiveness to the synthetic tethered-ligand peptide. Direct expression cloning in Xenopus oocytes; site-directed mutagenesis of thrombin cleavage site; synthetic peptide agonist assays; mRNA detection in human platelets and endothelial cells Cell High 1672265
1992 Characterization of PAR1 as a functional thrombin receptor confirmed tethered-ligand activation mechanism and defined receptor properties on platelets and endothelial cells. Functional receptor characterization; peptide agonist studies The Journal of Clinical Investigation High 1310691
1994 PAR1 (thrombin receptor) traffics differently from classical GPCRs: uncleaved receptors are stored in an intracellular compartment co-localizing with Golgi markers, and are protected from thrombin activation. Upon activation of cell-surface receptors, the intracellular pool translocates to the plasma membrane, replenishing surface receptors and restoring thrombin responsiveness—a novel resensitization mechanism distinct from internalization/recycling seen with beta2-adrenergic receptor. Activated (cleaved) receptors are targeted to lysosomes rather than recycled. Transfected Rat1 fibroblasts; subcellular fractionation; co-localization with Golgi markers; comparison with beta2-adrenergic receptor trafficking; agonist stimulation experiments The Journal of Biological Chemistry High 7961693
1994 PAR1 (thrombin receptor) couples to G proteins of the G12 and G13 family, as well as the Gq family, in human platelets. Both thrombin receptor and thromboxane A2 receptor activation led to increased GTP analog incorporation into alpha12 and alpha13 subunits. Subtype-specific antisera; photoreactive GTP analog ([alpha-32P]GTP azidoanilide) incorporation into immunoprecipitated G-protein alpha subunits from human platelet membranes; receptor agonist stimulation Proceedings of the National Academy of Sciences of the United States of America High 8290554
1999 PAR1 and PAR4 together account for virtually all thrombin-mediated platelet activation in humans. Inhibition of PAR1 alone blocked platelet activation at low thrombin concentrations (1 nM) but only partially at high concentrations (30 nM); simultaneous inhibition of both PAR1 and PAR4 virtually ablated platelet secretion and aggregation even at 30 nM thrombin. PAR3 was not detected as functional in human platelets. PAR1/PAR4 mRNA and protein detection in human platelets; PAR1 antagonist, blocking antibody, and desensitization experiments; PAR4 blocking antibody; platelet secretion and aggregation assays at multiple thrombin concentrations The Journal of Clinical Investigation High 10079109
1999 Plasmin desensitizes PAR1 by cleaving the N-terminal exodomain at sites R70/K76/K82 (distal to the thrombin cleavage site R41), thereby truncating the tethered ligand and preventing thrombin-dependent Ca2+ signaling. Mutation of R70/K76/K82 to alanines eliminated plasmin truncation and desensitization, converting PAR1 into a plasmin-activated receptor. Plasmin also cleaves at R41, transiently activating PAR1. The desensitization is rate-equivalent to thrombin cleavage (similar kcat and KM). Soluble N-terminal exodomain (TR78) as model; kinetic analysis (kcat, KM) of protease cleavage; mass spectrometry identification of cleavage sites; site-directed mutagenesis (R70A/K76A/K82A); full-length receptor expressed in yeast and COS7 cells; Ca2+ signaling assays Biochemistry High 10194379
2001 PAR1 overexpression in NIH3T3 cells causes oncogenic transformation through activation of RhoA-mediated signaling pathways. PAR1 transformation required receptor cleavage (uncleavable mutant was non-transforming), and was blocked by dominant negative RhoA, pertussis toxin (implicating Gαi), and the RGS domain of Lsc (implicating Gα12/Gα13). PAR1 cooperated synergistically with activated Raf-1 and activated serum response factor and NF-κB. cDNA expression library screen in NIH3T3 focus formation assay; uncleavable mutant receptor; co-expression with dominant negative RhoA; pertussis toxin treatment; RGS domain of Lsc co-expression; microinjection into PAE cells; SRF and NF-κB reporter assays Oncogene High 11360179
2002 Activated protein C (APC) signals through PAR1 on endothelial cells in an EPCR-dependent manner. APC-mediated MAP kinase phosphorylation and gene induction (including selective induction of MCP-1) were inhibited by cleavage-blocking antibodies to PAR1, demonstrating that APC signals exclusively through PAR1 in endothelial cells. Gene profiling showed PAR1 signaling accounted for all APC-induced protective genes. Fibroblast overexpression system; human endothelial cell (HUVEC) stimulation; cleavage-blocking PAR1 antibodies; high-density microarray gene expression profiling; MAP kinase phosphorylation assays Science High 12052963
2002 PAR1 activation in cancer cells promotes cellular invasion through a RhoA/Rho kinase (ROCK)-dependent mechanism via Gα12/Gα13 signaling. In the presence of pertussis toxin (blocking Gαo/i), PAR1 induced invasion through Gα12/Gα13–RhoA/ROCK. Inhibition of endogenous RhoA redirected PAR1 signaling to a Gαq–PLC–Ca2+/CaM-MLCK pathway to promote invasion via a different route, revealing RhoA and RhoD as molecular switches controlling PAR1-dependent invasion signaling. Pharmacological inhibitors (pertussis toxin, C3 exoenzyme, dominant negative N19-RhoA); activated G26V-RhoD; NO/cGMP pathway activators; invasion assays in kidney and colonic epithelial cells FASEB journal Medium 11919159
2003 Activated protein C (APC) signals through PAR1 in endothelial cells via EPCR as coreceptor; APC activates PAR1 and PAR2 in fibroblast overexpression systems in an EPCR-dependent manner. In HUVECs, APC, PAR1, and PAR2 agonist peptides induce similar early response genes; MCP-1 was selectively induced by APC and PAR1 agonist but not PAR2 agonist, confirming PAR1-exclusive APC signaling. Fibroblast overexpression; HUVEC stimulation; cleavage-blocking PAR1 antibodies; microarray gene profiling; MAP kinase assays Journal of Endotoxin Research Medium 14577849
2003 PAR1 activation induces VEGF expression and angiogenesis through PKC, Src, and PI3K kinase pathways. Par1-expressing cells significantly enhanced angiogenesis in Matrigel plug and tumor models in vivo. Multiple VEGF splice forms were induced, and neutralizing anti-VEGF antibodies inhibited PAR1-induced endothelial cell proliferation. In vivo Matrigel plug assay; tetracycline-inducible Par1 expression; VEGF mRNA/protein measurement; specific kinase inhibitors (PKC, Src, PI3K); anti-VEGF neutralizing antibodies; endothelial tube alignment and proliferation assays FASEB Journal Medium 12554695
2004 Regulated metalloproteinase-dependent shedding of the PAR1 N-terminal exodomain occurs in endothelial cells, mediated by ADAM17/TACE or a related metalloproteinase. Shedding is stimulated by phorbol ester (protein kinase C activation) or PAR1 agonist in trans, and is inhibited by TAPI-2, phenanthroline, and TIMP-3 but not TIMP-1 or -2. The shedding information resides within the exodomain, not the heptahelical segment. Regulated shedding reduced cell-surface PAR1 available for thrombin cleavage by half or more. PAR1 chimeric constructs (exodomain fused to unrelated transmembrane segment); phorbol ester and PAR1 agonist stimulation; metalloproteinase inhibitors (TAPI-2, phenanthroline, TIMP-1/2/3); domain-swap experiments in endothelial cells The Journal of Biological Chemistry High 14982936
2004 PAR1-dependent sphingosine 1-phosphate receptor-1 (S1P1) cross-activation mediates activated protein C (APC)-induced endothelial barrier protection. APC enhances endothelial barrier integrity dependent on EPCR binding, PAR1 activation, and sphingosine kinase activity. siRNA knockdown of sphingosine kinase-1 or S1P receptor-1 blocked APC-protective signaling. Low concentrations of thrombin (~40 pM) or PAR1 agonist peptide similarly enhanced barrier function, revealing that PAR1 can mediate both barrier-disruptive and barrier-protective responses. Dual-chamber endothelial barrier system; siRNA knockdown of sphingosine kinase-1 and S1P1; EPCR-blocking antibodies; PAR1 agonist peptides; thrombin dose-response Blood High 15626732
2005 Matrix metalloproteinase-1 (MMP-1) is a non-thrombin protease agonist of PAR1 that promotes breast cancer invasion and tumorigenesis. MMP-1 (derived from stromal fibroblasts) cleaves PAR1 at the proper site to generate PAR1-dependent Ca2+ signals and cell migration. PAR1 expression is required and sufficient to promote growth and invasion of breast carcinoma cells in xenograft models. Xenograft mouse model; Ca2+ signaling assays; cell migration assays; PAR1 knockdown; MMP-1 cleavage site analysis; fibroblast conditioned medium experiments Cell High 15707890
2005 PAR1 activation on human late endothelial progenitor cells (EPCs) promotes proliferation, migration, and capillary-like structure formation through upregulation of SDF-1 and its receptor CXCR4, leading to autocrine stimulation. Anti-CXCR4, anti-SDF-1, and MEK inhibitor pretreatment abrogated PAR1-induced capillary formation. EPC expansion from CD34+ cord blood; SFLLRN peptide stimulation; real-time RT-PCR for SDF-1/CXCR4 mRNA; Boyden chamber migration assay; Matrigel capillary formation; blocking antibodies; MEK inhibitor Arteriosclerosis, Thrombosis, and Vascular Biology Medium 16141404
2005 PAR1 activation on endothelial progenitor cells (EPCs) induces angiopoietin-2 gene expression and protein synthesis, which mediates PAR1-induced EPC proliferation. Polyclonal blocking antibodies against angiopoietin-2 inhibited PAR1-mediated proliferative effect. PAR1 also enhanced EPC migration toward angiopoietin-1. SFLLRN peptide stimulation of EPCs; RT-PCR and protein assay for angiopoietin-1/2; polyclonal blocking antibodies; Boyden chamber migration assay Journal of Thrombosis and Haemostasis Medium 16803467
2007 The critical amino acids for alpha-thrombin's interaction with PAR1 at the thrombin cleavage site were identified by mutagenesis of the P4 (L38), P3 (D39), and P2 (P40) positions of the PAR1 exodomain. Mutation of P4 (L38A) or P2 (P40A) reduced kcat without changing KM; mutation of P3 (D39A) reduced both Km and kcat (maintaining kcat/Km). PAR1 exodomain acts as a non-competitive inhibitor of thrombin hydrolysis of chromogenic substrate, while PAR4 exodomain is a competitive inhibitor, revealing fundamentally different thrombin-binding mechanisms. Recombinant PAR1 and PAR4 exodomain production; kinetic analysis (kcat, KM, kcat/Km); alanine-scanning mutagenesis of P4/P3/P2 positions; inhibition kinetics with chromogenic substrate Sar-Pro-Arg-pNA Biochemistry High 17595115
2007 PAR1 'role reversal' in sepsis: PAR1 functions as a vascular-disruptive receptor early in sepsis but switches to vascular-protective during disease progression. Protective effects of PAR1 required transactivation of PAR2 signaling pathways. Cell-penetrating pepducin approach demonstrated that selective PAR1-PAR2 complex activation is beneficial in sepsis. Cell-penetrating pepducin approach in mouse sepsis model; cecal ligation and puncture model; PAR1 and PAR2 genetic and pharmacological manipulation Nature Immunology Medium 17965715
2007 EPCR occupancy by protein C/APC switches PAR1 signaling specificity in endothelial cells from permeability-enhancing to barrier-protective by coupling PAR1 to pertussis toxin-sensitive Gi protein. EPCR is associated with caveolin-1 in lipid rafts; its occupancy by the Gla domain of protein C/APC dissociates EPCR from caveolin-1 and recruits PAR1 to a protective signaling pathway. When EPCR is bound, both thrombin and APC can elicit barrier-protective PAR1 signaling. Lipid raft isolation; co-immunoprecipitation of EPCR with caveolin-1; pertussis toxin blocking; Gla domain constructs; endothelial permeability assays; PAR1/EPCR signaling pathway analysis Blood High 17823308
2008 PAR1 signaling in dendritic cells couples coagulation and inflammation via a PAR1-S1P3 cross-talk mechanism. PAR1 activation sustains lethal inflammatory response in sepsis, and this is mediated downstream by the sphingosine 1-phosphate axis through S1P receptor 3 (S1P3). Loss of dendritic cell PAR1-S1P3 signaling sequesters dendritic cells into draining lymph nodes and attenuates IL-1β dissemination to lungs. Chemical and genetic probes for S1P3; PAR1-deficient mice; S1P3-deficient mice; endotoxin sepsis model; IL-1β measurement in lungs Nature High 18305483
2008 PAR1 and PAR2 activation in endothelial cells induces tissue factor (TF) expression via mitochondrial reactive oxygen species (ROS) generated primarily from complex III. ERK1/2 and p38 MAPK activation is critical for mitochondrial ROS generation. Downstream of receptor activation, a PAR1-specific module involving NF-κB activation also induces TF. HUVEC stimulation with PAR1 and PAR2 agonist peptides; TF real-time RT-PCR and procoagulant activity measurement; ROS fluorometric assay; mitochondrial complex inhibitors; ERK1/2 and p38 inhibitors; NF-κB pathway analysis Journal of Thrombosis and Haemostasis Medium 18983479
2009 Platelet MMP-1 (matrix metalloprotease-1) activates PAR1 on the platelet surface at a distinct cryptic cleavage site different from thrombin's site, promoting aggregation. Fibrillar collagen converts surface-bound proMMP-1 zymogen to active MMP-1 on platelets. MMP-1 cleavage of PAR1 preferentially activates Rho-GTP pathways, cell shape change, motility, and MAPK signaling—distinct from thrombin-induced PAR1 signaling. Blockade of MMP1-PAR1 curtails thrombogenesis under arterial flow and inhibits thrombosis in vivo. Platelet MMP-1 activation by fibrillar collagen; PAR1 cleavage site mapping; Rho-GTP and MAPK signaling assays; arterial flow thrombogenesis model; in vivo thrombosis model; MMP1-PAR1 blockade Cell High 19379698
2009 Zyxin, a LIM-domain-containing protein, binds to the C-terminal domain of PAR1 and mediates thrombin-induced actin cytoskeleton remodeling and SRE-dependent gene transcription in endothelial cells independently of G-protein (Gi, Gq, G12/13) activation. siRNA depletion of zyxin inhibited thrombin-induced stress fiber formation, SRE activation, and delayed endothelial barrier restoration. Zyxin recruits VASP to focal adhesions and along stress fibers upon thrombin stimulation. Co-immunoprecipitation of zyxin with PAR1 C-terminal domain; siRNA knockdown; stress fiber imaging; SRE reporter assay; RhoA activation assay; G-protein activation assays; barrier restoration assay FASEB Journal Medium 19690217
2010 PAR1 induces beta-catenin stabilization independent of Wnt, Frizzled, and LRP5/6 co-receptors through a novel Gα13–Dishevelled (DVL) axis. PAR1-Gα13 association recruits DVL via its DIX domain. siRNA silencing of DVL abrogated PAR1-induced Matrigel invasion, Lef/Tcf transcription activity, and beta-catenin accumulation. Dominant negative Gα13 (but not Gα12) inhibited PAR1-induced beta-catenin stabilization. PAR1 also promotes binding of beta-arrestin-2 to DVL. Dominant negative Gα13/Gα12; siRNA-DVL silencing; siRNA-LRP5/6; Wnt antagonists SFRP2/SFRP5; Lef/Tcf transcription reporter assay; Matrigel invasion assay; immunohistochemistry of hPar1-transgenic mouse mammary tissues; co-immunoprecipitation The Journal of Biological Chemistry Medium 20223821
2010 Thrombin specificity toward PAR1 (vs. protein C and fibrinogen) is determined primarily by Trp215. Saturation mutagenesis of Trp215 produced constructs with kcat/Km values spanning five orders of magnitude. W215E is 10-fold more specific for protein C than fibrinogen and PAR1. Combining W215E with deletion of 9 residues in the autolysis loop produced a construct with significant activity only toward PAR1, demonstrating context-dependent re-engineering of thrombin specificity. Ala-scanning mutagenesis of 97 residues covering 53% of solvent-accessible surface; saturation mutagenesis of Trp215; kinetic characterization (kcat/Km) for fibrinogen, PAR1, and protein C hydrolysis The Journal of Biological Chemistry High 20404340
2011 PAR1 signaling desensitization in human platelets (via PAR1 homologous activation) is counteracted by PAR4 signaling. PAR1 desensitization involves decreased Ca2+ mobilization, reduced PKC signaling, and loss of dense granule secretion. Subthreshold PAR4 activation re-establishes PAR1-induced aggregation by reconstituting these signaling events via PKC-mediated ADP release from dense granules and fibrinogen from alpha-granules; G(αi) signaling is required. Isolated human platelets; specific PAR1 (SFLLRN) and PAR4 (AYPGKF) activating hexapeptides; Ca2+ mobilization measurement; PKC signaling assay; granule secretion assays; 2-MeS-ADP and epinephrine mimicry of Gαi/z; aggregometry The Biochemical Journal Medium 21391917
2012 PAR1 deficiency (F2r-/-) reduces intestinal vessel density in germ-free mice colonized with microbiota, and inhibition of thrombin (PAR1 activator) decreased TF cytoplasmic domain phosphorylation, placing thrombin-PAR1 signaling upstream of TF phosphorylation in a microbiota-induced extravascular TF-PAR1 signaling loop promoting intestinal vascular remodeling. PAR2-deficient mice showed no such decrease. PAR1-deficient (F2r-/-) and PAR2-deficient (F2rl1-/-) mice; germ-free colonization; anti-TF treatment; TF cytoplasmic domain phosphorylation measurement; hirudin (thrombin inhibitor) treatment; vascular density quantification; angiopoietin-1 expression Nature High 22407318
2012 MMP-1 and MMP-13 cleave the N-terminal exodomain of PAR1 at noncanonical sites (different from the thrombin cleavage site R41), generating distinct tethered ligands that activate different G-protein signaling pathways—termed biased agonism—producing distinct functional cellular outputs compared to thrombin-activated PAR1. PAR1 cleavage site mapping; Ca2+ signaling; G-protein pathway activation assays; comparison of canonical (thrombin) vs. noncanonical (MMP-1, MMP-13) cleavage products Blood Medium 23086754
2012 High-resolution (2.2 Å) crystal structure of human PAR1 bound to vorapaxar reveals an unusual, superficial binding pocket with little solvent exposure—distinct from deep, solvent-exposed pockets of other peptide-activated GPCRs. Vorapaxar binding explains near-irreversible inhibition of receptor activation by the tethered ligand. The structure defines the molecular basis for PAR1 antagonism. X-ray crystallography at 2.2 Å resolution; PAR1 bound to vorapaxar antagonist Nature High 23222541
2013 Kallikrein 6 (Klk6) signals through PAR1 (and PAR2) to promote neuron injury and exacerbate glutamate neurotoxicity via ERK1/2 signaling in a phosphoinositide 3-kinase and MEK-dependent fashion. Lipopeptide inhibitors of PAR1 or PAR2, and PAR1 genetic deletion, each reduced Klk6-ERK1/2 activation. PAR1 genetic deletion blocked thrombin-mediated cerebellar neurotoxicity and reduced neurotoxic effects of Klk6. Cerebellar granule neurons and NSC34 motoneurons; recombinant Klk6; PAR1/PAR2 lipopeptide inhibitors; PAR1 genetic deletion mice; ERK1/2 phosphorylation; PI3K and MEK inhibitors; LDH release; Bim signaling; PARP cleavage Journal of Neurochemistry Medium 23647384
2013 Kallikrein 6 (KLK6) activates PAR1 to mediate loss of oligodendrocyte processes and impede oligodendrocyte progenitor cell morphological differentiation. PAR1-activating peptides and thrombin produce comparable oligodendrogliopathy. KLK6 suppresses proteolipid protein (PLP) RNA expression through PAR1-mediated Erk1/2 signaling. In vivo microinjection of PAR1 agonists into dorsal column white matter promoted vacuolating myelopathy and loss of MBP and CC-1+ oligodendrocytes in PAR1+/+ but not PAR1-/- mice. Primary oligodendrocyte cultures from WT and PAR1-deficient mice; Oli-neu cell line; Klk6, thrombin, and PAR1-AP stimulation; PAR1 genetic deletion; Erk1/2 signaling assay; PLP RNA quantification; in vivo microinjection; MBP and CC-1 immunostaining Glia High 23832758
2013 PAR1 and PAR3 cooperate to drive thrombin (FIIa)-induced epithelial-mesenchymal transition (EMT) in alveolar epithelial cells. Single knockdown of PAR1, PAR3, or PAR4 had no major impact on FIIa-induced EMT, but simultaneous depletion of PAR1 and PAR3 almost completely inhibited EMT. PAR1 and PAR3 co-localize within alveolar type II cells on the plasma membrane. siRNA knockdown (single and combined) of PAR1, PAR3, PAR4; thrombin stimulation; EMT markers (morphological, epithelial/mesenchymal protein expression, functional changes); co-localization immunostaining Thrombosis and Haemostasis Medium 23739922
2015 PAR1 induces a metastatic, hormone-refractory breast cancer phenotype through upregulation of HMGA2. Functionally active PAR1 (but not non-signaling mutant PAR1) in MCF-7 cells induced epithelial-mesenchymal transition, vimentin upregulation, E-cadherin and estrogen receptor downregulation, and lung metastasis in mice. HMGA2 was identified as a key mediator of PAR1-induced invasion, and inhibition of PAR1 signaling suppressed HMGA2-driven invasion. Ectopic PAR1 expression in MCF-7 cells; non-signaling PAR1 mutant; in vivo lung metastasis model; EMT marker analysis; HMGA2 expression analysis; PAR1 signaling inhibition; spheroid formation assay Oncogene Medium 26165842
2015 PAR1 and PAR2 contain pleckstrin homology (PH) domain-binding motifs that mediate association with Akt/PKB, Etk/Bmx, and Vav3 via their PH domains. PAR1 and PAR2 bind with priority to Etk/Bmx. A point mutation in PAR1 (hPar1-7A, unable to bind PH domain) reduced mammary tumors and trophoblast invasion in vivo, demonstrating physiological significance of PH-domain-binding motifs. Co-immunoprecipitation of PH-domain proteins with PAR1/PAR2; PAR2 point mutants (H349A, R352A); PAR1 hPar1-7A mutant; in vivo mammary tumor model; trophoblast invasion assay Nature Communications Medium 26600192
2017 PAR1 activation in astrocytes induces rapid structural reorganization of the neuropil surrounding glutamatergic synapses, associated with faster clearance of synaptically-released glutamate from the extracellular space. This leads to short- and long-term changes in excitatory synaptic transmission in the mouse hippocampus, identifying PAR1 as a regulator of glutamatergic signaling. Mouse hippocampal preparations; PAR1 activation; 3D Monte Carlo reaction-diffusion simulations; axial scanning transmission electron microscopy (STEM) tomography; glutamate uptake assays; electrophysiology Scientific Reports Medium 28256580
2018 FVIIa binding to EPCR elicits anti-inflammatory signaling via PAR1 and β-arrestin-1 in endothelial cells. Inhibition of EPCR or PAR1 (by antibodies or siRNA) abolished FVIIa-induced suppression of adhesion molecules and IL-6. β-arrestin-1 silencing blocked FVIIa's anti-inflammatory effect. Mechanistically, FVIIa-EPCR-PAR1 signaling inhibited ERK1/2, p38 MAPK, JNK, NF-κB, and C-Jun activation by impairing TRAF2 recruitment to the TNF receptor 1 signaling complex. Endothelial cell stimulation with FVIIa; PAR1/EPCR siRNA and blocking antibodies; β-arrestin-1 siRNA; cytokine expression; adhesion molecule expression; kinase activation assays (ERK1/2, p38, JNK, NF-κB); TRAF2 co-immunoprecipitation; in vivo LPS model in WT, EPCR-overexpressing, and EPCR-deficient mice Blood High 29669778
2019 Thrombin-PAR1 signaling in pancreatic ductal adenocarcinoma (PDAC) tumor cells promotes tumor growth through suppression of antitumor CD8+ T cell immunity. PAR1-deleted KPC cells failed to form tumors in immune-competent mice but showed robust growth in immune-compromised NSG mice. CD8 T cell depletion rescued tumor growth of PAR1-KO cells in competent mice. Tumor cell TF and circulating prothrombin activate PAR1 to mediate immune evasion. PAR1-deleted KPC cell lines (CRISPR/KO); allograft studies; immune-competent vs. NSG mice; CD8/CD4/NK cell depletion; TF/prothrombin depletion (ASO); expression profiling of immune regulation pathways Cancer Research High 31048498
2019 HIV-1 Tat induces expression of MMP-3 and MMP-13 in astrocytes, which then activate PAR1 to stimulate release of CCL2 (a chemokine promoting CNS entry of HIV-infected monocytes). Both genetic knockout and pharmacological inhibition of PAR1 reduced Tat/MMP-induced CCL2 release from astrocytes. Astrocyte cultures; HIV-1 Tat exposure; MMP-3 and MMP-13 expression; PAR1 genetic knockout and pharmacological inhibition; CCL2 ELISA; post-mortem HIV brain tissue correlation analysis Glia Medium 31124192
2020 BMX kinase represses thrombin-PAR1-mediated endothelial permeability by directly phosphorylating PAR1 and promoting its internalization and deactivation. BMX loss increased thrombin-mediated endothelial permeability 2-3 fold. Pretreatment with PAR1 antagonist SCH79797 rescued BMX-loss-mediated endothelial permeability and pulmonary leakage in early sepsis. BMX-KO mice; cecal ligation and puncture sepsis model; electric cell-substrate impedance sensing (transendothelial electrical resistance); modified Miles assay (vascular leakage); biochemical analysis of BMX-PAR1 phosphorylation; PAR1 internalization assays; PAR1 antagonist pretreatment Circulation Research High 31910739
2020 F2R (PAR1) negatively regulates osteoclastogenesis by inhibiting both the Akt and NF-κB signaling pathways in response to RANKL stimulation. F2r knockdown increased osteoclast activity, number, size, bone resorption, F-actin ring formation, and osteoclast marker gene expression with significantly increased pAkt levels and enhanced phosphorylation of p65 and IKBα. F2r overexpression blocked osteoclast formation, maturation, and acidification. sh-F2r lentivirus knockdown and pLX304-F2r overexpression in mouse bone marrow cells; RANKL-induced osteoclastogenesis; pAkt Western blot; p65 and IKBα phosphorylation; osteoclast activity assays; F-actin ring staining; bone resorption pit assay International Journal of Biological Sciences Medium 32226307
2022 GZMA secreted by cytotoxic T cells interacts with F2R (PAR1) expressed on hepatocellular carcinoma tumor cells via the LDPRSFLL motif at the N-terminus of F2R, activating the JAK2/STAT1 signaling pathway to promote tumor cell apoptosis and T cell-mediated killing. This interaction was demonstrated both in vivo and in vitro. Single-cell sequencing; co-culture in vitro; in vivo mouse tumor model; GZMA-F2R interaction studies; JAK2/STAT1 pathway activation assays; N-terminus LDPRSFLL motif analysis; apoptosis assays Cell Death & Disease Medium 35256589
2022 Platelet-derived MMP-2 triggers endothelial PAR1 to initiate atherosclerosis via p38MAPK signaling and expression of adhesion molecules. Double knockout mice lacking LDLR and blood cell MMP-2 developed significantly less femoral intima thickening and aortic atherosclerotic lesions. Transfusion of activated WT but not MMP-2-/- platelets enhanced atherosclerotic lesions in LDLR-/- mice. Double knockout mice (LDLR-/-/blood cell MMP-2-/-); platelet transfusion experiments; photochemical arterial injury model; atherogenic diet; en face aortic lesion quantification; in vitro co-incubation studies (platelets, monocytes/macrophages, endothelial cells); p38MAPK signaling assays European Heart Journal High 34529782
2023 Senescent hepatocytes upregulate the THBD-PAR1 signaling axis to remain viable ('undead'), and this promotes fibrogenic factor expression (including hedgehog ligands) that drives maladaptive liver repair in NASH. Inducing hepatocyte senescence upregulates THBD-PAR1 in hepatocytes. Inhibiting PAR1 with vorapaxar reduces the burden of senescent cells, limits HSC reprogramming, and improves NASH and fibrosis despite ongoing lipotoxic stress. Viral p16 overexpression to induce hepatocyte senescence; conditioned medium HSC reprogramming; vorapaxar treatment in NASH mouse models (genetic obesity and Western diet/CCl4); NAFLD liver biopsy analysis; transcriptomics of senescent hepatocytes; hedgehog ligand expression Hepatology Medium 37036206
2023 Parmodulins are small-molecule allosteric modulators that bind PAR1 intracellularly, inhibiting coagulation and platelet activation while maintaining cytoprotective endothelial signaling typically provoked by APC via PAR1. Structural analysis reveals parmodulins interact with the intracellular surface of PAR1, distinct from orthosteric antagonist binding. Review consolidating primary mechanistic data; structural interaction modeling comparing parmodulin binding to other intracellular allosteric GPCR modulators; preclinical pharmacological studies Blood Medium 36952648

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 2832 1672265
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1999 Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature genetics 1381 10391209
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2005 Protease-activated receptors in hemostasis, thrombosis and vascular biology. Journal of thrombosis and haemostasis : JTH 791 16102047
2011 Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 707 21673343
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2002 Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science (New York, N.Y.) 704 12052963
1999 Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. The Journal of clinical investigation 683 10079109
2005 PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 664 15707890
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2004 Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 411 15626732
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1994 G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets. Proceedings of the National Academy of Sciences of the United States of America 392 8290554
1998 Thrombin receptor overexpression in malignant and physiological invasion processes. Nature medicine 383 9701242
2012 High-resolution crystal structure of human protease-activated receptor 1. Nature 370 23222541
1991 The G protein coupled to the thromboxane A2 receptor in human platelets is a member of the novel Gq family. The Journal of biological chemistry 342 1851174
2011 New gene functions in megakaryopoiesis and platelet formation. Nature 332 22139419
2003 Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. Oncogene 331 12761501
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
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
1992 Characterization of a functional thrombin receptor. Issues and opportunities. The Journal of clinical investigation 277 1310691
2002 House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. Journal of immunology (Baltimore, Md. : 1950) 276 12370395
2008 Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature 236 18305483
2006 Protease-activated receptors in cardiovascular diseases. Circulation 236 16952995
2004 Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity. Current biology : CB 228 15084291
2012 Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 215 22407318
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2009 Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell 202 19379698
2004 Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis. Molecular cancer research : MCR 197 15280447
2007 The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood 195 17823308
1994 Intracellular targeting and trafficking of thrombin receptors. A novel mechanism for resensitization of a G protein-coupled receptor. The Journal of biological chemistry 190 7961693
2007 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. Nature immunology 189 17965715
2004 MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons. The Journal of cell biology 188 15466480
1999 Plasmin desensitization of the PAR1 thrombin receptor: kinetics, sites of truncation, and implications for thrombolytic therapy. Biochemistry 186 10194379
2003 Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Molecular pharmacology 180 14573770
2002 Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways. American journal of physiology. Cell physiology 172 12372796
2004 Mammalian PAR-1 determines epithelial lumen polarity by organizing the microtubule cytoskeleton. The Journal of cell biology 161 14981097
2012 Matrix metalloproteases and PAR1 activation. Blood 147 23086754
2003 The role of PAR-1 in regulating the polarised microtubule cytoskeleton in the Drosophila follicular epithelium. Development (Cambridge, England) 138 12874119
2001 Drosophila par-1 is required for oocyte differentiation and microtubule organization. Current biology : CB 122 11231123
2002 Drosophila 14-3-3/PAR-5 is an essential mediator of PAR-1 function in axis formation. Developmental cell 121 12431373
2012 Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1. PLoS genetics 112 22952452
2005 PAR-1 activation on human late endothelial progenitor cells enhances angiogenesis in vitro with upregulation of the SDF-1/CXCR4 system. Arteriosclerosis, thrombosis, and vascular biology 107 16141404
2001 The thrombin receptor, PAR-1, causes transformation by activation of Rho-mediated signaling pathways. Oncogene 104 11360179
2003 Oncogenic transformation induces tumor angiogenesis: a role for PAR1 activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 100 12554695
2005 Distinct PAR-1 proteins function in different branches of Wnt signaling during vertebrate development. Developmental cell 94 15935773
2011 Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects. European journal of clinical pharmacology 83 21935705
2002 A functional thrombin receptor (PAR1) is expressed on bone-derived prostate cancer cell lines. Urology 83 12429291
2017 Targeting PAR1: Now What? Trends in pharmacological sciences 73 28558960
2006 Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury. Blood 72 16990608
2017 Protease-activated receptor-1 (PAR-1): a promising molecular target for cancer. Oncotarget 70 29291033
2019 Thrombin Signaling Promotes Pancreatic Adenocarcinoma through PAR-1-Dependent Immune Evasion. Cancer research 68 31048498
2003 Activated protein C signals through the thrombin receptor PAR1 in endothelial cells. Journal of endotoxin research 67 14577849
2012 Par-1 controls myosin-II activity through myosin phosphatase to regulate border cell migration. Current biology : CB 66 22326025
2014 Recombination in the human Pseudoautosomal region PAR1. PLoS genetics 65 25033397
1991 Identification and characterization of a Saccharomyces cerevisiae gene (PAR1) conferring resistance to iron chelators. European journal of biochemistry 65 1889413
2009 PP2A antagonizes phosphorylation of Bazooka by PAR-1 to control apical-basal polarity in dividing embryonic neuroblasts. Developmental cell 62 19531360
2007 The Par-1/MARK family of protein kinases: from polarity to metabolism. Cell cycle (Georgetown, Tex.) 58 17721078
2013 Par-1 regulates tissue growth by influencing hippo phosphorylation status and hippo-salvador association. PLoS biology 56 23940457
2007 Interaction of thrombin with PAR1 and PAR4 at the thrombin cleavage site. Biochemistry 56 17595115
2013 Both PHYTOCHROME RAPIDLY REGULATED1 (PAR1) and PAR2 promote seedling photomorphogenesis in multiple light signaling pathways. Plant physiology 55 24335334
2011 Drosophila tao controls mushroom body development and ethanol-stimulated behavior through par-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 54 21248138
2013 Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity. Journal of neurochemistry 53 23647384
2013 Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy. Glia 53 23832758
2006 The angiopoietin pathway is modulated by PAR-1 activation on human endothelial progenitor cells. Journal of thrombosis and haemostasis : JTH 52 16803467
2018 Factor VIIa induces anti-inflammatory signaling via EPCR and PAR1. Blood 50 29669778
2004 Par-1 promotes a hepatic mode of apical protein trafficking in MDCK cells. Proceedings of the National Academy of Sciences of the United States of America 50 15365179
2022 Matrix metalloproteinase-2 on activated platelets triggers endothelial PAR-1 initiating atherosclerosis. European heart journal 48 34529782
2005 GSK-3beta directly phosphorylates and activates MARK2/PAR-1. The Journal of biological chemistry 48 16257959
2002 RhoA- and RhoD-dependent regulatory switch of Galpha subunit signaling by PAR-1 receptors in cellular invasion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 48 11919159
2008 Mitochondrial reactive oxygen species: a common pathway for PAR1- and PAR2-mediated tissue factor induction in human endothelial cells. Journal of thrombosis and haemostasis : JTH 46 18983479
2004 PAR-1 deficiency protects against neuronal damage and neurologic deficits after unilateral cerebral hypoxia/ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 46 15356417
1999 Activation of the protease-activated thrombin receptor (PAR)-1 induces motoneuron degeneration in the developing avian embryo. Journal of neuropathology and experimental neurology 46 10331438
2002 Structure-based design and synthesis of a thyroid hormone receptor (TR) antagonist. Endocrinology 45 11796506
2020 BMX Represses Thrombin-PAR1-Mediated Endothelial Permeability and Vascular Leakage During Early Sepsis. Circulation research 44 31910739
2017 Thyroid hormone regulates hematopoiesis via the TR-KLF9 axis. Blood 42 28972010
2015 Dysregulated protease activated receptor 1 (PAR1) promotes metastatic phenotype in breast cancer through HMGA2. Oncogene 41 26165842
2011 The emerging role of the thrombin receptor (PAR-1) in melanoma metastasis--a possible therapeutic target. Oncotarget 41 21378407
2006 Thrombin and PAR-1 stimulate differentiation of bone marrow-derived endothelial progenitor cells. Journal of thrombosis and haemostasis : JTH 41 16460448
2016 Regulation of Cell Polarity by PAR-1/MARK Kinase. Current topics in developmental biology 40 28236972
2020 Thrombin activation of PAR-1 contributes to microvascular stasis in mouse models of sickle cell disease. Blood 38 31977004
2015 PAR1 participates in the ability of multidrug resistance and tumorigenesis by controlling Hippo-YAP pathway. Oncotarget 38 26431277
2008 Emerging roles of PAR-1 and PAFR in melanoma metastasis. Cancer microenvironment : official journal of the International Cancer Microenvironment Society 38 19308689
2010 Engineering thrombin for selective specificity toward protein C and PAR1. The Journal of biological chemistry 37 20404340
2004 Regulated shedding of PAR1 N-terminal exodomain from endothelial cells. The Journal of biological chemistry 37 14982936
2017 PAR1 activation induces rapid changes in glutamate uptake and astrocyte morphology. Scientific reports 36 28256580
2002 HcSTK, a Caenorhabditis elegans PAR-1 homologue from the parasitic nematode, Haemonchus contortus. International journal for parasitology 35 12062493
2018 Inhibition of Protease-Activated Receptor (PAR1) Reduces Activation of the Endothelium, Coagulation, Fibrinolysis and Inflammation during Human Endotoxemia. Thrombosis and haemostasis 34 29864779
2020 Evolution of the T-Cell Receptor (TR) Loci in the Adaptive Immune Response: The Tale of the TRG Locus in Mammals. Genes 33 32517024
2009 Intracellular polarity protein PAR-1 regulates extracellular laminin assembly by regulating the dystroglycan complex. Genes to cells : devoted to molecular & cellular mechanisms 33 19549170
2022 Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma. Cell death & disease 32 35256589
2002 Hep Par 1 in gastric and bowel carcinomas: an immunohistochemical study. Pathology 32 12408340
2012 Residual platelet activation through protease-activated receptors (PAR)-1 and -4 in patients on P2Y12 inhibitors. International journal of cardiology 30 23041015
2010 Protease-activated receptor-1 (PAR1) acts via a novel Galpha13-dishevelled axis to stabilize beta-catenin levels. The Journal of biological chemistry 30 20223821
2020 The PAR-1 antagonist vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis. Clinical science (London, England : 1979) 29 33078834
2019 HIV-1 Tat promotes astrocytic release of CCL2 through MMP/PAR-1 signaling. Glia 29 31124192
2017 Doxycycline directly targets PAR1 to suppress tumor progression. Oncotarget 29 28187433
2020 Sarsasapogenin alleviates diabetic nephropathy through suppression of chronic inflammation by down-regulating PAR-1: In vivo and in vitro study. Phytomedicine : international journal of phytotherapy and phytopharmacology 28 32882582
2014 Canonical and noncanonical roles of Par-1/MARK kinases in cell migration. International review of cell and molecular biology 28 25262242
2023 Targeting biased signaling by PAR1: function and molecular mechanism of parmodulins. Blood 27 36952648
2015 PH motifs in PAR1&2 endow breast cancer growth. Nature communications 26 26600192
2010 PAR1- and PAR2-induced innate immune markers are negatively regulated by PI3K/Akt signaling pathway in oral keratinocytes. BMC immunology 26 21029417
1998 Thrombin receptor (PAR-1) antagonists. Heterocycle-based peptidomimetics of the SFLLR agonist motif. Bioorganic & medicinal chemistry letters 26 9873407
2023 Targeting senescent hepatocytes using the thrombomodulin-PAR1 inhibitor vorapaxar ameliorates NAFLD progression. Hepatology (Baltimore, Md.) 25 37036206
2017 NF-κB Links TLR2 and PAR1 to Soluble Immunomodulator Factor Secretion in Human Platelets. Frontiers in immunology 25 28220122
2011 Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets. The Biochemical journal 25 21391917
2009 Variants in the coagulation factor 2 receptor (F2R) gene influence the risk of myocardial infarction in men through an interaction with interleukin 6 serum levels. Thrombosis and haemostasis 25 19404549
2005 The Drosophila PAR-1 spacer domain is required for lateral membrane association and for polarization of follicular epithelial cells. Current biology : CB 25 15694310
2013 Protease-activated receptors (PAR)-1 and -3 drive epithelial-mesenchymal transition of alveolar epithelial cells - potential role in lung fibrosis. Thrombosis and haemostasis 24 23739922
2013 Thrombin induces epithelial-mesenchymal transition via PAR-1, PKC, and ERK1/2 pathways in A549 cells. Experimental lung research 24 23919450
2011 Neural crest specification by noncanonical Wnt signaling and PAR-1. Development (Cambridge, England) 24 22110058
2008 PAR1 and PAR2 integrate shade and hormone transcriptional networks. Plant signaling & behavior 24 19704482
2020 Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes. Biochemical pharmacology 23 32059841
2011 PAR1 plays a role in epithelial malignancies: transcriptional regulation and novel signaling pathway. IUBMB life 23 21557443
2006 Thrombin receptor (PAR-1) antagonists as novel antithrombotic agents. Expert opinion on therapeutic patents 23 20144050
2002 Thrombin receptor antagonists; recent advances in PAR-1 antagonist development. Current medicinal chemistry 23 12052165
2020 F2r negatively regulates osteoclastogenesis through inhibiting the Akt and NFκB signaling pathways. International journal of biological sciences 22 32226307
2018 Protease-activated receptor-1 (PAR1) promotes epithelial-endothelial transition through Twist1 in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 22 30081924
2018 Establishment of the PAR-1 cortical gradient by the aPKC-PRBH circuit. Nature chemical biology 22 30177850
2019 Spatial regulation of the polarity kinase PAR-1 by parallel inhibitory mechanisms. Development (Cambridge, England) 21 30814118
2011 PAR-1/MARK: a kinase essential for maintaining the dynamic state of microtubules. Cell structure and function 21 22139392
2006 Thrombin induces rapid PAR1-mediated non-classical FGF1 release. Biochemical and biophysical research communications 21 17027650
2011 MARK2/Par-1 guides the directionality of neuroblasts migrating to the olfactory bulb. Molecular and cellular neurosciences 20 22061967
2007 Retrospective analysis of coagulation factor II receptor (F2R) sequence variation and coronary heart disease in hypertensive patients. Arteriosclerosis, thrombosis, and vascular biology 20 17347481
2013 Streptococcal SpeB cleaved PAR-1 suppresses ERK phosphorylation and blunts thrombin-induced platelet aggregation. PloS one 19 24278414
2010 X-ray imaging of differential vascular density in MMP-9-/-, PAR-1-/+, hyperhomocysteinemic (CBS-/+) and diabetic (Ins2-/+) mice. Archives of physiology and biochemistry 19 20839901
2009 Zyxin is involved in thrombin signaling via interaction with PAR-1 receptor. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 19690217
2009 MAP kinase signaling antagonizes PAR-1 function during polarization of the early Caenorhabditis elegans embryo. Genetics 19 19720857