Affinage

PROCR

Endothelial protein C receptor · UniProt Q9UNN8

Length
238 aa
Mass
26.7 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PROCR (endothelial protein C receptor, EPCR) is a type I transmembrane glycoprotein with a CD1/MHC class I-like fold that serves dual roles as a co-receptor amplifying anticoagulant and cytoprotective signaling on endothelial cells and as a functional marker and signaling receptor on multipotent stem/progenitor cells across diverse tissues. On the endothelium, EPCR binds protein C, APC, FVIIa, and FXa via their Gla domains, with a phosphatidylcholine-occupied hydrophobic groove essential for ligand recognition; EPCR amplifies thrombomodulin–thrombin-mediated protein C activation and, when occupied by protein C/APC, redirects PAR1 signaling from proinflammatory RhoA/NF-κB to cytoprotective Rac1/β-arrestin-2 pathways through GRK5 recruitment, thereby maintaining vascular barrier integrity, suppressing inflammation, and promoting postischemic neovascularization (PMID:7890676, PMID:19277413, PMID:27561318, PMID:35700057). EPCR ectodomain shedding by ADAM17 or ADAM10 generates soluble EPCR that inhibits protein C activation, and a natural variant (Ser219Gly) enhances this shedding, producing a dual phenotype of reduced vascular inflammation but increased venous thrombosis risk (PMID:29630665, PMID:35264566). Beyond hemostasis, Procr marks stem/progenitor cells in bone marrow, mammary gland, pancreatic islets, ovary, fascia, and articular cartilage, where it functions as a signaling receptor that—upon protein C binding—recruits an HSP90/Src/IGF1R complex to regulate self-renewal, differentiation, and tissue repair (PMID:32200801, PMID:35320720, PMID:37968392, PMID:40695281).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1995 High

    Establishing that EPCR is a conserved APC-binding receptor on endothelium answered the question of whether a dedicated receptor for protein C existed on cell surfaces.

    Evidence cDNA cloning and transfection of murine/bovine EPCR into 293T cells with APC binding assay

    PMID:7890676

    Open questions at the time
    • No structural basis for ligand recognition
    • No in vivo functional data
  2. 1999 High

    Genomic analysis revealing CD1/MHC-like α1/α2 domain architecture and functional blocking antibody studies established EPCR as a structurally unique immune-superfamily receptor essential for protein C activation across vascular beds.

    Evidence Genomic sequencing with structural homology prediction; anti-EPCR mAb blocking of PC activation on arterial, venous, and microvascular endothelial cells

    PMID:10364477 PMID:10397730

    Open questions at the time
    • No crystal structure yet available
    • Lipid content of the binding groove unknown
  3. 2005 High

    Quantitative binding kinetics and mutagenesis dissociated EPCR–Gla domain binding from phospholipid-dependent APC anticoagulant activity, while conditional knockouts demonstrated that extraembryonic EPCR prevents lethal placental thrombosis, establishing both the molecular specificity and in vivo necessity of the receptor.

    Evidence SPR kinetics with Gla domain mutants; conditional KO in trophoblasts with tissue factor epistasis rescue

    PMID:15634335 PMID:15956290

    Open questions at the time
    • Mechanism of EPCR-mediated signaling downstream of ligand binding unresolved
    • Role of bound lipid unknown
  4. 2009 High

    Discovery that EPCR occupancy by protein C switches PAR1 signaling from pro-inflammatory (RhoA/NF-κB) to anti-inflammatory (Rac1) and that this pathway prevents vascular leakage in vivo answered how EPCR transduces cytoprotective signals beyond anticoagulation.

    Evidence Inactive PC-S195A occupancy with Rho GTPase/NF-κB assays; pharmacological/genetic blockade in LPS vascular permeability model with S1P receptor epistasis

    PMID:19141861 PMID:19277413

    Open questions at the time
    • Molecular mediator linking EPCR occupancy to PAR1 signaling bias not identified
    • Whether EPCR-PAR1 signaling switch occurs in non-endothelial cells unknown
  5. 2011 High

    Identification of phosphatidylcholine as the lipid occupying EPCR's hydrophobic groove, and demonstration that lipid exchange by sPLA2 impairs PC binding, revealed that EPCR function is regulated by its bound phospholipid species.

    Evidence Mass spectrometry identification; lipid exchange assay with sPLA2-V; sEPCR binding and APC functional assays

    PMID:22167755

    Open questions at the time
    • Whether lipid exchange occurs in vivo during inflammation is untested
    • Structural basis of lipid-dependent binding modulation not resolved
  6. 2014 High

    Crystal structures of P. falciparum PfEMP1 CIDR domains bound to EPCR showed that the parasite hijacks EPCR by mimicking the protein C binding interface, explaining how EPCR serves as a virulence receptor in severe malaria.

    Evidence X-ray crystallography of CIDRα1:EPCR complexes with sequence analysis of 885 variants and blocking antibody validation

    PMID:25482433

    Open questions at the time
    • Therapeutic strategies to selectively block parasite binding without disrupting PC activation not yet developed
    • In vivo confirmation in human malaria lacking
  7. 2015 High

    Multiple studies established EPCR's role beyond coagulation: in myeloid cells, EPCR mediates TF–FVIIa–FXa/PAR2-dependent interferon signaling; in bone marrow, aPC-EPCR-PAR1 retains LT-HSCs via NO/Cdc42/VLA4 regulation while thrombin-PAR1 triggers EPCR shedding and HSC mobilization; and EPCR-R84A knock-in mice lacking PC/APC binding develop bone marrow failure.

    Evidence EPCR KO mice with LPS/IRF pathway analysis; mouse BM transplantation with NO/Cdc42/VLA4 assays; R84A knock-in with BM transplant epistasis

    PMID:25733582 PMID:26045607 PMID:26457757

    Open questions at the time
    • Whether EPCR signals through PAR1-independent mechanisms in HSCs not excluded
    • Structural basis for differential PAR1 bias by APC vs thrombin on HSCs unclear
  8. 2016 High

    Identification of β-arrestin-2 and GRK5 as the molecular mediators of EPCR-biased PAR1 signaling resolved the mechanism by which EPCR occupancy redirects thrombin signaling toward cytoprotection, while PROCR was shown to negatively regulate Th17 differentiation via APC.

    Evidence siRNA of β-arrestin-2/GRK5 with PAR1 construct transfection and Dvl-2 assays; T cell-specific PROCR conditional KO in EAE model

    PMID:27561318 PMID:27670590

    Open questions at the time
    • How GRK5 is recruited to EPCR-occupied PAR1 at structural level unknown
    • Whether PROCR on Th17 cells signals through PAR1 or an independent pathway not determined
  9. 2017 High

    FVIIa was established as an anti-inflammatory EPCR ligand that signals through PAR1/β-arrestin-1 and simultaneously displaces protein C from EPCR to reduce APC generation, providing a mechanistic basis for rFVIIa hemostatic efficacy in hemophilia.

    Evidence EPCR KO/overexpressing mice, active-site inhibited FVIIa, siRNA of β-arrestin-1, hemophilia bleeding model

    PMID:28932824 PMID:29669778

    Open questions at the time
    • Relative contributions of PC displacement vs direct FVIIa-EPCR signaling to hemostasis not fully quantified
  10. 2018 High

    ADAM10 was identified as the sheddase responsible for pathological EPCR shedding during meningococcal infection, distinct from the constitutive ADAM17-mediated shedding, establishing context-dependent regulation of EPCR surface expression.

    Evidence siRNA and CRISPR/Cas9 of ADAM10 in meningococcal adhesion assay with EPCR shedding and PC activation readouts

    PMID:29630665

    Open questions at the time
    • Whether ADAM10 shedding occurs in other infectious contexts not tested
    • Signaling pathway from bacterial adhesion to ADAM10 activation not mapped
  11. 2020 High

    Procr+ cells were identified as multipotent endocrine progenitors in adult pancreatic islets, capable of clonal expansion into all four endocrine lineages and reversing diabetes upon transplantation, extending PROCR's stem cell marker function to a therapeutically relevant tissue.

    Evidence Genetic lineage tracing, scRNA-seq, organoid formation, glucose-stimulated insulin secretion, transplantation into diabetic mice

    PMID:32200801

    Open questions at the time
    • Whether protein C–EPCR signaling drives islet progenitor self-renewal (as in mammary) not tested
    • Human islet Procr+ progenitor equivalence not established
  12. 2022 High

    PROCR was shown to function as a bona fide signaling receptor in mammary stem cells, recruiting an HSP90/Src/IGF1R complex via its cytoplasmic tail upon protein C stimulation, with conditional KO phenocopied by IGF1R deletion, establishing a stem cell signaling mechanism distinct from PAR1-mediated endothelial signaling.

    Evidence Conditional KO, co-IP proteomics, signaling assays, IGF1R genetic epistasis

    PMID:35320720

    Open questions at the time
    • Whether HSP90/Src/IGF1R complex operates in non-mammary Procr+ progenitors untested
    • Structure of PROCR cytoplasmic tail interaction with HSP90 unknown
  13. 2023 High

    Procr+ fascia progenitors were shown to generate multiple fibroblast subtypes in a spatiotemporally controlled sequence during wound healing, with retinoic acid and hypoxia signaling controlling differentiation transitions.

    Evidence Genetic lineage tracing, cell ablation, gene deletion, scRNA-seq in skin wound models

    PMID:37968392

    Open questions at the time
    • Whether PROCR-protein C signaling directly regulates fascia progenitor fate decisions not tested
    • Relationship between fascia Procr+ cells and heterotopic ossification-driving Procr+ fibroblasts unclear
  14. 2025 High

    Procr+ superficial zone cells in articular cartilage were established as mechanosensitive chondroprogenitors requiring Piezo1 for activation, linking mechanical loading to Procr+ stem cell-driven cartilage homeostasis and osteoarthritis protection.

    Evidence Genetic lineage tracing, Procr+ ablation, Piezo1 KO/pharmacological modulation, forced running/unloading, transplantation

    PMID:40695281

    Open questions at the time
    • Whether Piezo1 acts cell-autonomously in Procr+ cells or via paracrine signals not fully resolved
    • Molecular link between Piezo1 activation and Procr expression not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: whether the HSP90/Src/IGF1R signaling axis discovered in mammary stem cells operates in other Procr+ progenitor populations; how EPCR's bound phospholipid species is regulated in vivo during inflammation; and what structural features of EPCR's cytoplasmic tail mediate differential signaling in stem cells versus endothelial cells.
  • No structural model of full-length EPCR including transmembrane and cytoplasmic domains
  • HSP90/Src/IGF1R pathway not tested outside mammary context
  • In vivo lipid exchange and its functional consequences not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 3
Pathway
R-HSA-109582 Hemostasis 6 R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 5 R-HSA-168256 Immune System 4
Partners
ARRB2F2RF7GRK5HSP90AA1IGF1RPROCTHBD
Complex memberships
EPCR-PAR1 signaling complexHSP90/Src/IGF1R stem cell complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Murine and bovine EPCR are structural and functional orthologs of human EPCR; both murine and bovine EPCR bind human activated protein C when cDNA clones are transfected into 293T cells, confirming conserved ligand-binding function across species. EPCR mRNA is restricted to endothelium among cell lines tested. cDNA cloning, transfection into 293T cells, binding assay The Journal of biological chemistry High 7890676
1999 The human EPCR gene spans ~6 kbp with four exons; exons II and III encode the extracellular domain and are structurally homologous to the alpha1 and alpha2 domains of the CD1/MHC class I superfamily, predicting that EPCR folds with a beta-sheet platform supporting two alpha-helices forming a binding pocket for protein C/APC. Genomic sequencing, exon/intron organization analysis, secondary structure prediction compared to known crystal structures of HLA-A2 and CD1 Blood Medium 10397730
1999 EPCR functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries; function-blocking anti-EPCR monoclonal antibodies strongly inhibited protein C activation mediated by primary cultured arterial and microvascular endothelial cells. Monoclonal antibody blocking assay, protein C activation assay, immunohistochemistry Biochemical and biophysical research communications High 10364477
1999 The CCD41 centrosome-associated protein is encoded by the same single mRNA as EPCR; deletion of the signal sequence from the EPCR/CCD41 construct targets the resulting fusion protein exclusively to a perinuclear centrosomal structure, whereas the full-length protein is incorporated into cell membranes, demonstrating that post-translational removal of the signal sequence determines centrosomal localization. EGFP fusion protein transfection, fluorescence microscopy, deletion mutagenesis FEBS letters Medium 10518938
2001 A 23 bp insertion in the EPCR gene produces a truncated protein that is not localized on the cell surface, cannot be secreted into culture medium, and does not bind activated protein C, demonstrating that the transmembrane and extracellular domains are required for surface expression and ligand binding. Expression studies, cell surface localization assay, APC binding assay Thrombosis and haemostasis Medium 11686350
2001 EPCR is expressed in cancer cell lines and contributes to protein C activation in cells co-expressing both EPCR and thrombomodulin; anti-EPCR monoclonal antibodies specifically inhibited this activation, demonstrating anticoagulant function of EPCR on cancer cells. Anti-EPCR monoclonal antibody blocking, protein C activation assay on cancer cell lines Thrombosis and haemostasis Medium 11246560
2002 EPCR is detected in trophoblast giant cells at the feto-maternal boundary from embryonic day E7.5 and in embryonic aortic endothelial cells only from E13.5, with distribution mimicking adults only from postnatal day 7, establishing a spatiotemporal pattern of EPCR expression during mouse embryogenesis. Immunohistological analysis across developmental time points Thrombosis and haemostasis Medium 12195698
2004 EPCR, thrombomodulin, and activated protein C (APC) form an integrated system: EPCR amplifies thrombin-thrombomodulin-mediated protein C activation; APC exerts anticoagulant, anti-inflammatory, antifibrinolytic, and anti-apoptotic effects; and this system regulates coagulation and inflammation in vascular endothelial cells. Review integrating in vitro assays, mouse models, and clinical studies from multiple labs Arteriosclerosis, thrombosis, and vascular biology High 15178554
2005 Extraembryonic EPCR expression (on placental giant trophoblast cells) is essential for embryonic viability; conditional knockout mice lacking EPCR only in trophoblasts are lethal, while embryos with EPCR restricted to trophoblasts are viable; the lethality is rescued in low tissue factor activity backgrounds, indicating EPCR prevents lethal placental thrombosis. Conditional knockout mouse, genetic rescue experiments, coagulation assays Blood High 15956290
2005 Protein C binds to EPCR via its Gla domain; SPR kinetics show an association rate of 5.23×10^5 M^-1s^-1, dissociation rate of 7.61×10^-2 s^-1, and KD of 147 nM; selective mutagenesis of the Gla domain (R9H, QGNSEDY variants) differentially affects sEPCR binding versus phospholipid-dependent FVa inactivation, demonstrating that EPCR binding and phospholipid binding by protein C can be functionally dissociated. Surface plasmon resonance, recombinant Gla domain mutagenesis, endothelial cell activation assay, FVa inactivation assay The FEBS journal High 15634335
2005 The EPCR Ser219Gly (transmembrane domain) variant increases basal shedding of EPCR from the cell surface in vitro, resulting in elevated plasma sEPCR levels; soluble EPCR inhibits protein C activation and APC anticoagulant activity. In vitro EPCR-transfected cell shedding assay, ELISA for sEPCR, coagulation assays Atherosclerosis Medium 15921688
2006 APC promotes breast cancer cell migration and invasion through interactions with both EPCR and PAR-1; blocking antibodies to EPCR or PAR-1 attenuated APC-induced chemotaxis, identifying EPCR as a required component for APC-induced cell motility signaling in cancer cells. Chemotaxis/invasion assay, blocking antibody experiments, inactive APC controls Experimental cell research Medium 17254565
2007 The A3 haplotype of EPCR generates an alternative truncated mRNA (lacking the transmembrane domain) that is 16-fold more abundant in A3 HUVECs; the encoded isoform protein binds protein C with similar affinity to soluble EPCR and inhibits APC anticoagulant activity, representing a second mechanism by which A3 haplotype elevates plasma sEPCR levels. mRNA expression analysis, recombinant protein production, protein C binding assay, anticoagulant activity assay Blood Medium 18073349
2007 Non-hematopoietic (endothelial) EPCR is the primary regulator of protein C activation and inflammatory response during endotoxemia; bone marrow transplantation chimera experiments showed that loss of EPCR on non-hematopoietic cells (not hematopoietic cells) reduced protein C activation and exaggerated thrombin and cytokine responses to LPS. Bone marrow transplantation chimera, LPS challenge, protein C activation assay, cytokine measurement Journal of thrombosis and haemostasis High 17445091
2006 Membrane EPCR (but not physiologically elevated soluble EPCR) regulates protein C activation; EPCR heterozygosity reduces protein C activation by ~30% and increases coagulant response to Factor Xa; only supraphysiologic sEPCR levels influence protein C activation. Thrombin infusion experiments in Procr+/- mice, factor Xa/phospholipid challenge, protein C activation measurement Blood High 17023579
2009 When EPCR is occupied by protein C (using catalytically inactive protein C-S195A), thrombin-PAR1 signaling switches from pro-inflammatory to anti-inflammatory, activating Rac1 and inhibiting RhoA and NF-κB pathways, and reducing adhesion molecule expression and neutrophil binding in TNF-α-stimulated endothelial cells. EPCR occupancy with inactive protein C mutant, PAR1 agonist stimulation, Rho GTPase assays, NF-κB pathway analysis, adhesion molecule expression Thrombosis and haemostasis High 19277413
2009 Endogenous aPC-EPCR-PAR1 signaling prevents inflammation-induced vascular leakage; pharmacological or genetic blockade of the aPC pathway increases vascular hyperpermeability and sensitizes mice to LPS-induced lethality; EPCR-PAR1 signaling modulates the vascular S1P1/S1P3 balance, with S1P3 deficiency compensating for loss of aPC pathway. Pharmacological antibody blockade, genetic mouse models, LPS challenge, vascular permeability assay, genetic S1P receptor manipulation Blood High 19141861
2010 EPCR on endothelial cells downregulates FVIIa generation by sequestering FVII away from phosphatidylserine-rich regions; EPCR and phospholipid binding to FVII are mutually exclusive (SPR); blocking anti-EPCR mAb doubled catalytic efficiency of FXa-dependent FVIIa generation, identifying a novel anticoagulant role for EPCR. Blocking anti-EPCR monoclonal antibody, kinetic analysis, surface plasmon resonance, immunofluorescence co-localization British journal of haematology High 20085578
2010 Blocking EPCR with a function-blocking anti-EPCR monoclonal antibody accelerates thrombus formation in vivo (ferric chloride carotid artery injury model), shortening time to occlusion and increasing thrombus persistence, demonstrating a direct causal relationship between EPCR blockade and thrombosis. In vivo thrombosis model (ferric chloride), blocking vs. non-blocking anti-EPCR mAbs, surface plasmon resonance for antibody characterization Thrombosis and haemostasis High 20352165
2010 HK-2 proximal tubule epithelial cells express EPCR; occupancy of EPCR by protein C switches thrombin-PAR1 signaling from pro-inflammatory to anti-inflammatory, inhibiting TNF-α-mediated IL-6 and IL-8 synthesis and TGF-β-mediated extracellular matrix protein expression. EPCR expression detection, protein C-S195A occupancy, cytokine and ECM protein measurement, PAR-1 signaling assays Journal of cellular physiology Medium 20506163
2011 Phosphatidylcholine (PCh) is the major phospholipid bound in the hydrophobic groove of soluble EPCR; PCh can be exchanged for lysophosphatidylcholine (lysoPCh) or PAF by secretory group V phospholipase A2 (sPLA2-V), and this exchange impairs protein C binding to EPCR and reduces APC-mediated protein C activation and anti-apoptotic effects on endothelial cells. Phospholipid identification by mass spectrometry/biochemistry, lipid exchange assay, sEPCR protein C binding assay, sPLA2-V inhibition, APC anti-apoptotic assay Blood High 22167755
2011 APC-EPCR signaling in vascular endothelial cells activates noncanonical NF-κB and ERK1/2 pathways; both PAR1 and EPCR are required for ERK activation and VCAM-1 induction by APC; this preemptive activation attenuates subsequent TNF-induced inflammatory signaling. siRNA silencing of EPCR and PAR1, NF-κB pathway analysis, ERK/Akt phosphorylation assays, adhesion molecule expression American journal of physiology. Cell physiology Medium 21228323
2014 Crystal structures of CIDRα1 domains of Plasmodium falciparum PfEMP1 in complex with EPCR show that CIDRα1 domains mimic features of the natural EPCR ligand (protein C) and compete for the same binding surface; the EPCR-binding surfaces of CIDRα1 are conserved in shape despite dramatic sequence diversity. Crystal structure determination of CIDRα1:EPCR complexes, sequence analysis of 885 CIDRα1 variants, antibody blocking assays Cell host & microbe High 25482433
2015 EPCR-dependent PAR2 activation by the ternary TF-VIIa-Xa initiation complex is required for normal LPS-induced interferon-regulated gene expression; EPCR-deficient mice and cells fail to induce IRF8 and Pellino-1 and downstream interferon-regulated genes, establishing EPCR as a required receptor for TF complex-mediated PAR2 signaling in myeloid cells. EPCR knockout mice, LPS challenge, bone marrow-derived myeloid cells, siRNA knockdown, gene expression analysis Blood High 25733582
2015 PAR1 mediates two distinct signaling cascades regulating EPCR+ HSC retention and mobilization: (1) aPC-EPCR-PAR1 signaling retains LT-HSCs in bone marrow by limiting NO production, reducing Cdc42 activity, and enhancing VLA4 integrin affinity/adhesion; (2) thrombin-PAR1 signaling induces NO production, TACE-mediated EPCR shedding, and CXCL12-CXCR4-driven HSC mobilization. Mouse genetic models, bone marrow transplantation, NO measurement, EPCR shedding assay, VLA4 adhesion assay, HSC mobilization assay, pharmacological inhibition Nature medicine High 26457757
2015 CIDRα1.1 domain of PfEMP1 binding to EPCR blocks APC binding, severely impairs PC activation on endothelial cells, and blocks APC-mediated PAR1 activation and barrier protective effects; a soluble EPCR decoy variant (E86A-sEPCR) captures PfEMP1, restoring normal PC activation and barrier protection while reducing cytoadhesion. Recombinant protein competition assay, endothelial PC activation assay, PAR1 cleavage assay, barrier permeability assay, cytoadhesion assay Thrombosis and haemostasis High 26155776
2015 EPCR carrying the R84A point mutation (EPCR^R84A/R84A knock-in mice) lacks the ability to bind PC/APC; these mice develop normally but show enhanced thrombin generation, reduced APC production, increased inflammatory responses to LPS, and splenomegaly due to bone marrow failure, with BM transplant experiments indicating roles for EPCR on both HSCs and BM stromal cells in hematopoiesis. Point mutation knock-in mouse, factor Xa challenge, LPS challenge, BM transplantation Blood High 26045607
2016 EPCR occupancy by protein C induces β-arrestin-2 biased PAR1 signaling by both APC and thrombin; EPCR occupancy recruits GRK5, leading to β-arrestin-2 recruitment and Dvl-2 signaling regardless of PAR1 cleavage site; this mechanism underlies cytoprotective thrombin signaling in EPCR-occupied endothelial cells. Gene silencing (siRNA), β-arrestin-2 recruitment assay, GRK5 interaction assay, PAR1 construct transfection in HeLa cells, in vivo inflammatory model with PC-S195A Blood High 27561318
2016 PROCR is expressed on Th17 cells under control of RORγt, IRF4, and STAT3; PROCR negatively regulates Th17 differentiation and pathogenicity; PROCR-low expressor mice show increased Th17 differentiation; activated protein C (PROCR ligand) inhibits Th17 differentiation in vitro; T cell-specific PROCR deficiency exacerbates EAE and increases Th17 frequency in vivo. Single-cell RNA-seq, conditional knockout, in vitro Th17 differentiation assay, EAE model, in vivo Th17 frequency measurement The Journal of experimental medicine High 27670590
2017 FVIIa binds EPCR and induces anti-inflammatory signaling via PAR1 and β-arrestin-1, suppressing TNF-α- and LPS-induced adhesion molecule expression and cytokine production; FVIIa treatment impairs TRAF2 recruitment to TNF-receptor 1 complex; in EPCR-deficient mice, FVIIa anti-inflammatory effects are abolished. Antibody blockade, siRNA knockdown of EPCR/PAR1/β-arrestin-1, in vivo LPS model with EPCR KO and overexpressing mice, TRAF2 recruitment assay Blood High 29669778
2017 FVIIa interaction with EPCR displaces protein C from EPCR, downregulating APC generation rather than directly enhancing FX activation; this is the mechanism by which EPCR-FVIIa interaction modulates hemostatic effect of rFVIIa in hemophilia; active-site inhibited FVIIa (EPCR-binding but non-proteolytic) reduces rFVIIa doses needed for hemostasis. Hemophilia mouse model, active-site inhibited FVIIa, EPCR overexpressing/deficient hemophilia mice, protein C plasma level measurement, saphenous vein bleeding assay Blood advances High 28932824
2018 Neisseria meningitidis adhesion to endothelial cells induces EPCR shedding via ADAM10 (not ADAM17), leading to impaired protein C activation; siRNA and CRISPR/Cas9 experiments identified ADAM10 as the responsible sheddase in this pathological context. siRNA knockdown, CRISPR/Cas9 genome editing, EPCR shedding assay, protein C activation assay PLoS pathogens High 29630665
2019 Procr+ cells in the adult mouse ovarian surface epithelium (OSE) are progenitor cells responsible for OSE repair after ovulatory rupture; Procr+ cells undergo immediate expansion upon OSE rupture; targeted ablation of Procr+ cells impedes the repair process; Procr+ cells form robust colonies in culture. Genetic lineage tracing, targeted cell ablation, colony-formation assay, single-cell analysis Nature communications High 31672973
2020 Procr+ cells in adult mouse pancreatic islets are endocrine progenitors with EMT characteristics that do not express differentiation markers; by genetic lineage tracing, Procr+ cells undergo clonal expansion and generate all four endocrine cell types (β, α, δ, PP) during adult homeostasis; sorted Procr+ cells (~1% of islet cells) form glucose-responsive, insulin-secreting islet-like organoids; transplantation reverses diabetes in mice. Single-cell RNA-seq, genetic lineage tracing, clonal organoid formation, glucose-stimulated insulin secretion assay, transplantation into diabetic mice Cell High 32200801
2020 EPCR deficiency in hemophilia A mice reduces severity of hemophilic synovitis after joint bleeding by attenuating IL-6 production, macrophage infiltration, and neoangiogenesis; a single dose of rFVIIa fully prevented milder hemophilic synovitis in EPCR-deficient mice; EPCR-blocking monoclonal antibody markedly reduced synovitis in hemophilic mice. EPCR KO and overexpressing hemophilia A mice, needle puncture joint injury, histopathology, cytokine measurement, rFVIIa treatment, EPCR-blocking antibody Blood High 32294155
2021 Procr+ granulosa cells in ovarian follicles display higher proliferation capacity and lower hormone receptor levels; knockdown of Procr inhibits proliferation; lineage tracing shows Procr+ GCs contribute to GC expansion during folliculogenesis; targeted ablation of Procr+ cells disrupts follicle development and produces PCOS-like phenotypes. Genetic lineage tracing, targeted cell ablation, siRNA knockdown, BrdU proliferation assay iScience Medium 33644709
2022 PROCR-p.Ser219Gly increases plasma levels of (activated) protein C through EPCR ectodomain shedding in endothelial cells, attenuating leukocyte-endothelial adhesion and vascular inflammation; it also increases FVII (an EPCR ligand) levels, promoting pro-thrombotic signaling, explaining the variant's dual association with lower CAD but higher VTE risk. Human recall-by-genotype study, in vitro shedding assay, leukocyte-endothelial adhesion assay, Mendelian randomization Nature communications High 35264566
2022 Procr acts as a functional signaling receptor in mammary stem cells (MaSCs); upon protein C stimulation, Procr interacts via its cytoplasmic tail with HSP90AA1, recruiting Src and IGF1R to a complex at the plasma membrane; conditional Procr KO impairs mammary gland development; IGF1R deletion in MaSCs phenocopies Procr deletion. Conditional knockout, proteomics profiling, co-immunoprecipitation, signaling assays, in vitro functional assays Cell reports High 35320720
2022 Endothelial EPCR-PAR1 biased signaling supports postischemic reperfusion and neovascularization; EPCR or PAR1 deficiency or PAR1 resistance to APC cleavage reduces angiogenesis in hindlimb ischemia; mechanistically, loss of EPCR-PAR1 signaling upregulates hemoglobin expression and reduces endothelial NO bioavailability; NO donor rescues defective angiogenic sprouting. PAR2/PAR4 KO comparison, EPCR and PAR1 KO mouse hindlimb ischemia model, biased PAR1 agonism, NO measurement, hemoglobin expression, DETA-NO rescue JCI insight High 35700057
2023 CD201+ (PROCR+) fascia progenitor cells in the skin generate multiple specialized fibroblast subtypes (proinflammatory fibroblasts to myofibroblasts) in a spatiotemporally tuned sequence during wound healing; retinoic acid signaling controls entry into proinflammatory state and hypoxia signaling controls myofibroblast differentiation; modulating CD201+ progenitor differentiation chronically delayed wound healing. Single-cell transcriptomics, genetic lineage tracing, cell ablation, gene deletion models, skin injury models Nature High 37968392
2024 PROCR+ fibroblasts in tendon tissue secrete calcified apoptotic vesicles (apoVs) that initiate heterotopic ossification (HO); apoVs enrich calcium via annexin channels, adhere to collagen I via electrostatic interaction, and aggregate to form calcifying nodules; inhibiting apoV release or macrophage deletion reverses HO development. Single-cell transcriptomics, apoV isolation and characterization, annexin channel assay, calcium enrichment assay, macrophage deletion, apoV-release inhibition Journal of extracellular vesicles Medium 38594791
2025 Procr+ cells in the superficial layer of articular cartilage and meniscus are mechanosensitive chondroprogenitors that replenish chondrocytes; mechanical stimulation (forced running) increases Procr+ cell frequency while unloading decreases it; Piezo1 mechanosensor is required for Procr+ cell activation and cartilage regeneration; genetic ablation of Procr+ cells accelerates OA progression. Genetic lineage tracing, Procr+ cell ablation, Piezo1 genetic/pharmacological inhibition and activation, running/suspension mechanical stimulation, in vivo transplantation of purified Procr+ cells Cell High 40695281

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arteriosclerosis, thrombosis, and vascular biology 298 15178554
2005 Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow. Blood 238 16304059
2017 EPCR expression marks UM171-expanded CD34+ cord blood stem cells. Blood 157 28408459
2003 A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis. Blood 157 14576048
2020 Long-Term Expansion of Pancreatic Islet Organoids from Resident Procr+ Progenitors. Cell 149 32200801
2014 Structural conservation despite huge sequence diversity allows EPCR binding by the PfEMP1 family implicated in severe childhood malaria. Cell host & microbe 145 25482433
2015 PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nature medicine 122 26457757
2004 Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis. Journal of thrombosis and haemostasis : JTH 94 15304035
2017 Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria. Cell host & microbe 91 29107642
1999 Structural and functional implications of the intron/exon organization of the human endothelial cell protein C/activated protein C receptor (EPCR) gene: comparison with the structure of CD1/major histocompatibility complex alpha1 and alpha2 domains. Blood 81 10397730
2005 Extraembryonic expression of EPCR is essential for embryonic viability. Blood 79 15956290
2009 Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality. Blood 73 19141861
2015 EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice. Blood 72 25733582
1995 Molecular cloning and expression of murine and bovine endothelial cell protein C/activated protein C receptor (EPCR). The structural and functional conservation in human, bovine, and murine EPCR. The Journal of biological chemistry 72 7890676
2004 Autoantibodies against EPCR are found in antiphospholipid syndrome and are a risk factor for fetal death. Blood 68 15150078
2023 CD201+ fascia progenitors choreograph injury repair. Nature 67 37968392
2016 EPCR and Malaria Severity: The Center of a Perfect Storm. Trends in parasitology 67 27939609
2016 Occupancy of human EPCR by protein C induces β-arrestin-2 biased PAR1 signaling by both APC and thrombin. Blood 66 27561318
2017 Parasites Causing Cerebral Falciparum Malaria Bind Multiple Endothelial Receptors and Express EPCR and ICAM-1-Binding PfEMP1. The Journal of infectious diseases 65 28863469
1999 The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries. Biochemical and biophysical research communications 63 10364477
2012 The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies. Blood 62 22251481
2006 Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1. Experimental cell research 58 17254565
2005 EPCR Ser219Gly: elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro. Atherosclerosis 58 15921688
2001 A 23bp insertion in the endothelial protein C receptor (EPCR) gene impairs EPCR function. Thrombosis and haemostasis 56 11686350
2007 Activated protein C decreases tumor necrosis factor related apoptosis-inducing ligand by an EPCR- independent mechanism involving Egr-1/Erk-1/2 activation. Arteriosclerosis, thrombosis, and vascular biology 53 17932312
2016 Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity. The Journal of experimental medicine 52 27670590
2007 Alternative mRNA is favored by the A3 haplotype of the EPCR gene PROCR and generates a novel soluble form of EPCR in plasma. Blood 52 18073349
2018 Factor VIIa induces anti-inflammatory signaling via EPCR and PAR1. Blood 50 29669778
2015 Diverse functional outcomes of Plasmodium falciparum ligation of EPCR: potential implications for malarial pathogenesis. Cellular microbiology 50 26119044
2008 PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study. Journal of thrombosis and haemostasis : JTH 49 18680534
2007 Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. Journal of thrombosis and haemostasis : JTH 48 17445091
2019 Binding Heterogeneity of Plasmodium falciparum to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1. mBio 47 31138740
2017 Plasmodium falciparum EPCR-binding PfEMP1 expression increases with malaria disease severity and is elevated in retinopathy negative cerebral malaria. BMC medicine 47 29025399
2009 Thrombin inhibits nuclear factor kappaB and RhoA pathways in cytokine-stimulated vascular endothelial cells when EPCR is occupied by protein C. Thrombosis and haemostasis 47 19277413
2005 Influence of the 4600A/G and 4678G/C polymorphisms in the endothelial protein C receptor (EPCR) gene on the risk of venous thromboembolism in carriers of factor V Leiden. Thrombosis and haemostasis 46 16113830
2001 Expression and anticoagulant function of the endothelial cell protein C receptor (EPCR) in cancer cell lines. Thrombosis and haemostasis 46 11246560
2015 Protein C system defects inflicted by the malaria parasite protein PfEMP1 can be overcome by a soluble EPCR variant. Thrombosis and haemostasis 45 26155776
2008 Haplotypes of the EPCR gene, prothrombin levels, and the risk of venous thrombosis in carriers of the prothrombin G20210A mutation. Haematologica 42 18403391
2002 Distribution of endothelial cell protein C/activated protein C receptor (EPCR) during mouse embryo development. Thrombosis and haemostasis 39 12195698
2014 Increased coagulation activity and genetic polymorphisms in the F5, F10 and EPCR genes are associated with breast cancer: a case-control study. BMC cancer 37 25407022
2019 CD34 and EPCR coordinately enrich functional murine hematopoietic stem cells under normal and inflammatory conditions. Experimental hematology 36 31863798
2005 Selective modulation of protein C affinity for EPCR and phospholipids by Gla domain mutation. The FEBS journal 36 15634335
2013 Plasmodium falciparum picks (on) EPCR. Blood 32 24246501
2010 Thrombin down-regulates the TGF-beta-mediated synthesis of collagen and fibronectin by human proximal tubule epithelial cells through the EPCR-dependent activation of PAR-1. Journal of cellular physiology 32 20506163
2015 CD201 and CD27 identify hematopoietic stem and progenitor cells across multiple murine strains independently of Kit and Sca-1. Experimental hematology 30 25892186
2014 The anticoagulant activated protein C (aPC) promotes metaplasticity in the hippocampus through an EPCR-PAR1-S1P1 receptors dependent mechanism. Hippocampus 27 24753100
2011 Protective cross talk between activated protein C and TNF signaling in vascular endothelial cells: implication of EPCR, noncanonical NF-κB, and ERK1/2 MAP kinases. American journal of physiology. Cell physiology 27 21228323
2019 Endothelial Protein C Receptor (EPCR), Protease Activated Receptor-1 (PAR-1) and Their Interplay in Cancer Growth and Metastatic Dissemination. Cancers 26 30626007
2016 Expression of MHC class I-related molecules MICA, HLA-E and EPCR shape endothelial cells with unique functions in innate and adaptive immunity. Human immunology 26 26916837
2015 Characterization of mice harboring a variant of EPCR with impaired ability to bind protein C: novel role of EPCR in hematopoiesis. Blood 26 26045607
2016 Regulation of long-term repopulating hematopoietic stem cells by EPCR/PAR1 signaling. Annals of the New York Academy of Sciences 25 26928241
2012 Is EPCR a multi-ligand receptor? Pros and cons. Thrombosis and haemostasis 25 22318610
2006 Effects of membrane and soluble EPCR on the hemostatic balance and endotoxemia in mice. Blood 25 17023579
2011 sPLA2-V inhibits EPCR anticoagulant and antiapoptotic properties by accommodating lysophosphatidylcholine or PAF in the hydrophobic groove. Blood 24 22167755
2010 Blocking endothelial protein C receptor (EPCR) accelerates thrombus development in vivo. Thrombosis and haemostasis 24 20352165
2017 Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: Mode of its action. Blood advances 23 28932824
2014 Association of the endothelial protein C receptor (PROCR) rs867186-G allele with protection from severe malaria. Malaria journal 23 24635948
2018 Infected erythrocytes expressing DC13 PfEMP1 differ from recombinant proteins in EPCR-binding function. Proceedings of the National Academy of Sciences of the United States of America 22 29339517
2018 An ADAM-10 dependent EPCR shedding links meningococcal interaction with endothelial cells to purpura fulminans. PLoS pathogens 22 29630665
2009 FVII, FVIIa, and downstream markers of extrinsic pathway activation differ by EPCR Ser219Gly variant in healthy men. Arteriosclerosis, thrombosis, and vascular biology 22 19696402
2020 EPCR deficiency or function-blocking antibody protects against joint bleeding-induced pathology in hemophilia mice. Blood 21 32294155
2017 EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth. Journal of hematology & oncology 21 28103946
2007 BiSearch: ePCR tool for native or bisulfite-treated genomic template. Methods in molecular biology (Clifton, N.J.) 20 17951807
2021 Col6a1+/CD201+ mesenchymal cells regulate intestinal morphogenesis and homeostasis. Cellular and molecular life sciences : CMLS 19 34910257
2016 The role of EPCR in the pathogenesis of severe malaria. Thrombosis research 19 27207424
2009 Lack of association of soluble endothelial protein C receptor and PROCR 6936A/G polymorphism with the risk of venous thromboembolism in a prospective study. British journal of haematology 19 19222470
2019 Procr-expressing progenitor cells are responsible for murine ovulatory rupture repair of ovarian surface epithelium. Nature communications 17 31672973
2012 Association of soluble endothelial protein C receptor plasma levels and PROCR rs867186 with cardiovascular risk factors and cardiovascular events in coronary artery disease patients: the Athero Gene study. BMC medical genetics 17 23136988
2009 Thrombin and activated protein C inhibit the expression of secretory group IIA phospholipase A(2) in the TNF-alpha-activated endothelial cells by EPCR and PAR-1 dependent mechanisms. Thrombosis research 17 19683795
2006 EPCR gene A3 haplotype and elevated soluble endothelial protein C receptor (sEPCR) levels in Turkish pediatric stroke patients. Thrombosis research 17 17027065
2002 CBS 844ins68, MTHFR TT677 and EPCR 4031ins23 genotypes in patients with deep-vein thrombosis. Thrombosis research 17 12413583
2024 Calcified apoptotic vesicles from PROCR+ fibroblasts initiate heterotopic ossification. Journal of extracellular vesicles 16 38594791
2022 Procr functions as a signaling receptor and is essential for the maintenance and self-renewal of mammary stem cells. Cell reports 16 35320720
2022 Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus. Nature communications 15 35264566
2022 Isolation of mouse pancreatic islet Procr+ progenitors and long-term expansion of islet organoids in vitro. Nature protocols 15 35396545
2021 Isoorientin suppresses sepsis-induced acute lung injury in mice by activating an EPCR-dependent JAK2/STAT3 pathway. Journal of molecular histology 15 34787735
2021 Procr-expressing granulosa cells are highly proliferative and are important for follicle development. iScience 14 33644709
2013 Endothelial cell protein C receptor (EPCR) is expressed by lung carcinoma and correlated with clinical parameters. Clinical laboratory 14 23724628
2015 Beninese children with cerebral malaria do not develop humoral immunity against the IT4-VAR19-DC8 PfEMP1 variant linked to EPCR and brain endothelial binding. Malaria journal 13 26646943
2010 The endothelial cells downregulate the generation of factor VIIa through EPCR binding. British journal of haematology 13 20085578
1999 One single mRNA encodes the centrosomal protein CCD41 and the endothelial cell protein C receptor (EPCR). FEBS letters 13 10518938
2022 Factor VII, EPCR, aPC Modulators: novel treatment for neuroinflammation. Journal of neuroinflammation 12 35690769
2022 EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia. JCI insight 12 35700057
2018 EPCR promotes MGC803 human gastric cancer cell tumor angiogenesis in vitro through activating ERK1/2 and AKT in a PAR1-dependent manner. Oncology letters 12 30008838
2016 Plasma Ang2 and ADAM17 levels are elevated during clinical malaria; Ang2 level correlates with severity and expression of EPCR-binding PfEMP1. Scientific reports 12 27784899
2012 Free fatty acids inhibit TM-EPCR expression through JNK pathway: an implication for the development of the prothrombotic state in metabolic syndrome. Journal of thrombosis and thrombolysis 12 22903729
2011 High levels of protein C are determined by PROCR haplotype 3. Journal of thrombosis and haemostasis : JTH 12 21392254
2020 Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells. Frontiers in cell and developmental biology 11 33384995
2016 The endothelial protein C receptor rs867186-GG genotype is associated with increased soluble EPCR and could mediate protection against severe malaria. Scientific reports 11 27255786
2025 Procr+ chondroprogenitors sense mechanical stimuli to govern articular cartilage maintenance and regeneration. Cell 10 40695281
2021 Sickle-trait hemoglobin reduces adhesion to both CD36 and EPCR by Plasmodium falciparum-infected erythrocytes. PLoS pathogens 10 34115805
2015 A Label-Free, Sensitive, Real-Time, Semiquantitative Electrochemical Measurement Method for DNA Polymerase Amplification (ePCR). Analytical chemistry 10 25946200
2012 The Dual Diverse Dynamic Reversible Effects of Ankaferd Blood Stopper on EPCR and PAI-1 Inside Vascular Endothelial Cells With and Without LPS Challenge. Turkish journal of haematology : official journal of Turkish Society of Haematology 10 24385723
2022 Thrombotic Risk Determined by Protein C Receptor (PROCR) Variants among Middle-Aged and Older Adults: A Population-Based Cohort Study. Thrombosis and haemostasis 9 35021256
2019 CD27, CD201, FLT3, CD48, and CD150 cell surface staining identifies long-term mouse hematopoietic stem cells in immunodeficient non-obese diabetic severe combined immune deficient-derived strains. Haematologica 9 31073070
2017 Prevalence of protein C receptor (PROCR) is associated with inferior clinical outcome in Breast invasive ductal carcinoma. Pathology, research and practice 9 28756987
2008 Recombinant expression of biologically active murine soluble EPCR. Protein expression and purification 9 19041722
2017 Endothelial microparticles released by activated protein C protect beta cells through EPCR/PAR1 and annexin A1/FPR2 pathways in islets. Journal of cellular and molecular medicine 8 28524456
2017 EPCR Gene Ser219Gly Polymorphism and Venous Thromboembolism: A Meta-Analysis of 9,494 Subjects. Frontiers in physiology 8 28603500
2015 Cell painting with an engineered EPCR to augment the protein C system. Thrombosis and haemostasis 8 26272345