{"gene":"PROCR","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1995,"finding":"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.","method":"cDNA cloning, transfection into 293T cells, binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct binding reconstitution in transfected cells, replicated across species","pmids":["7890676"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Genomic sequencing, exon/intron organization analysis, secondary structure prediction compared to known crystal structures of HLA-A2 and CD1","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 1 structural prediction validated by sequence/structural conservation with solved structures, single study","pmids":["10397730"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Monoclonal antibody blocking assay, protein C activation assay, immunohistochemistry","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — functional blocking antibody with defined cellular phenotype, replicated across vessel types","pmids":["10364477"],"is_preprint":false},{"year":1999,"finding":"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.","method":"EGFP fusion protein transfection, fluorescence microscopy, deletion mutagenesis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence of signal peptide deletion, single study","pmids":["10518938"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Expression studies, cell surface localization assay, APC binding assay","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function variant with defined molecular phenotype, single study","pmids":["11686350"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Anti-EPCR monoclonal antibody blocking, protein C activation assay on cancer cell lines","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 — blocking antibody with defined functional readout, single study","pmids":["11246560"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Immunohistological analysis across developmental time points","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization by immunohistochemistry across developmental stages, single study","pmids":["12195698"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Review integrating in vitro assays, mouse models, and clinical studies from multiple labs","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1–2 — Strong; replicated across multiple labs with diverse methods","pmids":["15178554"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Conditional knockout mouse, genetic rescue experiments, coagulation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — conditional KO with defined cellular phenotype and epistasis rescue, single rigorous study","pmids":["15956290"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Surface plasmon resonance, recombinant Gla domain mutagenesis, endothelial cell activation assay, FVa inactivation assay","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 — SPR kinetics combined with mutagenesis and multiple functional assays, single rigorous study","pmids":["15634335"],"is_preprint":false},{"year":2005,"finding":"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.","method":"In vitro EPCR-transfected cell shedding assay, ELISA for sEPCR, coagulation assays","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro shedding assay with genetic variant, single study","pmids":["15921688"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Chemotaxis/invasion assay, blocking antibody experiments, inactive APC controls","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — blocking antibody with defined phenotypic readout, single study","pmids":["17254565"],"is_preprint":false},{"year":2007,"finding":"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.","method":"mRNA expression analysis, recombinant protein production, protein C binding assay, anticoagulant activity assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — mRNA characterization plus functional reconstitution, single study","pmids":["18073349"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Bone marrow transplantation chimera, LPS challenge, protein C activation assay, cytokine measurement","journal":"Journal of thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via BM chimeras with defined functional readouts, single rigorous study","pmids":["17445091"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Thrombin infusion experiments in Procr+/- mice, factor Xa/phospholipid challenge, protein C activation measurement","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic mouse model with quantitative biochemical readouts","pmids":["17023579"],"is_preprint":false},{"year":2009,"finding":"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.","method":"EPCR occupancy with inactive protein C mutant, PAR1 agonist stimulation, Rho GTPase assays, NF-κB pathway analysis, adhesion molecule expression","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays (Rho GTPases, NF-κB, adhesion molecules, neutrophil binding) with mechanistic controls, single study","pmids":["19277413"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Pharmacological antibody blockade, genetic mouse models, LPS challenge, vascular permeability assay, genetic S1P receptor manipulation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — pharmacological plus genetic approaches with epistasis, multiple labs","pmids":["19141861"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Blocking anti-EPCR monoclonal antibody, kinetic analysis, surface plasmon resonance, immunofluorescence co-localization","journal":"British journal of haematology","confidence":"High","confidence_rationale":"Tier 1–2 — SPR plus functional blocking assays with mechanistic explanation, single rigorous study","pmids":["20085578"],"is_preprint":false},{"year":2010,"finding":"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.","method":"In vivo thrombosis model (ferric chloride), blocking vs. non-blocking anti-EPCR mAbs, surface plasmon resonance for antibody characterization","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 — in vivo model with mechanistic blocking antibody controls, single study","pmids":["20352165"],"is_preprint":false},{"year":2010,"finding":"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.","method":"EPCR expression detection, protein C-S195A occupancy, cytokine and ECM protein measurement, PAR-1 signaling assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — functional signaling switch with EPCR occupancy in non-endothelial cells, single study","pmids":["20506163"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Phospholipid identification by mass spectrometry/biochemistry, lipid exchange assay, sEPCR protein C binding assay, sPLA2-V inhibition, APC anti-apoptotic assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — identification of bound lipid plus mechanistic exchange with functional consequences, multiple orthogonal assays, single rigorous study","pmids":["22167755"],"is_preprint":false},{"year":2011,"finding":"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.","method":"siRNA silencing of EPCR and PAR1, NF-κB pathway analysis, ERK/Akt phosphorylation assays, adhesion molecule expression","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with multiple signaling readouts, single study","pmids":["21228323"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Crystal structure determination of CIDRα1:EPCR complexes, sequence analysis of 885 CIDRα1 variants, antibody blocking assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation and large-scale sequence analysis","pmids":["25482433"],"is_preprint":false},{"year":2015,"finding":"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.","method":"EPCR knockout mice, LPS challenge, bone marrow-derived myeloid cells, siRNA knockdown, gene expression analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic KO plus siRNA with defined transcriptional pathway, replicated in vitro and in vivo","pmids":["25733582"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Mouse genetic models, bone marrow transplantation, NO measurement, EPCR shedding assay, VLA4 adhesion assay, HSC mobilization assay, pharmacological inhibition","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vivo and in vitro methods across multiple signaling nodes, single study with strong mechanistic resolution","pmids":["26457757"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Recombinant protein competition assay, endothelial PC activation assay, PAR1 cleavage assay, barrier permeability assay, cytoadhesion assay","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 1–2 — multiple functional assays with decoy rescue demonstrating mechanism, single rigorous study","pmids":["26155776"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Point mutation knock-in mouse, factor Xa challenge, LPS challenge, BM transplantation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — knock-in mutation with multiple defined phenotypes and epistasis via BM transplant, single rigorous study","pmids":["26045607"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Gene silencing (siRNA), β-arrestin-2 recruitment assay, GRK5 interaction assay, PAR1 construct transfection in HeLa cells, in vivo inflammatory model with PC-S195A","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — siRNA, transfection with PAR1 constructs, signaling assays, and in vivo model, single comprehensive study","pmids":["27561318"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Single-cell RNA-seq, conditional knockout, in vitro Th17 differentiation assay, EAE model, in vivo Th17 frequency measurement","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with in vivo disease model plus in vitro mechanistic assays, single rigorous study","pmids":["27670590"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Antibody blockade, siRNA knockdown of EPCR/PAR1/β-arrestin-1, in vivo LPS model with EPCR KO and overexpressing mice, TRAF2 recruitment assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and pharmacological approaches in vitro and in vivo with defined signaling mechanism, single comprehensive study","pmids":["29669778"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Hemophilia mouse model, active-site inhibited FVIIa, EPCR overexpressing/deficient hemophilia mice, protein C plasma level measurement, saphenous vein bleeding assay","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic models with mechanistic controls (active-site inhibited FVIIa), single rigorous study","pmids":["28932824"],"is_preprint":false},{"year":2018,"finding":"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.","method":"siRNA knockdown, CRISPR/Cas9 genome editing, EPCR shedding assay, protein C activation assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 — siRNA plus CRISPR validation with defined biochemical outcome, single rigorous study","pmids":["29630665"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Genetic lineage tracing, targeted cell ablation, colony-formation assay, single-cell analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic lineage tracing plus ablation with defined tissue repair phenotype, single rigorous study","pmids":["31672973"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Single-cell RNA-seq, genetic lineage tracing, clonal organoid formation, glucose-stimulated insulin secretion assay, transplantation into diabetic mice","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — lineage tracing, organoid reconstitution, and in vivo transplantation rescue, multiple orthogonal methods in a single rigorous study","pmids":["32200801"],"is_preprint":false},{"year":2020,"finding":"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.","method":"EPCR KO and overexpressing hemophilia A mice, needle puncture joint injury, histopathology, cytokine measurement, rFVIIa treatment, EPCR-blocking antibody","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic models with pharmacological rescue and defined inflammatory phenotype","pmids":["32294155"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Genetic lineage tracing, targeted cell ablation, siRNA knockdown, BrdU proliferation assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — lineage tracing and ablation with defined phenotype, single study","pmids":["33644709"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Human recall-by-genotype study, in vitro shedding assay, leukocyte-endothelial adhesion assay, Mendelian randomization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — human genetics integrated with in vitro mechanistic experiments and Mendelian randomization, multiple orthogonal methods","pmids":["35264566"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Conditional knockout, proteomics profiling, co-immunoprecipitation, signaling assays, in vitro functional assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — conditional KO with proteomics-identified complex, co-IP, signaling assays, and genetic epistasis (IGF1R KO phenocopy), single rigorous study","pmids":["35320720"],"is_preprint":false},{"year":2022,"finding":"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.","method":"PAR2/PAR4 KO comparison, EPCR and PAR1 KO mouse hindlimb ischemia model, biased PAR1 agonism, NO measurement, hemoglobin expression, DETA-NO rescue","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic KO models with pharmacological rescue identifying NO as mechanistic link, single rigorous study","pmids":["35700057"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Single-cell transcriptomics, genetic lineage tracing, cell ablation, gene deletion models, skin injury models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — genetic lineage tracing plus ablation plus gene deletion with defined wound healing phenotype, single rigorous study","pmids":["37968392"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Single-cell transcriptomics, apoV isolation and characterization, annexin channel assay, calcium enrichment assay, macrophage deletion, apoV-release inhibition","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 — scRNA-seq identifies source, functional assays characterize mechanism, single study","pmids":["38594791"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Genetic lineage tracing, Procr+ cell ablation, Piezo1 genetic/pharmacological inhibition and activation, running/suspension mechanical stimulation, in vivo transplantation of purified Procr+ cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — lineage tracing, cell ablation, genetic epistasis (Piezo1 KO), pharmacological rescue, and transplantation, multiple orthogonal methods in a single rigorous study","pmids":["40695281"],"is_preprint":false}],"current_model":"PROCR/EPCR is a type I transmembrane glycoprotein with a CD1/MHC-like extracellular domain that binds protein C, APC, FVIIa, and FXa via their Gla domains, with a phosphatidylcholine-occupied hydrophobic groove; on endothelial cells it amplifies thrombomodulin-thrombin-mediated protein C activation, and when occupied by protein C/APC it redirects PAR1 signaling from proinflammatory (RhoA/NF-κB) to cytoprotective (Rac1/β-arrestin-2/GRK5) pathways; EPCR ectodomain shedding by ADAM17 (or ADAM10 during meningococcal infection) generates soluble EPCR that inhibits PC activation; beyond hemostasis, PROCR marks multipotent stem/progenitor cells in bone marrow, mammary gland, pancreatic islets, ovary, fascia, cartilage, and other tissues where it functions as a signaling receptor that—upon protein C binding—recruits HSP90/Src/IGF1R to regulate stem cell self-renewal and differentiation."},"narrative":{"teleology":[{"year":1995,"claim":"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","pmids":["7890676"],"confidence":"High","gaps":["No structural basis for ligand recognition","No in vivo functional data"]},{"year":1999,"claim":"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","pmids":["10397730","10364477"],"confidence":"High","gaps":["No crystal structure yet available","Lipid content of the binding groove unknown"]},{"year":2005,"claim":"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","pmids":["15634335","15956290"],"confidence":"High","gaps":["Mechanism of EPCR-mediated signaling downstream of ligand binding unresolved","Role of bound lipid unknown"]},{"year":2009,"claim":"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","pmids":["19277413","19141861"],"confidence":"High","gaps":["Molecular mediator linking EPCR occupancy to PAR1 signaling bias not identified","Whether EPCR-PAR1 signaling switch occurs in non-endothelial cells unknown"]},{"year":2011,"claim":"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","pmids":["22167755"],"confidence":"High","gaps":["Whether lipid exchange occurs in vivo during inflammation is untested","Structural basis of lipid-dependent binding modulation not resolved"]},{"year":2014,"claim":"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","pmids":["25482433"],"confidence":"High","gaps":["Therapeutic strategies to selectively block parasite binding without disrupting PC activation not yet developed","In vivo confirmation in human malaria lacking"]},{"year":2015,"claim":"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","pmids":["25733582","26457757","26045607"],"confidence":"High","gaps":["Whether EPCR signals through PAR1-independent mechanisms in HSCs not excluded","Structural basis for differential PAR1 bias by APC vs thrombin on HSCs unclear"]},{"year":2016,"claim":"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","pmids":["27561318","27670590"],"confidence":"High","gaps":["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"]},{"year":2017,"claim":"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","pmids":["29669778","28932824"],"confidence":"High","gaps":["Relative contributions of PC displacement vs direct FVIIa-EPCR signaling to hemostasis not fully quantified"]},{"year":2018,"claim":"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","pmids":["29630665"],"confidence":"High","gaps":["Whether ADAM10 shedding occurs in other infectious contexts not tested","Signaling pathway from bacterial adhesion to ADAM10 activation not mapped"]},{"year":2020,"claim":"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","pmids":["32200801"],"confidence":"High","gaps":["Whether protein C–EPCR signaling drives islet progenitor self-renewal (as in mammary) not tested","Human islet Procr+ progenitor equivalence not established"]},{"year":2022,"claim":"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","pmids":["35320720"],"confidence":"High","gaps":["Whether HSP90/Src/IGF1R complex operates in non-mammary Procr+ progenitors untested","Structure of PROCR cytoplasmic tail interaction with HSP90 unknown"]},{"year":2023,"claim":"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","pmids":["37968392"],"confidence":"High","gaps":["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"]},{"year":2025,"claim":"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","pmids":["40695281"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,9,15,27]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[15,27,37]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,17,28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4,37]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[10,12,36]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[2,7,14,17,18,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,16,21,27,29,38]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,23,28,29]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,33,37,39,41]}],"complexes":["EPCR-PAR1 signaling complex","HSP90/Src/IGF1R stem cell complex"],"partners":["PROC","THBD","F2R","F7","ARRB2","GRK5","HSP90AA1","IGF1R"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q9UNN8","full_name":"Endothelial protein C receptor","aliases":["Activated protein C receptor","APC receptor","Endothelial cell protein C receptor"],"length_aa":238,"mass_kda":26.7,"function":"Binds activated protein C. Enhances protein C activation by the thrombin-thrombomodulin complex; plays a role in the protein C pathway controlling blood coagulation","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9UNN8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PROCR","classification":"Not Classified","n_dependent_lines":26,"n_total_lines":1208,"dependency_fraction":0.02152317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PROCR","total_profiled":1310},"omim":[{"mim_id":"612283","title":"PROTEIN C; PROC","url":"https://www.omim.org/entry/612283"},{"mim_id":"608863","title":"PODOPLANIN; PDPN","url":"https://www.omim.org/entry/608863"},{"mim_id":"603423","title":"PR DOMAIN-CONTAINING PROTEIN 1; PRDM1","url":"https://www.omim.org/entry/603423"},{"mim_id":"603149","title":"INTERLEUKIN 17A; IL17A","url":"https://www.omim.org/entry/603149"},{"mim_id":"600646","title":"PROTEIN C RECEPTOR; PROCR","url":"https://www.omim.org/entry/600646"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":120.1}],"url":"https://www.proteinatlas.org/search/PROCR"},"hgnc":{"alias_symbol":["EPCR","CCD41","CD201"],"prev_symbol":[]},"alphafold":{"accession":"Q9UNN8","domains":[{"cath_id":"3.30.500.10","chopping":"27-201","consensus_level":"high","plddt":95.1597,"start":27,"end":201}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UNN8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UNN8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UNN8-F1-predicted_aligned_error_v6.png","plddt_mean":86.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PROCR","jax_strain_url":"https://www.jax.org/strain/search?query=PROCR"},"sequence":{"accession":"Q9UNN8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UNN8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UNN8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UNN8"}},"corpus_meta":[{"pmid":"15178554","id":"PMC_15178554","title":"Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation.","date":"2004","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15178554","citation_count":298,"is_preprint":false},{"pmid":"16304059","id":"PMC_16304059","title":"Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16304059","citation_count":238,"is_preprint":false},{"pmid":"14576048","id":"PMC_14576048","title":"A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/14576048","citation_count":157,"is_preprint":false},{"pmid":"28408459","id":"PMC_28408459","title":"EPCR expression marks UM171-expanded CD34+ cord blood stem cells.","date":"2017","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/28408459","citation_count":157,"is_preprint":false},{"pmid":"32200801","id":"PMC_32200801","title":"Long-Term Expansion of Pancreatic Islet Organoids from Resident Procr+ Progenitors.","date":"2020","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/32200801","citation_count":149,"is_preprint":false},{"pmid":"25482433","id":"PMC_25482433","title":"Structural conservation despite huge sequence diversity allows EPCR binding by the PfEMP1 family implicated in severe childhood malaria.","date":"2014","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/25482433","citation_count":145,"is_preprint":false},{"pmid":"26457757","id":"PMC_26457757","title":"PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells.","date":"2015","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26457757","citation_count":122,"is_preprint":false},{"pmid":"15304035","id":"PMC_15304035","title":"Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis.","date":"2004","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/15304035","citation_count":94,"is_preprint":false},{"pmid":"29107642","id":"PMC_29107642","title":"Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria.","date":"2017","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/29107642","citation_count":91,"is_preprint":false},{"pmid":"10397730","id":"PMC_10397730","title":"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.","date":"1999","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10397730","citation_count":81,"is_preprint":false},{"pmid":"15956290","id":"PMC_15956290","title":"Extraembryonic expression of EPCR is essential for embryonic viability.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15956290","citation_count":79,"is_preprint":false},{"pmid":"19141861","id":"PMC_19141861","title":"Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19141861","citation_count":73,"is_preprint":false},{"pmid":"7890676","id":"PMC_7890676","title":"Molecular cloning and expression of murine and bovine endothelial cell protein C/activated protein C receptor (EPCR). 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expression through JNK pathway: an implication for the development of the prothrombotic state in metabolic syndrome.","date":"2012","source":"Journal of thrombosis and thrombolysis","url":"https://pubmed.ncbi.nlm.nih.gov/22903729","citation_count":12,"is_preprint":false},{"pmid":"30008838","id":"PMC_30008838","title":"EPCR promotes MGC803 human gastric cancer cell tumor angiogenesis in vitro through activating ERK1/2 and AKT in a PAR1-dependent manner.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30008838","citation_count":12,"is_preprint":false},{"pmid":"27784899","id":"PMC_27784899","title":"Plasma Ang2 and ADAM17 levels are elevated during clinical malaria; Ang2 level correlates with severity and expression of EPCR-binding PfEMP1.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27784899","citation_count":12,"is_preprint":false},{"pmid":"33384995","id":"PMC_33384995","title":"Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33384995","citation_count":11,"is_preprint":false},{"pmid":"27255786","id":"PMC_27255786","title":"The endothelial protein C receptor rs867186-GG genotype is associated with increased soluble EPCR and could mediate protection against severe malaria.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27255786","citation_count":11,"is_preprint":false},{"pmid":"40695281","id":"PMC_40695281","title":"Procr+ chondroprogenitors sense mechanical stimuli to govern articular cartilage maintenance and regeneration.","date":"2025","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/40695281","citation_count":10,"is_preprint":false},{"pmid":"34115805","id":"PMC_34115805","title":"Sickle-trait hemoglobin reduces adhesion to both CD36 and EPCR by Plasmodium falciparum-infected erythrocytes.","date":"2021","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/34115805","citation_count":10,"is_preprint":false},{"pmid":"24385723","id":"PMC_24385723","title":"The Dual Diverse Dynamic Reversible Effects of Ankaferd Blood Stopper on EPCR and PAI-1 Inside Vascular Endothelial Cells With and Without LPS Challenge.","date":"2012","source":"Turkish journal of haematology : official journal of Turkish Society of Haematology","url":"https://pubmed.ncbi.nlm.nih.gov/24385723","citation_count":10,"is_preprint":false},{"pmid":"25946200","id":"PMC_25946200","title":"A Label-Free, Sensitive, Real-Time, Semiquantitative Electrochemical Measurement Method for DNA Polymerase Amplification (ePCR).","date":"2015","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25946200","citation_count":10,"is_preprint":false},{"pmid":"28756987","id":"PMC_28756987","title":"Prevalence of protein C receptor (PROCR) is associated with inferior clinical outcome in Breast invasive ductal carcinoma.","date":"2017","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/28756987","citation_count":9,"is_preprint":false},{"pmid":"31073070","id":"PMC_31073070","title":"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.","date":"2019","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/31073070","citation_count":9,"is_preprint":false},{"pmid":"19041722","id":"PMC_19041722","title":"Recombinant expression of biologically active murine soluble EPCR.","date":"2008","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/19041722","citation_count":9,"is_preprint":false},{"pmid":"35021256","id":"PMC_35021256","title":"Thrombotic Risk Determined by Protein C Receptor (PROCR) Variants among Middle-Aged and Older Adults: A Population-Based Cohort Study.","date":"2022","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/35021256","citation_count":9,"is_preprint":false},{"pmid":"26272345","id":"PMC_26272345","title":"Cell painting with an engineered EPCR to augment the protein C system.","date":"2015","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/26272345","citation_count":8,"is_preprint":false},{"pmid":"28603500","id":"PMC_28603500","title":"EPCR Gene Ser219Gly Polymorphism and Venous Thromboembolism: A Meta-Analysis of 9,494 Subjects.","date":"2017","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28603500","citation_count":8,"is_preprint":false},{"pmid":"28524456","id":"PMC_28524456","title":"Endothelial microparticles released by activated protein C protect beta cells through EPCR/PAR1 and annexin A1/FPR2 pathways in islets.","date":"2017","source":"Journal of cellular and molecular 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EPCR mRNA is restricted to endothelium among cell lines tested.\",\n      \"method\": \"cDNA cloning, transfection into 293T cells, binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding reconstitution in transfected cells, replicated across species\",\n      \"pmids\": [\"7890676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Genomic sequencing, exon/intron organization analysis, secondary structure prediction compared to known crystal structures of HLA-A2 and CD1\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 structural prediction validated by sequence/structural conservation with solved structures, single study\",\n      \"pmids\": [\"10397730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Monoclonal antibody blocking assay, protein C activation assay, immunohistochemistry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional blocking antibody with defined cellular phenotype, replicated across vessel types\",\n      \"pmids\": [\"10364477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"EGFP fusion protein transfection, fluorescence microscopy, deletion mutagenesis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence of signal peptide deletion, single study\",\n      \"pmids\": [\"10518938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Expression studies, cell surface localization assay, APC binding assay\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function variant with defined molecular phenotype, single study\",\n      \"pmids\": [\"11686350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Anti-EPCR monoclonal antibody blocking, protein C activation assay on cancer cell lines\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — blocking antibody with defined functional readout, single study\",\n      \"pmids\": [\"11246560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistological analysis across developmental time points\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization by immunohistochemistry across developmental stages, single study\",\n      \"pmids\": [\"12195698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Review integrating in vitro assays, mouse models, and clinical studies from multiple labs\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — Strong; replicated across multiple labs with diverse methods\",\n      \"pmids\": [\"15178554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mouse, genetic rescue experiments, coagulation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — conditional KO with defined cellular phenotype and epistasis rescue, single rigorous study\",\n      \"pmids\": [\"15956290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Surface plasmon resonance, recombinant Gla domain mutagenesis, endothelial cell activation assay, FVa inactivation assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — SPR kinetics combined with mutagenesis and multiple functional assays, single rigorous study\",\n      \"pmids\": [\"15634335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro EPCR-transfected cell shedding assay, ELISA for sEPCR, coagulation assays\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro shedding assay with genetic variant, single study\",\n      \"pmids\": [\"15921688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Chemotaxis/invasion assay, blocking antibody experiments, inactive APC controls\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — blocking antibody with defined phenotypic readout, single study\",\n      \"pmids\": [\"17254565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"mRNA expression analysis, recombinant protein production, protein C binding assay, anticoagulant activity assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mRNA characterization plus functional reconstitution, single study\",\n      \"pmids\": [\"18073349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Bone marrow transplantation chimera, LPS challenge, protein C activation assay, cytokine measurement\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via BM chimeras with defined functional readouts, single rigorous study\",\n      \"pmids\": [\"17445091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Thrombin infusion experiments in Procr+/- mice, factor Xa/phospholipid challenge, protein C activation measurement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic mouse model with quantitative biochemical readouts\",\n      \"pmids\": [\"17023579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"EPCR occupancy with inactive protein C mutant, PAR1 agonist stimulation, Rho GTPase assays, NF-κB pathway analysis, adhesion molecule expression\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays (Rho GTPases, NF-κB, adhesion molecules, neutrophil binding) with mechanistic controls, single study\",\n      \"pmids\": [\"19277413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological antibody blockade, genetic mouse models, LPS challenge, vascular permeability assay, genetic S1P receptor manipulation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological plus genetic approaches with epistasis, multiple labs\",\n      \"pmids\": [\"19141861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Blocking anti-EPCR monoclonal antibody, kinetic analysis, surface plasmon resonance, immunofluorescence co-localization\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — SPR plus functional blocking assays with mechanistic explanation, single rigorous study\",\n      \"pmids\": [\"20085578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo thrombosis model (ferric chloride), blocking vs. non-blocking anti-EPCR mAbs, surface plasmon resonance for antibody characterization\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model with mechanistic blocking antibody controls, single study\",\n      \"pmids\": [\"20352165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"EPCR expression detection, protein C-S195A occupancy, cytokine and ECM protein measurement, PAR-1 signaling assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional signaling switch with EPCR occupancy in non-endothelial cells, single study\",\n      \"pmids\": [\"20506163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Phospholipid identification by mass spectrometry/biochemistry, lipid exchange assay, sEPCR protein C binding assay, sPLA2-V inhibition, APC anti-apoptotic assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — identification of bound lipid plus mechanistic exchange with functional consequences, multiple orthogonal assays, single rigorous study\",\n      \"pmids\": [\"22167755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA silencing of EPCR and PAR1, NF-κB pathway analysis, ERK/Akt phosphorylation assays, adhesion molecule expression\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with multiple signaling readouts, single study\",\n      \"pmids\": [\"21228323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure determination of CIDRα1:EPCR complexes, sequence analysis of 885 CIDRα1 variants, antibody blocking assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation and large-scale sequence analysis\",\n      \"pmids\": [\"25482433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"EPCR knockout mice, LPS challenge, bone marrow-derived myeloid cells, siRNA knockdown, gene expression analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus siRNA with defined transcriptional pathway, replicated in vitro and in vivo\",\n      \"pmids\": [\"25733582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse genetic models, bone marrow transplantation, NO measurement, EPCR shedding assay, VLA4 adhesion assay, HSC mobilization assay, pharmacological inhibition\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vivo and in vitro methods across multiple signaling nodes, single study with strong mechanistic resolution\",\n      \"pmids\": [\"26457757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein competition assay, endothelial PC activation assay, PAR1 cleavage assay, barrier permeability assay, cytoadhesion assay\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple functional assays with decoy rescue demonstrating mechanism, single rigorous study\",\n      \"pmids\": [\"26155776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Point mutation knock-in mouse, factor Xa challenge, LPS challenge, BM transplantation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — knock-in mutation with multiple defined phenotypes and epistasis via BM transplant, single rigorous study\",\n      \"pmids\": [\"26045607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Gene silencing (siRNA), β-arrestin-2 recruitment assay, GRK5 interaction assay, PAR1 construct transfection in HeLa cells, in vivo inflammatory model with PC-S195A\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA, transfection with PAR1 constructs, signaling assays, and in vivo model, single comprehensive study\",\n      \"pmids\": [\"27561318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell RNA-seq, conditional knockout, in vitro Th17 differentiation assay, EAE model, in vivo Th17 frequency measurement\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with in vivo disease model plus in vitro mechanistic assays, single rigorous study\",\n      \"pmids\": [\"27670590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Antibody blockade, siRNA knockdown of EPCR/PAR1/β-arrestin-1, in vivo LPS model with EPCR KO and overexpressing mice, TRAF2 recruitment assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological approaches in vitro and in vivo with defined signaling mechanism, single comprehensive study\",\n      \"pmids\": [\"29669778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Hemophilia mouse model, active-site inhibited FVIIa, EPCR overexpressing/deficient hemophilia mice, protein C plasma level measurement, saphenous vein bleeding assay\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic models with mechanistic controls (active-site inhibited FVIIa), single rigorous study\",\n      \"pmids\": [\"28932824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, CRISPR/Cas9 genome editing, EPCR shedding assay, protein C activation assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — siRNA plus CRISPR validation with defined biochemical outcome, single rigorous study\",\n      \"pmids\": [\"29630665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic lineage tracing, targeted cell ablation, colony-formation assay, single-cell analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic lineage tracing plus ablation with defined tissue repair phenotype, single rigorous study\",\n      \"pmids\": [\"31672973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell RNA-seq, genetic lineage tracing, clonal organoid formation, glucose-stimulated insulin secretion assay, transplantation into diabetic mice\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — lineage tracing, organoid reconstitution, and in vivo transplantation rescue, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"32200801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"EPCR KO and overexpressing hemophilia A mice, needle puncture joint injury, histopathology, cytokine measurement, rFVIIa treatment, EPCR-blocking antibody\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic models with pharmacological rescue and defined inflammatory phenotype\",\n      \"pmids\": [\"32294155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic lineage tracing, targeted cell ablation, siRNA knockdown, BrdU proliferation assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — lineage tracing and ablation with defined phenotype, single study\",\n      \"pmids\": [\"33644709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Human recall-by-genotype study, in vitro shedding assay, leukocyte-endothelial adhesion assay, Mendelian randomization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetics integrated with in vitro mechanistic experiments and Mendelian randomization, multiple orthogonal methods\",\n      \"pmids\": [\"35264566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout, proteomics profiling, co-immunoprecipitation, signaling assays, in vitro functional assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — conditional KO with proteomics-identified complex, co-IP, signaling assays, and genetic epistasis (IGF1R KO phenocopy), single rigorous study\",\n      \"pmids\": [\"35320720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"PAR2/PAR4 KO comparison, EPCR and PAR1 KO mouse hindlimb ischemia model, biased PAR1 agonism, NO measurement, hemoglobin expression, DETA-NO rescue\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic KO models with pharmacological rescue identifying NO as mechanistic link, single rigorous study\",\n      \"pmids\": [\"35700057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell transcriptomics, genetic lineage tracing, cell ablation, gene deletion models, skin injury models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic lineage tracing plus ablation plus gene deletion with defined wound healing phenotype, single rigorous study\",\n      \"pmids\": [\"37968392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell transcriptomics, apoV isolation and characterization, annexin channel assay, calcium enrichment assay, macrophage deletion, apoV-release inhibition\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — scRNA-seq identifies source, functional assays characterize mechanism, single study\",\n      \"pmids\": [\"38594791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic lineage tracing, Procr+ cell ablation, Piezo1 genetic/pharmacological inhibition and activation, running/suspension mechanical stimulation, in vivo transplantation of purified Procr+ cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — lineage tracing, cell ablation, genetic epistasis (Piezo1 KO), pharmacological rescue, and transplantation, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"40695281\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PROCR/EPCR is a type I transmembrane glycoprotein with a CD1/MHC-like extracellular domain that binds protein C, APC, FVIIa, and FXa via their Gla domains, with a phosphatidylcholine-occupied hydrophobic groove; on endothelial cells it amplifies thrombomodulin-thrombin-mediated protein C activation, and when occupied by protein C/APC it redirects PAR1 signaling from proinflammatory (RhoA/NF-κB) to cytoprotective (Rac1/β-arrestin-2/GRK5) pathways; EPCR ectodomain shedding by ADAM17 (or ADAM10 during meningococcal infection) generates soluble EPCR that inhibits PC activation; beyond hemostasis, PROCR marks multipotent stem/progenitor cells in bone marrow, mammary gland, pancreatic islets, ovary, fascia, cartilage, and other tissues where it functions as a signaling receptor that—upon protein C binding—recruits HSP90/Src/IGF1R to regulate stem cell self-renewal and differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA cloning and transfection of murine/bovine EPCR into 293T cells with APC binding assay\",\n      \"pmids\": [\"7890676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for ligand recognition\", \"No in vivo functional data\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genomic sequencing with structural homology prediction; anti-EPCR mAb blocking of PC activation on arterial, venous, and microvascular endothelial cells\",\n      \"pmids\": [\"10397730\", \"10364477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure yet available\", \"Lipid content of the binding groove unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"SPR kinetics with Gla domain mutants; conditional KO in trophoblasts with tissue factor epistasis rescue\",\n      \"pmids\": [\"15634335\", \"15956290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of EPCR-mediated signaling downstream of ligand binding unresolved\", \"Role of bound lipid unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Inactive PC-S195A occupancy with Rho GTPase/NF-κB assays; pharmacological/genetic blockade in LPS vascular permeability model with S1P receptor epistasis\",\n      \"pmids\": [\"19277413\", \"19141861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mediator linking EPCR occupancy to PAR1 signaling bias not identified\", \"Whether EPCR-PAR1 signaling switch occurs in non-endothelial cells unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mass spectrometry identification; lipid exchange assay with sPLA2-V; sEPCR binding and APC functional assays\",\n      \"pmids\": [\"22167755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lipid exchange occurs in vivo during inflammation is untested\", \"Structural basis of lipid-dependent binding modulation not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography of CIDRα1:EPCR complexes with sequence analysis of 885 variants and blocking antibody validation\",\n      \"pmids\": [\"25482433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic strategies to selectively block parasite binding without disrupting PC activation not yet developed\", \"In vivo confirmation in human malaria lacking\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"EPCR KO mice with LPS/IRF pathway analysis; mouse BM transplantation with NO/Cdc42/VLA4 assays; R84A knock-in with BM transplant epistasis\",\n      \"pmids\": [\"25733582\", \"26457757\", \"26045607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EPCR signals through PAR1-independent mechanisms in HSCs not excluded\", \"Structural basis for differential PAR1 bias by APC vs thrombin on HSCs unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA of β-arrestin-2/GRK5 with PAR1 construct transfection and Dvl-2 assays; T cell-specific PROCR conditional KO in EAE model\",\n      \"pmids\": [\"27561318\", \"27670590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"EPCR KO/overexpressing mice, active-site inhibited FVIIa, siRNA of β-arrestin-1, hemophilia bleeding model\",\n      \"pmids\": [\"29669778\", \"28932824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of PC displacement vs direct FVIIa-EPCR signaling to hemostasis not fully quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA and CRISPR/Cas9 of ADAM10 in meningococcal adhesion assay with EPCR shedding and PC activation readouts\",\n      \"pmids\": [\"29630665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADAM10 shedding occurs in other infectious contexts not tested\", \"Signaling pathway from bacterial adhesion to ADAM10 activation not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic lineage tracing, scRNA-seq, organoid formation, glucose-stimulated insulin secretion, transplantation into diabetic mice\",\n      \"pmids\": [\"32200801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether protein C–EPCR signaling drives islet progenitor self-renewal (as in mammary) not tested\", \"Human islet Procr+ progenitor equivalence not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional KO, co-IP proteomics, signaling assays, IGF1R genetic epistasis\",\n      \"pmids\": [\"35320720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HSP90/Src/IGF1R complex operates in non-mammary Procr+ progenitors untested\", \"Structure of PROCR cytoplasmic tail interaction with HSP90 unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic lineage tracing, cell ablation, gene deletion, scRNA-seq in skin wound models\",\n      \"pmids\": [\"37968392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic lineage tracing, Procr+ ablation, Piezo1 KO/pharmacological modulation, forced running/unloading, transplantation\",\n      \"pmids\": [\"40695281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 9, 15, 27]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [15, 27, 37]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 17, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4, 37]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [10, 12, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [2, 7, 14, 17, 18, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 16, 21, 27, 29, 38]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 23, 28, 29]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 33, 37, 39, 41]}\n    ],\n    \"complexes\": [\n      \"EPCR-PAR1 signaling complex\",\n      \"HSP90/Src/IGF1R stem cell complex\"\n    ],\n    \"partners\": [\n      \"PROC\",\n      \"THBD\",\n      \"F2R\",\n      \"F7\",\n      \"ARRB2\",\n      \"GRK5\",\n      \"HSP90AA1\",\n      \"IGF1R\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}