{"gene":"F10","run_date":"2026-06-14T21:06:16+00:00","timeline":{"discoveries":[{"year":2019,"finding":"Myeloid cell-derived FXa promotes tumor immune evasion by signaling through protease-activated receptor 2 (PAR2), reprogramming tumor-associated macrophages; monocytes and macrophages were identified as crucial extravascular sources of FX in the tumor microenvironment.","method":"Conditional knockout mice lacking myeloid cell FX production; pharmacological inhibition with rivaroxaban; mechanistic signaling studies in tumor models","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (conditional KO) plus pharmacological intervention with defined cellular phenotype, replicated across multiple mouse cancer models","pmids":["31541031"],"is_preprint":false},{"year":2013,"finding":"FX binding to Ad5 hexon protein protects adenovirus from neutralization by natural IgM and the classical complement pathway, enabling liver transduction; FX was not required for liver transduction in mice lacking antibodies, C1q, or C4.","method":"In vitro serum neutralization assays with FX-blocking; in vivo liver transduction in antibody-deficient, C1q-deficient, and C4-deficient mice","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic mouse models (antibody-deficient, C1q-KO, C4-KO) with consistent in vitro and in vivo results","pmids":["23524342"],"is_preprint":false},{"year":2012,"finding":"The HAdv-FX complex activates a distinct NF-κB-dependent innate immune gene network downstream of TLR4/MyD88/TRIF/TRAF6 signaling; misplacement of FX from blood into intracellular macrophage compartments upon virus entry triggers this innate immune response.","method":"Structure-guided mutagenesis to ablate HAdv-FX complex formation; in vivo genome-wide transcriptional profiling comparing wild-type vs. FX-binding-ablated virus","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis to ablate specific interaction combined with genome-wide transcriptional profiling and defined signaling pathway","pmids":["23019612"],"is_preprint":false},{"year":2010,"finding":"Ad5 binds FX via the hexon protein; the Ad5:FX complex targets heparan sulfate proteoglycans (HSPGs) on cell surfaces, with O-linked sulfate groups critical for binding; integrin αv engagement is required for efficient post-attachment internalization.","method":"Enzymatic removal of HS side chains; competition with sulfated heparins; in vivo liver accumulation assays; Ad5 vectors with CAR- and αv-integrin binding mutations","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (enzymatic, genetic, in vivo) consistently demonstrating HSPG-dependent FX-mediated cell entry","pmids":["20949078"],"is_preprint":false},{"year":2024,"finding":"FXa promotes androgen-independent prostate tumor growth by activating PAR2 and phosphorylation of ERK1/2 in tumor cells; immunosuppressive PMN-MDSCs are a key extrahepatic source of FX in the prostate TME; CD84 ligation on PMN-MDSCs enhances F10 expression.","method":"scRNA-seq; genetic and pharmacological inhibition of FXa; ERK1/2 phosphorylation assays; CD84 ligation experiments in mouse CRPC models","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic inhibition plus pharmacological inhibition with defined downstream signaling (PAR2/ERK1/2), replicated across multiple approaches","pmids":["39303726"],"is_preprint":false},{"year":1997,"finding":"Arginine-specific cysteine proteinases (gingipain-Rs) from Porphyromonas gingivalis directly activate human factor X in a dose- and time-dependent manner with Km below normal plasma FX concentration; the 95-kDa form is 5-fold more efficient than the 50-kDa form and is potentiated by phospholipids.","method":"In vitro enzyme kinetics assays; clotting time assays in factor-deficient plasmas; reconstitution with purified FX","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with kinetic characterization (Km determination) in a single focused study","pmids":["9188512"],"is_preprint":false},{"year":1998,"finding":"X-bp from Deinagkistrodon acutus venom is a heterodimeric C-type lectin-like protein that binds the Gla domain of factor X (residues 1-44); the C-terminal region of the Gla domain peptide is critical for correct folding and binding; X-bp binds two Ca2+ ions per molecule.","method":"Protein isolation; complete amino acid sequencing; solid-phase binding inhibition assays with Gla domain peptide fragments; Ca2+ binding measurements; 3D model construction","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays with domain-deletion peptides and structural modeling, single lab","pmids":["9860851"],"is_preprint":false},{"year":2001,"finding":"FXa acts as a mitogen for human mesangial cells via proteolytic activity, inducing calcium mobilization, JNK activation, tyrosine kinase signaling, and PDGF A/B chain upregulation through a protease-activated receptor (not EPR-1); PKC activation is partially involved.","method":"DNA synthesis assays; serine protease inhibitor (leupeptin); neutralizing anti-PDGF antibody; tyrosine kinase inhibitors (genistein, herbimycin A); PKC downregulation; RT-PCR for EPR-1","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological interventions dissecting signaling pathway in cultured human cells, single lab","pmids":["11316847"],"is_preprint":false},{"year":2017,"finding":"The Gla domain of FX mediates PS-specific membrane binding; molecular dynamics simulations identified PS-specific binding sites in FX-GLA and showed convergent membrane-bound configuration across 14 independent simulations.","method":"Molecular dynamics simulations using highly mobile membrane mimetic (HMMM); conventional membrane simulations","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — computational simulation without experimental mutagenesis or direct biophysical validation of identified binding sites","pmids":["28782177"],"is_preprint":false},{"year":2021,"finding":"Factor X binds exactly one PS molecule per Gla domain when PE is present in excess (stoichiometry ~1.05 PS per FX molecule), identifying a single truly PS-specific binding site per Gla domain while remaining membrane interactions are satisfied by PE.","method":"Surface plasmon resonance with Nanodiscs of defined phospholipid composition","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative biophysical assay (SPR with Nanodiscs) measuring stoichiometry directly, single lab","pmids":["34894064"],"is_preprint":false},{"year":2017,"finding":"The C. canimorsus protease CcDPP7 (type 7 dipeptidyl peptidase, S46 serine protease family) inactivates human FX by N-terminal cleavage of both heavy and light chains, inhibiting thrombin generation and prolonging clotting times in vivo.","method":"Mutagenesis of Cc5 genes; protein purification; Edman degradation for N-terminal cleavage site; clotting assays; in vivo tail bleeding time in mice","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — gene-specific mutagenesis, purified protease biochemistry, N-terminal sequencing, and in vivo validation in a single focused study","pmids":["28029716"],"is_preprint":false},{"year":2000,"finding":"FX deficiency causes partial embryonic lethality (~1/3 of FX-/- embryos die ~E11.5-12.5) and fatal neonatal bleeding (90% die within 5 days from intraabdominal hemorrhage), establishing FX as essential for embryonic and postnatal hemostasis.","method":"Targeted gene replacement (knockout mice); genotyping of offspring; histological analysis","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 / Strong — complete loss-of-function genetic model with precise phenotypic characterization at multiple developmental stages","pmids":["10739370"],"is_preprint":false},{"year":2000,"finding":"The murine FX promoter is TATA-less with two transcription start sites; NF-Y, HNF-4, and GATA-4 bind the proximal promoter and regulate FX expression, with NF-Y being most critical (ablation reduces activity to 10% of wild-type).","method":"DNase I footprinting; EMSA; transient transfection in HepG2 cells; promoter deletion analysis","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary methods (footprinting, EMSA, functional reporter assays) in a single lab study","pmids":["11154110"],"is_preprint":false},{"year":2015,"finding":"The FX carboxyl-terminal region (downstream of K467) is not essential for secretion or procoagulant activity; deletion of up to 21 carboxyl-terminal residues does not affect secretion or amidolytic activity, in contrast to the homologous regions in FVII, FIX, and PC.","method":"Recombinant expression of progressively truncated FX variants in HEK293, HepG2, and BHK21 cells; ELISA; coagulant and amidolytic assays; chimeric FX-FVII constructs","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell systems and orthogonal functional assays, single lab","pmids":["26083275"],"is_preprint":false},{"year":2021,"finding":"FXa promotes RPE epithelial-mesenchymal transition (EMT) and intraocular fibrosis via PAR1-dependent phospho-activation of p38 MAPK; TGF-β receptor signaling also contributes to FXa-induced fibrosis in vivo.","method":"FXa ELISA in vitreous; in vitro RPE cell EMT assays; in vivo mouse PVR model with FXa injection; Western blotting for p38, α-SMA; pharmacological inhibitors of FXa, thrombin, and TGF-βR","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with defined signaling pathway (PAR1/p38), single lab","pmids":["34283209"],"is_preprint":false},{"year":2011,"finding":"The Ad5-FX-HSPG pathway mediating liver transduction in rodents is conserved in non-human primates (Microcebus murinus); FX-binding-ablated Ad5 vectors target the spleen rather than the liver in these animals.","method":"Quantitative viral genome and gene transfer measurement in non-human primates after IV administration of wild-type vs. FX-binding-ablated Ad5","journal":"Gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo non-human primate study comparing wild-type vs. ablated vectors, single lab","pmids":["21677690"],"is_preprint":false},{"year":1986,"finding":"Human FX is synthesized as a single-chain precursor that is proteolytically cleaved to a dimeric form; it contains a leader (prepro) sequence; the 5'-coding region is 60% homologous to factor IX and 40% homologous to prothrombin, consistent with gene duplication.","method":"cDNA cloning and sequencing from human liver library using synthetic oligonucleotide probes","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct cDNA sequencing establishing primary structure and processing, single study","pmids":["3011603"],"is_preprint":false},{"year":2024,"finding":"Substitution of phenylalanine 174 (F174) in FXa with alanine, isoleucine, or serine reduces binding affinity for direct FXa inhibitors (apixaban, rivaroxaban, edoxaban) and also partially reduces inhibition by TFPI, enabling these variants to restore thrombin generation in inhibitor-containing plasma.","method":"Site-directed mutagenesis; stable expression in HEK293; thrombin generation assays; molecular dynamics simulations for binding affinity; testing in patient plasma","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional assays and computational validation, single lab","pmids":["38729577"],"is_preprint":false},{"year":2018,"finding":"FX recruits macrophages and promotes M2 polarization in GBM by binding ERK1/2 (inhibiting p-ERK1/2 in tumor cells) and increasing p-ERK1/2 and p-AKT phosphorylation in macrophages; FX expression is regulated by miR-338-3p and lncRNA CASC2c.","method":"Chemotaxis assays; macrophage polarization assays; co-immunoprecipitation/binding for ERK1/2; ERK/AKT phosphorylation western blots; miRNA overexpression/knockdown","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic detail relies on co-IP and phosphorylation assays without rigorous controls for specificity of FX-ERK1/2 interaction","pmids":["30034397"],"is_preprint":false},{"year":2025,"finding":"Glioblastoma cells express and secrete catalytically active FX (including a C-terminal truncated alternatively spliced form); secreted FX is active in promoting thrombin generation and is upregulated by LPS stimulation or oxygen/glucose starvation.","method":"RT-PCR and Sanger/amplicon sequencing of F10 isoforms; Western blotting; chromogenic FX activity assay; thrombin generation assay on conditioned medium","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzymatic activity measurements and isoform sequencing in cell lines and patient tissue, single lab","pmids":["40149552"],"is_preprint":false}],"current_model":"Coagulation factor X (FX) is a vitamin K-dependent serine protease zymogen that, upon activation to FXa by intrinsic (FIXa/FVIIIa) or extrinsic (FVIIa/TF) tenase complexes on phosphatidylserine-containing membranes (engaging a single PS-specific Gla domain binding site), generates thrombin as part of the prothrombinase complex; beyond hemostasis, FXa signals through protease-activated receptors (PAR1/PAR2) to drive tumor immune evasion, macrophage M2 polarization, mesangial cell proliferation, and epithelial-mesenchymal transition, while extravascular FX produced by myeloid cells (monocytes, macrophages, PMN-MDSCs) acts in the tumor microenvironment to suppress antitumor immunity via PAR2/ERK1/2 signaling; additionally, FX is exploited by adenovirus type 5, which binds FX via its hexon protein to shield itself from complement-mediated neutralization and to target heparan sulfate proteoglycans for liver transduction, and FX can be inactivated by bacterial proteases (CcDPP7 via N-terminal cleavage) or activated by snake venom and bacterial cysteine proteinases."},"narrative":{"mechanistic_narrative":"Coagulation factor X (F10) is a vitamin K-dependent serine protease zymogen synthesized as a single-chain precursor with a prepro leader and processed to a dimeric form, with a coding sequence homologous to factor IX and prothrombin consistent with origin by gene duplication [PMID:3011603]; it is essential for hemostasis, as its loss in mice causes partial embryonic lethality and fatal neonatal intraabdominal hemorrhage [PMID:10739370]. Membrane engagement is mediated by its Gla domain, which binds a single phosphatidylserine molecule per domain while remaining membrane contacts are satisfied by phosphatidylethanolamine [PMID:34894064]. Beyond clotting, the activated protease FXa functions as a signaling molecule: it drives mesangial cell mitogenesis through a protease-activated receptor with calcium mobilization, JNK/tyrosine kinase activation and PDGF induction [PMID:11316847], promotes retinal pigment epithelial epithelial-mesenchymal transition and fibrosis via PAR1/p38 MAPK [PMID:34283209], and in tumors promotes androgen-independent prostate growth through PAR2/ERK1/2 signaling [PMID:39303726]. Extravascular F10 produced by myeloid cells—monocytes, macrophages, and PMN-MDSCs whose expression is enhanced by CD84 ligation—reprograms tumor-associated macrophages through PAR2 to drive immune evasion [PMID:31541031, PMID:39303726]. F10 is regulated transcriptionally by a TATA-less promoter bound by NF-Y, HNF-4 and GATA-4 [PMID:11154110], and its carboxyl-terminal region downstream of K467 is dispensable for secretion and procoagulant activity, unlike the homologous regions of related zymogens [PMID:26083275]. F10 is also a key host factor exploited by adenovirus type 5, which binds the viral hexon protein to shield the virus from IgM/classical-complement neutralization and to bridge it to heparan sulfate proteoglycans for liver transduction [PMID:23524342, PMID:20949078]. Several pathogen proteases target FX directly: Porphyromonas gingivalis gingipain-R cysteine proteinases activate it [PMID:9188512], whereas the Capnocytophaga canimorsus dipeptidyl peptidase CcDPP7 inactivates it by N-terminal cleavage, prolonging clotting in vivo [PMID:28029716].","teleology":[{"year":1986,"claim":"Establishing the primary structure showed FX is a single-chain precursor processed to a dimeric protease and revealed its evolutionary relationship to factor IX and prothrombin.","evidence":"cDNA cloning and sequencing from a human liver library","pmids":["3011603"],"confidence":"Medium","gaps":["Does not define functional domain boundaries","No experimental processing kinetics"]},{"year":1997,"claim":"Demonstrated that a bacterial cysteine proteinase can directly activate FX, broadening activators beyond the physiological tenase complexes.","evidence":"In vitro enzyme kinetics and clotting assays with P. gingivalis gingipain-Rs and purified FX","pmids":["9188512"],"confidence":"High","gaps":["In vivo relevance to periodontal coagulopathy not established","Cleavage site not mapped here"]},{"year":1998,"claim":"Mapped a snake venom protein's binding to the FX Gla domain, identifying residues 1-44 and the Gla C-terminus as critical for folding and binding.","evidence":"Protein sequencing, Gla-peptide solid-phase binding inhibition, Ca2+ binding measurements, 3D modeling","pmids":["9860851"],"confidence":"Medium","gaps":["No co-crystal structure","Physiological consequence of Gla-domain sequestration in vivo not addressed"]},{"year":2000,"claim":"Genetic knockout established FX as non-redundantly essential for both embryonic and postnatal hemostasis.","evidence":"Targeted gene replacement knockout mice with developmental phenotyping","pmids":["10739370"],"confidence":"High","gaps":["Cause of partial embryonic lethality versus neonatal bleeding not molecularly dissected","No conditional/tissue-specific resolution"]},{"year":2000,"claim":"Defined the transcriptional control of F10, identifying NF-Y as the dominant activator of the TATA-less promoter.","evidence":"DNase I footprinting, EMSA, and reporter assays in HepG2 cells","pmids":["11154110"],"confidence":"Medium","gaps":["Mapped in murine promoter/hepatic context only","Does not address extravascular/myeloid expression control"]},{"year":2001,"claim":"Showed FXa is a mitogen acting through a protease-activated receptor (not EPR-1), establishing a non-hemostatic signaling role in proliferative kidney disease.","evidence":"DNA synthesis, signaling inhibitor panel, and RT-PCR in cultured human mesangial cells","pmids":["11316847"],"confidence":"Medium","gaps":["Specific PAR subtype not identified","In vivo glomerular relevance not tested"]},{"year":2010,"claim":"Defined the mechanism of FX-mediated adenovirus liver targeting, showing the Ad5:FX complex bridges to heparan sulfate proteoglycans with integrin requirement for internalization.","evidence":"Enzymatic HS removal, sulfated-heparin competition, integrin-mutant vectors, in vivo liver assays","pmids":["20949078"],"confidence":"High","gaps":["Hexon binding interface not structurally resolved here","Quantitative contribution of distinct HSPGs unresolved"]},{"year":2011,"claim":"Demonstrated that the Ad5-FX-HSPG liver-targeting pathway is conserved in non-human primates, supporting translational relevance.","evidence":"Quantitative biodistribution of wild-type vs FX-binding-ablated Ad5 in Microcebus murinus","pmids":["21677690"],"confidence":"Medium","gaps":["Single species/single lab","Does not address human in vivo behavior"]},{"year":2012,"claim":"Established that virus-bound FX, when mislocalized into macrophages, triggers a defined TLR4/MyD88/TRIF/TRAF6/NF-κB innate immune program.","evidence":"Interaction-ablating mutagenesis with genome-wide transcriptional profiling in vivo","pmids":["23019612"],"confidence":"High","gaps":["Intracellular FX sensor not identified","Does not address whether endogenous FX triggers similar sensing"]},{"year":2013,"claim":"Resolved the protective function of FX binding, showing it shields adenovirus from IgM and classical-complement neutralization to enable liver transduction.","evidence":"Serum neutralization assays with FX blocking and in vivo transduction in antibody-, C1q-, and C4-deficient mice","pmids":["23524342"],"confidence":"High","gaps":["Does not extend to alternative complement pathway","Human serum context not fully resolved"]},{"year":2015,"claim":"Showed the FX C-terminal region (downstream of K467) is dispensable for secretion and activity, distinguishing FX from homologous zymogens.","evidence":"Truncated and chimeric recombinant FX variants across multiple cell lines with functional assays","pmids":["26083275"],"confidence":"Medium","gaps":["Functional role of the C-terminus, if any, undefined","No in vivo correlate"]},{"year":2017,"claim":"Identified the structural basis of PS-specific membrane recognition by the FX Gla domain through simulation.","evidence":"Molecular dynamics simulations with highly mobile membrane mimetic","pmids":["28782177"],"confidence":"Low","gaps":["Computational only, no mutagenesis or biophysical validation of the identified sites","Predicted binding residues not experimentally confirmed"]},{"year":2017,"claim":"Demonstrated a bacterial protease that inactivates FX, defining a mechanism of pathogen-induced anticoagulation.","evidence":"Gene mutagenesis, purified CcDPP7 biochemistry, N-terminal sequencing, and in vivo bleeding time","pmids":["28029716"],"confidence":"High","gaps":["Clinical relevance in C. canimorsus infection not established","Effect on FX signaling functions untested"]},{"year":2018,"claim":"Proposed that FX recruits and M2-polarizes macrophages in glioblastoma via direct ERK1/2 binding under miRNA/lncRNA control.","evidence":"Chemotaxis, polarization, co-IP for ERK1/2, phosphorylation blots, miRNA modulation","pmids":["30034397"],"confidence":"Low","gaps":["FX-ERK1/2 interaction lacks rigorous specificity controls","Direct binding versus indirect signaling not distinguished"]},{"year":2019,"claim":"Established myeloid cells as a critical extravascular FX source and FXa-PAR2 signaling as a driver of tumor immune evasion.","evidence":"Myeloid-specific conditional FX knockout plus rivaroxaban across multiple mouse cancer models","pmids":["31541031"],"confidence":"High","gaps":["Receptor downstream effectors in macrophages incompletely mapped","Human tumor translation not established"]},{"year":2021,"claim":"Quantified single-site PS specificity of the Gla domain, refining the membrane-binding model.","evidence":"Surface plasmon resonance with defined-composition Nanodiscs","pmids":["34894064"],"confidence":"Medium","gaps":["Structural identity of the single PS site not directly mapped","Implications for tenase/prothrombinase assembly not tested"]},{"year":2021,"claim":"Extended FXa signaling to ocular fibrosis through a PAR1/p38 MAPK and TGF-β-cooperative pathway.","evidence":"RPE EMT assays, in vivo PVR model, and inhibitor panels for FXa/thrombin/TGF-βR","pmids":["34283209"],"confidence":"Medium","gaps":["Relative contribution of PAR1 vs TGF-βR not quantified","Source of intraocular FX not defined"]},{"year":2024,"claim":"Defined PMN-MDSCs as an extrahepatic FX source driving prostate cancer growth via PAR2/ERK1/2, with CD84 ligation enhancing F10 expression.","evidence":"scRNA-seq, genetic/pharmacological FXa inhibition, ERK1/2 assays, CD84 ligation in mouse CRPC models","pmids":["39303726"],"confidence":"High","gaps":["Mechanism linking CD84 to F10 transcription unresolved","Human CRPC validation limited"]},{"year":2024,"claim":"Identified an FXa residue (F174) governing direct-inhibitor and TFPI sensitivity, informing engineered variants that bypass anticoagulants.","evidence":"Site-directed mutagenesis, thrombin generation in patient plasma, and MD simulation","pmids":["38729577"],"confidence":"Medium","gaps":["In vivo efficacy and safety untested","Structural mechanism of altered TFPI binding not resolved"]},{"year":2025,"claim":"Showed glioblastoma cells autonomously express and secrete catalytically active FX, including a C-terminal-truncated splice form, inducible by inflammatory and metabolic stress.","evidence":"Isoform sequencing, chromogenic activity, and thrombin generation on conditioned medium","pmids":["40149552"],"confidence":"Medium","gaps":["Functional role of the truncated isoform unclear","Link to tumor coagulopathy in patients not established"]},{"year":null,"claim":"How extravascular/tumor-derived FX is activated, which PAR subtype dominates in each tissue context, and the structural basis of FX-mediated host signaling versus hemostatic activation remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified structural model linking Gla-domain membrane binding to PAR signaling","Tissue-specific FX activator(s) in tumors unidentified","Mechanism connecting myeloid F10 expression control to immune evasion incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,7,10,19]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[5,19]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8,9]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4,7,14]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[11,13,19]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[9,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3,4]}],"complexes":[],"partners":["PAR2","PAR1","ERK1","ERK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P00742","full_name":"Coagulation factor X","aliases":["Stuart factor","Stuart-Prower factor"],"length_aa":488,"mass_kda":54.7,"function":"Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting (PubMed:22409427, PubMed:39880037). Factor Xa activates pro-inflammatory signaling pathways in a protease-activated receptor (PAR)-dependent manner (PubMed:24041930, PubMed:30568593, PubMed:34831181, PubMed:18202198). Up-regulates expression of protease-activated receptors (PARs) F2R, F2RL1 and F2RL2 in dermal microvascular endothelial cells (PubMed:35738824). Triggers the production of pro-inflammatory cytokines, such as MCP-1/CCL2 and IL6, in cardiac fibroblasts and umbilical vein endothelial cells in PAR-1/F2R-dependent manner (PubMed:30568593, PubMed:34831181). Triggers the production of pro-inflammatory cytokines, such as MCP-1/CCL2, IL6, TNF/TNF, IL-1beta/IL1B, IL8/CXCL8 and IL18, in endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824, PubMed:9780208). Induces expression of adhesion molecules, such as ICAM1, VCAM1 and SELE, in endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824, PubMed:9780208). Increases expression of phosphorylated ERK1/2 in dermal microvascular endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824). Triggers activation of the transcription factor NF-kappa-B in dermal microvascular endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824). Activates pro-inflammatory and pro-fibrotic responses in dermal fibroblasts and enhances wound healing probably via PAR-2/F2RL1-dependent mechanism (PubMed:18202198). Activates barrier protective signaling responses in endothelial cells in PAR-2/F2RL1-dependent manner; the activity depends on the cleavage of PAR-2/F2RL1 by factor Xa (PubMed:22409427). Up-regulates expression of plasminogen activator inhibitor 1 (SERPINE1) in atrial tissues (PubMed:24041930)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P00742/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/F10","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/F10","total_profiled":1310},"omim":[{"mim_id":"621535","title":"SPINOCEREBELLAR ATAXIA 52; SCA52","url":"https://www.omim.org/entry/621535"},{"mim_id":"621295","title":"CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY 1; CARASIL1","url":"https://www.omim.org/entry/621295"},{"mim_id":"620793","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 29; LGMDR29","url":"https://www.omim.org/entry/620793"},{"mim_id":"619844","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH OR WITHOUT PERIPHERAL NEUROPATHY; IDDPN","url":"https://www.omim.org/entry/619844"},{"mim_id":"617362","title":"DEAH-BOX HELICASE 37; DHX37","url":"https://www.omim.org/entry/617362"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":149.7}],"url":"https://www.proteinatlas.org/search/F10"},"hgnc":{"alias_symbol":["fX"],"prev_symbol":[]},"alphafold":{"accession":"P00742","domains":[{"cath_id":"2.10.25.10","chopping":"131-165","consensus_level":"high","plddt":92.0294,"start":131,"end":165},{"cath_id":"2.40.10.10","chopping":"238-327","consensus_level":"medium","plddt":93.7857,"start":238,"end":327},{"cath_id":"2.40.10.10","chopping":"345-459","consensus_level":"medium","plddt":88.4886,"start":345,"end":459}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P00742","model_url":"https://alphafold.ebi.ac.uk/files/AF-P00742-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P00742-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=F10","jax_strain_url":"https://www.jax.org/strain/search?query=F10"},"sequence":{"accession":"P00742","fasta_url":"https://rest.uniprot.org/uniprotkb/P00742.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P00742/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P00742"}},"corpus_meta":[{"pmid":"31541031","id":"PMC_31541031","title":"Myeloid cell-synthesized coagulation factor X dampens antitumor immunity.","date":"2019","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31541031","citation_count":128,"is_preprint":false},{"pmid":"23524342","id":"PMC_23524342","title":"Coagulation factor X shields adenovirus type 5 from attack by natural antibodies and complement.","date":"2013","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23524342","citation_count":127,"is_preprint":false},{"pmid":"23019612","id":"PMC_23019612","title":"Coagulation factor X activates innate immunity to human species C adenovirus.","date":"2012","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23019612","citation_count":126,"is_preprint":false},{"pmid":"10739370","id":"PMC_10739370","title":"Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice.","date":"2000","source":"Thrombosis and 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Bio","url":"https://pubmed.ncbi.nlm.nih.gov/41111485","citation_count":0,"is_preprint":false},{"pmid":"40288296","id":"PMC_40288296","title":"A mathematical model for activated platelet-dependent activation of coagulation factor X by factor IXa.","date":"2025","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40288296","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"sonnet_model":"claude-sonnet-4-6","sonnet_input_tokens":20449,"sonnet_output_tokens":4806,"sonnet_usd":0.1334,"sonnet_elapsed_seconds":91.1,"stage1_stop_reason":"end_turn"},"stage2":{"opus_model":"claude-opus-4-8","opus_input_tokens":12896,"opus_output_tokens":5241,"opus_usd":0.1955,"opus_elapsed_seconds":58.6,"stage2_stop_reason":"end_turn"},"total_usd":0.3289},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"Myeloid cell-derived FXa promotes tumor immune evasion by signaling through protease-activated receptor 2 (PAR2), reprogramming tumor-associated macrophages; monocytes and macrophages were identified as crucial extravascular sources of FX in the tumor microenvironment.\",\n      \"method\": \"Conditional knockout mice lacking myeloid cell FX production; pharmacological inhibition with rivaroxaban; mechanistic signaling studies in tumor models\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (conditional KO) plus pharmacological intervention with defined cellular phenotype, replicated across multiple mouse cancer models\",\n      \"pmids\": [\"31541031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FX binding to Ad5 hexon protein protects adenovirus from neutralization by natural IgM and the classical complement pathway, enabling liver transduction; FX was not required for liver transduction in mice lacking antibodies, C1q, or C4.\",\n      \"method\": \"In vitro serum neutralization assays with FX-blocking; in vivo liver transduction in antibody-deficient, C1q-deficient, and C4-deficient mice\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic mouse models (antibody-deficient, C1q-KO, C4-KO) with consistent in vitro and in vivo results\",\n      \"pmids\": [\"23524342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The HAdv-FX complex activates a distinct NF-κB-dependent innate immune gene network downstream of TLR4/MyD88/TRIF/TRAF6 signaling; misplacement of FX from blood into intracellular macrophage compartments upon virus entry triggers this innate immune response.\",\n      \"method\": \"Structure-guided mutagenesis to ablate HAdv-FX complex formation; in vivo genome-wide transcriptional profiling comparing wild-type vs. FX-binding-ablated virus\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis to ablate specific interaction combined with genome-wide transcriptional profiling and defined signaling pathway\",\n      \"pmids\": [\"23019612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ad5 binds FX via the hexon protein; the Ad5:FX complex targets heparan sulfate proteoglycans (HSPGs) on cell surfaces, with O-linked sulfate groups critical for binding; integrin αv engagement is required for efficient post-attachment internalization.\",\n      \"method\": \"Enzymatic removal of HS side chains; competition with sulfated heparins; in vivo liver accumulation assays; Ad5 vectors with CAR- and αv-integrin binding mutations\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (enzymatic, genetic, in vivo) consistently demonstrating HSPG-dependent FX-mediated cell entry\",\n      \"pmids\": [\"20949078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FXa promotes androgen-independent prostate tumor growth by activating PAR2 and phosphorylation of ERK1/2 in tumor cells; immunosuppressive PMN-MDSCs are a key extrahepatic source of FX in the prostate TME; CD84 ligation on PMN-MDSCs enhances F10 expression.\",\n      \"method\": \"scRNA-seq; genetic and pharmacological inhibition of FXa; ERK1/2 phosphorylation assays; CD84 ligation experiments in mouse CRPC models\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic inhibition plus pharmacological inhibition with defined downstream signaling (PAR2/ERK1/2), replicated across multiple approaches\",\n      \"pmids\": [\"39303726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Arginine-specific cysteine proteinases (gingipain-Rs) from Porphyromonas gingivalis directly activate human factor X in a dose- and time-dependent manner with Km below normal plasma FX concentration; the 95-kDa form is 5-fold more efficient than the 50-kDa form and is potentiated by phospholipids.\",\n      \"method\": \"In vitro enzyme kinetics assays; clotting time assays in factor-deficient plasmas; reconstitution with purified FX\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with kinetic characterization (Km determination) in a single focused study\",\n      \"pmids\": [\"9188512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"X-bp from Deinagkistrodon acutus venom is a heterodimeric C-type lectin-like protein that binds the Gla domain of factor X (residues 1-44); the C-terminal region of the Gla domain peptide is critical for correct folding and binding; X-bp binds two Ca2+ ions per molecule.\",\n      \"method\": \"Protein isolation; complete amino acid sequencing; solid-phase binding inhibition assays with Gla domain peptide fragments; Ca2+ binding measurements; 3D model construction\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays with domain-deletion peptides and structural modeling, single lab\",\n      \"pmids\": [\"9860851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"FXa acts as a mitogen for human mesangial cells via proteolytic activity, inducing calcium mobilization, JNK activation, tyrosine kinase signaling, and PDGF A/B chain upregulation through a protease-activated receptor (not EPR-1); PKC activation is partially involved.\",\n      \"method\": \"DNA synthesis assays; serine protease inhibitor (leupeptin); neutralizing anti-PDGF antibody; tyrosine kinase inhibitors (genistein, herbimycin A); PKC downregulation; RT-PCR for EPR-1\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological interventions dissecting signaling pathway in cultured human cells, single lab\",\n      \"pmids\": [\"11316847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The Gla domain of FX mediates PS-specific membrane binding; molecular dynamics simulations identified PS-specific binding sites in FX-GLA and showed convergent membrane-bound configuration across 14 independent simulations.\",\n      \"method\": \"Molecular dynamics simulations using highly mobile membrane mimetic (HMMM); conventional membrane simulations\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — computational simulation without experimental mutagenesis or direct biophysical validation of identified binding sites\",\n      \"pmids\": [\"28782177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Factor X binds exactly one PS molecule per Gla domain when PE is present in excess (stoichiometry ~1.05 PS per FX molecule), identifying a single truly PS-specific binding site per Gla domain while remaining membrane interactions are satisfied by PE.\",\n      \"method\": \"Surface plasmon resonance with Nanodiscs of defined phospholipid composition\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative biophysical assay (SPR with Nanodiscs) measuring stoichiometry directly, single lab\",\n      \"pmids\": [\"34894064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The C. canimorsus protease CcDPP7 (type 7 dipeptidyl peptidase, S46 serine protease family) inactivates human FX by N-terminal cleavage of both heavy and light chains, inhibiting thrombin generation and prolonging clotting times in vivo.\",\n      \"method\": \"Mutagenesis of Cc5 genes; protein purification; Edman degradation for N-terminal cleavage site; clotting assays; in vivo tail bleeding time in mice\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — gene-specific mutagenesis, purified protease biochemistry, N-terminal sequencing, and in vivo validation in a single focused study\",\n      \"pmids\": [\"28029716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"FX deficiency causes partial embryonic lethality (~1/3 of FX-/- embryos die ~E11.5-12.5) and fatal neonatal bleeding (90% die within 5 days from intraabdominal hemorrhage), establishing FX as essential for embryonic and postnatal hemostasis.\",\n      \"method\": \"Targeted gene replacement (knockout mice); genotyping of offspring; histological analysis\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complete loss-of-function genetic model with precise phenotypic characterization at multiple developmental stages\",\n      \"pmids\": [\"10739370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The murine FX promoter is TATA-less with two transcription start sites; NF-Y, HNF-4, and GATA-4 bind the proximal promoter and regulate FX expression, with NF-Y being most critical (ablation reduces activity to 10% of wild-type).\",\n      \"method\": \"DNase I footprinting; EMSA; transient transfection in HepG2 cells; promoter deletion analysis\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary methods (footprinting, EMSA, functional reporter assays) in a single lab study\",\n      \"pmids\": [\"11154110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The FX carboxyl-terminal region (downstream of K467) is not essential for secretion or procoagulant activity; deletion of up to 21 carboxyl-terminal residues does not affect secretion or amidolytic activity, in contrast to the homologous regions in FVII, FIX, and PC.\",\n      \"method\": \"Recombinant expression of progressively truncated FX variants in HEK293, HepG2, and BHK21 cells; ELISA; coagulant and amidolytic assays; chimeric FX-FVII constructs\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell systems and orthogonal functional assays, single lab\",\n      \"pmids\": [\"26083275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FXa promotes RPE epithelial-mesenchymal transition (EMT) and intraocular fibrosis via PAR1-dependent phospho-activation of p38 MAPK; TGF-β receptor signaling also contributes to FXa-induced fibrosis in vivo.\",\n      \"method\": \"FXa ELISA in vitreous; in vitro RPE cell EMT assays; in vivo mouse PVR model with FXa injection; Western blotting for p38, α-SMA; pharmacological inhibitors of FXa, thrombin, and TGF-βR\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with defined signaling pathway (PAR1/p38), single lab\",\n      \"pmids\": [\"34283209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Ad5-FX-HSPG pathway mediating liver transduction in rodents is conserved in non-human primates (Microcebus murinus); FX-binding-ablated Ad5 vectors target the spleen rather than the liver in these animals.\",\n      \"method\": \"Quantitative viral genome and gene transfer measurement in non-human primates after IV administration of wild-type vs. FX-binding-ablated Ad5\",\n      \"journal\": \"Gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo non-human primate study comparing wild-type vs. ablated vectors, single lab\",\n      \"pmids\": [\"21677690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Human FX is synthesized as a single-chain precursor that is proteolytically cleaved to a dimeric form; it contains a leader (prepro) sequence; the 5'-coding region is 60% homologous to factor IX and 40% homologous to prothrombin, consistent with gene duplication.\",\n      \"method\": \"cDNA cloning and sequencing from human liver library using synthetic oligonucleotide probes\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct cDNA sequencing establishing primary structure and processing, single study\",\n      \"pmids\": [\"3011603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Substitution of phenylalanine 174 (F174) in FXa with alanine, isoleucine, or serine reduces binding affinity for direct FXa inhibitors (apixaban, rivaroxaban, edoxaban) and also partially reduces inhibition by TFPI, enabling these variants to restore thrombin generation in inhibitor-containing plasma.\",\n      \"method\": \"Site-directed mutagenesis; stable expression in HEK293; thrombin generation assays; molecular dynamics simulations for binding affinity; testing in patient plasma\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional assays and computational validation, single lab\",\n      \"pmids\": [\"38729577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FX recruits macrophages and promotes M2 polarization in GBM by binding ERK1/2 (inhibiting p-ERK1/2 in tumor cells) and increasing p-ERK1/2 and p-AKT phosphorylation in macrophages; FX expression is regulated by miR-338-3p and lncRNA CASC2c.\",\n      \"method\": \"Chemotaxis assays; macrophage polarization assays; co-immunoprecipitation/binding for ERK1/2; ERK/AKT phosphorylation western blots; miRNA overexpression/knockdown\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic detail relies on co-IP and phosphorylation assays without rigorous controls for specificity of FX-ERK1/2 interaction\",\n      \"pmids\": [\"30034397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Glioblastoma cells express and secrete catalytically active FX (including a C-terminal truncated alternatively spliced form); secreted FX is active in promoting thrombin generation and is upregulated by LPS stimulation or oxygen/glucose starvation.\",\n      \"method\": \"RT-PCR and Sanger/amplicon sequencing of F10 isoforms; Western blotting; chromogenic FX activity assay; thrombin generation assay on conditioned medium\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzymatic activity measurements and isoform sequencing in cell lines and patient tissue, single lab\",\n      \"pmids\": [\"40149552\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Coagulation factor X (FX) is a vitamin K-dependent serine protease zymogen that, upon activation to FXa by intrinsic (FIXa/FVIIIa) or extrinsic (FVIIa/TF) tenase complexes on phosphatidylserine-containing membranes (engaging a single PS-specific Gla domain binding site), generates thrombin as part of the prothrombinase complex; beyond hemostasis, FXa signals through protease-activated receptors (PAR1/PAR2) to drive tumor immune evasion, macrophage M2 polarization, mesangial cell proliferation, and epithelial-mesenchymal transition, while extravascular FX produced by myeloid cells (monocytes, macrophages, PMN-MDSCs) acts in the tumor microenvironment to suppress antitumor immunity via PAR2/ERK1/2 signaling; additionally, FX is exploited by adenovirus type 5, which binds FX via its hexon protein to shield itself from complement-mediated neutralization and to target heparan sulfate proteoglycans for liver transduction, and FX can be inactivated by bacterial proteases (CcDPP7 via N-terminal cleavage) or activated by snake venom and bacterial cysteine proteinases.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Coagulation factor X (F10) is a vitamin K-dependent serine protease zymogen synthesized as a single-chain precursor with a prepro leader and processed to a dimeric form, with a coding sequence homologous to factor IX and prothrombin consistent with origin by gene duplication [#16]; it is essential for hemostasis, as its loss in mice causes partial embryonic lethality and fatal neonatal intraabdominal hemorrhage [#11]. Membrane engagement is mediated by its Gla domain, which binds a single phosphatidylserine molecule per domain while remaining membrane contacts are satisfied by phosphatidylethanolamine [#9]. Beyond clotting, the activated protease FXa functions as a signaling molecule: it drives mesangial cell mitogenesis through a protease-activated receptor with calcium mobilization, JNK/tyrosine kinase activation and PDGF induction [#7], promotes retinal pigment epithelial epithelial-mesenchymal transition and fibrosis via PAR1/p38 MAPK [#14], and in tumors promotes androgen-independent prostate growth through PAR2/ERK1/2 signaling [#4]. Extravascular F10 produced by myeloid cells—monocytes, macrophages, and PMN-MDSCs whose expression is enhanced by CD84 ligation—reprograms tumor-associated macrophages through PAR2 to drive immune evasion [#0, #4]. F10 is regulated transcriptionally by a TATA-less promoter bound by NF-Y, HNF-4 and GATA-4 [#12], and its carboxyl-terminal region downstream of K467 is dispensable for secretion and procoagulant activity, unlike the homologous regions of related zymogens [#13]. F10 is also a key host factor exploited by adenovirus type 5, which binds the viral hexon protein to shield the virus from IgM/classical-complement neutralization and to bridge it to heparan sulfate proteoglycans for liver transduction [#1, #3]. Several pathogen proteases target FX directly: Porphyromonas gingivalis gingipain-R cysteine proteinases activate it [#5], whereas the Capnocytophaga canimorsus dipeptidyl peptidase CcDPP7 inactivates it by N-terminal cleavage, prolonging clotting in vivo [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Establishing the primary structure showed FX is a single-chain precursor processed to a dimeric protease and revealed its evolutionary relationship to factor IX and prothrombin.\",\n      \"evidence\": \"cDNA cloning and sequencing from a human liver library\",\n      \"pmids\": [\"3011603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define functional domain boundaries\", \"No experimental processing kinetics\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated that a bacterial cysteine proteinase can directly activate FX, broadening activators beyond the physiological tenase complexes.\",\n      \"evidence\": \"In vitro enzyme kinetics and clotting assays with P. gingivalis gingipain-Rs and purified FX\",\n      \"pmids\": [\"9188512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance to periodontal coagulopathy not established\", \"Cleavage site not mapped here\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapped a snake venom protein's binding to the FX Gla domain, identifying residues 1-44 and the Gla C-terminus as critical for folding and binding.\",\n      \"evidence\": \"Protein sequencing, Gla-peptide solid-phase binding inhibition, Ca2+ binding measurements, 3D modeling\",\n      \"pmids\": [\"9860851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-crystal structure\", \"Physiological consequence of Gla-domain sequestration in vivo not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Genetic knockout established FX as non-redundantly essential for both embryonic and postnatal hemostasis.\",\n      \"evidence\": \"Targeted gene replacement knockout mice with developmental phenotyping\",\n      \"pmids\": [\"10739370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cause of partial embryonic lethality versus neonatal bleeding not molecularly dissected\", \"No conditional/tissue-specific resolution\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the transcriptional control of F10, identifying NF-Y as the dominant activator of the TATA-less promoter.\",\n      \"evidence\": \"DNase I footprinting, EMSA, and reporter assays in HepG2 cells\",\n      \"pmids\": [\"11154110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mapped in murine promoter/hepatic context only\", \"Does not address extravascular/myeloid expression control\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed FXa is a mitogen acting through a protease-activated receptor (not EPR-1), establishing a non-hemostatic signaling role in proliferative kidney disease.\",\n      \"evidence\": \"DNA synthesis, signaling inhibitor panel, and RT-PCR in cultured human mesangial cells\",\n      \"pmids\": [\"11316847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific PAR subtype not identified\", \"In vivo glomerular relevance not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the mechanism of FX-mediated adenovirus liver targeting, showing the Ad5:FX complex bridges to heparan sulfate proteoglycans with integrin requirement for internalization.\",\n      \"evidence\": \"Enzymatic HS removal, sulfated-heparin competition, integrin-mutant vectors, in vivo liver assays\",\n      \"pmids\": [\"20949078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hexon binding interface not structurally resolved here\", \"Quantitative contribution of distinct HSPGs unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that the Ad5-FX-HSPG liver-targeting pathway is conserved in non-human primates, supporting translational relevance.\",\n      \"evidence\": \"Quantitative biodistribution of wild-type vs FX-binding-ablated Ad5 in Microcebus murinus\",\n      \"pmids\": [\"21677690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single species/single lab\", \"Does not address human in vivo behavior\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that virus-bound FX, when mislocalized into macrophages, triggers a defined TLR4/MyD88/TRIF/TRAF6/NF-κB innate immune program.\",\n      \"evidence\": \"Interaction-ablating mutagenesis with genome-wide transcriptional profiling in vivo\",\n      \"pmids\": [\"23019612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular FX sensor not identified\", \"Does not address whether endogenous FX triggers similar sensing\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the protective function of FX binding, showing it shields adenovirus from IgM and classical-complement neutralization to enable liver transduction.\",\n      \"evidence\": \"Serum neutralization assays with FX blocking and in vivo transduction in antibody-, C1q-, and C4-deficient mice\",\n      \"pmids\": [\"23524342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not extend to alternative complement pathway\", \"Human serum context not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed the FX C-terminal region (downstream of K467) is dispensable for secretion and activity, distinguishing FX from homologous zymogens.\",\n      \"evidence\": \"Truncated and chimeric recombinant FX variants across multiple cell lines with functional assays\",\n      \"pmids\": [\"26083275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the C-terminus, if any, undefined\", \"No in vivo correlate\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the structural basis of PS-specific membrane recognition by the FX Gla domain through simulation.\",\n      \"evidence\": \"Molecular dynamics simulations with highly mobile membrane mimetic\",\n      \"pmids\": [\"28782177\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational only, no mutagenesis or biophysical validation of the identified sites\", \"Predicted binding residues not experimentally confirmed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a bacterial protease that inactivates FX, defining a mechanism of pathogen-induced anticoagulation.\",\n      \"evidence\": \"Gene mutagenesis, purified CcDPP7 biochemistry, N-terminal sequencing, and in vivo bleeding time\",\n      \"pmids\": [\"28029716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Clinical relevance in C. canimorsus infection not established\", \"Effect on FX signaling functions untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Proposed that FX recruits and M2-polarizes macrophages in glioblastoma via direct ERK1/2 binding under miRNA/lncRNA control.\",\n      \"evidence\": \"Chemotaxis, polarization, co-IP for ERK1/2, phosphorylation blots, miRNA modulation\",\n      \"pmids\": [\"30034397\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"FX-ERK1/2 interaction lacks rigorous specificity controls\", \"Direct binding versus indirect signaling not distinguished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established myeloid cells as a critical extravascular FX source and FXa-PAR2 signaling as a driver of tumor immune evasion.\",\n      \"evidence\": \"Myeloid-specific conditional FX knockout plus rivaroxaban across multiple mouse cancer models\",\n      \"pmids\": [\"31541031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor downstream effectors in macrophages incompletely mapped\", \"Human tumor translation not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Quantified single-site PS specificity of the Gla domain, refining the membrane-binding model.\",\n      \"evidence\": \"Surface plasmon resonance with defined-composition Nanodiscs\",\n      \"pmids\": [\"34894064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural identity of the single PS site not directly mapped\", \"Implications for tenase/prothrombinase assembly not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended FXa signaling to ocular fibrosis through a PAR1/p38 MAPK and TGF-β-cooperative pathway.\",\n      \"evidence\": \"RPE EMT assays, in vivo PVR model, and inhibitor panels for FXa/thrombin/TGF-βR\",\n      \"pmids\": [\"34283209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of PAR1 vs TGF-βR not quantified\", \"Source of intraocular FX not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined PMN-MDSCs as an extrahepatic FX source driving prostate cancer growth via PAR2/ERK1/2, with CD84 ligation enhancing F10 expression.\",\n      \"evidence\": \"scRNA-seq, genetic/pharmacological FXa inhibition, ERK1/2 assays, CD84 ligation in mouse CRPC models\",\n      \"pmids\": [\"39303726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking CD84 to F10 transcription unresolved\", \"Human CRPC validation limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified an FXa residue (F174) governing direct-inhibitor and TFPI sensitivity, informing engineered variants that bypass anticoagulants.\",\n      \"evidence\": \"Site-directed mutagenesis, thrombin generation in patient plasma, and MD simulation\",\n      \"pmids\": [\"38729577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo efficacy and safety untested\", \"Structural mechanism of altered TFPI binding not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed glioblastoma cells autonomously express and secrete catalytically active FX, including a C-terminal-truncated splice form, inducible by inflammatory and metabolic stress.\",\n      \"evidence\": \"Isoform sequencing, chromogenic activity, and thrombin generation on conditioned medium\",\n      \"pmids\": [\"40149552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the truncated isoform unclear\", \"Link to tumor coagulopathy in patients not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How extravascular/tumor-derived FX is activated, which PAR subtype dominates in each tissue context, and the structural basis of FX-mediated host signaling versus hemostatic activation remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural model linking Gla-domain membrane binding to PAR signaling\", \"Tissue-specific FX activator(s) in tumors unidentified\", \"Mechanism connecting myeloid F10 expression control to immune evasion incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 7, 10, 19]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [5, 19]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4, 7, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [11, 13, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PAR2\", \"PAR1\", \"ERK1\", \"ERK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie"}}