{"gene":"ANXA5","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1989,"finding":"The ANXA5 (endonexin II/ENX2) gene was mapped to human chromosome 4q28-q32 by Southern transfer analysis of human x rodent somatic cell hybrid DNAs and in situ chromosome hybridization, identifying it as a member of the Ca2+-dependent phospholipid-binding annexin gene family.","method":"Somatic cell hybrid panel Southern blot analysis and in situ chromosome hybridization","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal mapping methods in a single study establishing chromosomal localization","pmids":["2534288"],"is_preprint":false},{"year":1990,"finding":"ANXA5 (placental anticoagulant protein-I/PAP-I) protein was localized to the microvilli of placental syncytiotrophoblast cells and their cortical cytoplasm beneath the villi, consistent with its anticoagulant function at the maternal-fetal interface.","method":"Immunocytochemistry (light and electron microscopy)","journal":"Rinsho byori. The Japanese journal of clinical pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization by immunoelectron microscopy, single study","pmids":["2148197"],"is_preprint":false},{"year":1995,"finding":"ANXA5 (CPB-I/calphobindin I) acts as an endogenous inhibitor of protein kinase C; its transcription is markedly suppressed in cervical and endometrial carcinoma cells compared to normal counterparts, as shown by immunohistochemistry, Northern blot, and in situ hybridization.","method":"Immunohistochemistry, Northern blot, in situ hybridization","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal methods confirming transcriptional suppression; protein kinase C inhibition attributed from prior literature cited in abstract","pmids":["7672695"],"is_preprint":false},{"year":2007,"finding":"The M2 haplotype (four consecutive nucleotide substitutions) in the ANXA5 promoter reduces in vitro ANXA5 promoter activity to 37–42% of normal levels, as demonstrated by reporter gene assays, establishing a mechanistic link between this promoter variant and reduced ANXA5 expression associated with recurrent pregnancy loss.","method":"Reporter gene (luciferase/CAT) assay with M2 vs. wild-type promoter constructs","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro promoter activity assay with M2 constructs, replicated across multiple subsequent studies confirming the same functional effect","pmids":["17339269"],"is_preprint":false},{"year":2007,"finding":"Anxa5-expressing (Anxa5-LacZ+) perivascular cells isolated from mouse meningeal vasculature express pericyte markers (NG2, desmin, αSMA, PDGFR-β) and Sca-1, stimulate angiogenesis when co-cultured with endothelial cells (increased PECAM expression), and promote vascularization when grafted onto quail chorioallantoic membranes, demonstrating ANXA5 as a marker of pericyte identity with a functional role in angiogenic support.","method":"Cell isolation using Anxa5-LacZ reporter, co-culture with endothelial cells, in vivo CAM graft assay, immunophenotyping","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro co-culture and in vivo graft assay with functional readouts in a single study","pmids":["17543301"],"is_preprint":false},{"year":2010,"finding":"The M2 allele of ANXA5 in heterozygous placentas results in an average 42% reduction in ANXA5 mRNA levels compared to the normal allele, directly demonstrating allele-specific reduction of ANXA5 expression in the functionally relevant organ.","method":"Allele-specific mRNA quantification in heterozygous placental tissue","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct allele-specific expression analysis in human placental tissue, single lab","pmids":["20805002"],"is_preprint":false},{"year":2014,"finding":"Exogenous AnxA5 reduces plaque macrophage content in advanced atherosclerotic lesions of apoE-/- mice (59–73% reduction) and inhibits monocyte capture, rolling, adhesion, and transmigration on TNF-α-activated endothelial cells in vitro, demonstrating an anti-inflammatory mechanism through interference with monocyte recruitment via binding to phosphatidylserine on the cell surface.","method":"In vivo AnxA5 injection in apoE-/- mice with immunohistochemistry; in vitro flow chamber monocyte adhesion assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro orthogonal methods in a single study, single lab","pmids":["25214012"],"is_preprint":false},{"year":2016,"finding":"Pharmacological concentrations of AnxA5 (1 µM) inhibit wound hemostasis and delay coagulation pathway activation in vitro; this effect requires AnxA5's ability to form 2D arrays on the cell surface, as an AnxA5 mutant that binds phosphatidylserine but cannot form 2D arrays failed to induce bleeding. Endogenous AnxA5 (at physiological levels) is dispensable for wound healing and hemostasis in AnxA5-deficient mice.","method":"AnxA5-deficient mouse wound model, recombinant wild-type and mutant AnxA5 injection, in vitro coagulation assay","journal":"Cells, tissues, organs","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with mutagenesis (2D array-deficient mutant) plus in vivo KO phenotyping, two orthogonal approaches in one study","pmids":["27178140"],"is_preprint":false},{"year":2016,"finding":"Anxa5 knockdown in murine hepatocarcinoma Hca-F cells reduces proliferation, migration, invasion, and lymph node adhesion; mechanistically, Anxa5 mediates these effects specifically via the ERK2/p-ERK2/c-Jun/p-c-Jun(Ser73) pathway and through regulation of E-cadherin levels, not through p38MAPK/c-Jun, Jnk/c-Jun, or AKT/c-Jun pathways.","method":"shRNA knockdown, CCK-8, Boyden transwell, in situ adhesion assay, Western blot, qRT-PCR for pathway components","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple functional readouts and pathway dissection using multiple signaling inhibitors, single lab","pmids":["27697636"],"is_preprint":false},{"year":2018,"finding":"Physiological micromolar Zn2+ stimulates ANXA5 transcription, raising ANXA5 protein expression and surface abundance on BeWo and HUVEC cells, resulting in prolonged coagulation times; Zn2+-fed AnxA5-deficient pregnant mice showed a trend toward increased litter size, demonstrating that zinc can upregulate ANXA5 expression to restore anticoagulant function.","method":"Cell culture transcription assay, flow cytometry for surface ANXA5, coagulation time assay, AnxA5-deficient mouse pregnancy model","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo approaches, single lab, functional coagulation readout","pmids":["29716435"],"is_preprint":false},{"year":2019,"finding":"ANXA5 overexpression in mouse Leydig and Sertoli cells activates the Nrf2/HO-1/NQO1 antioxidant pathway and attenuates DBP-induced oxidative stress; this protective effect operates through increased ERK phosphorylation, as ERK inhibition reverses the ANXA5-mediated Nrf2 pathway activation.","method":"Overexpression in cell culture, DHE staining for ROS, ELISA for MDA/SOD, Western blot for pathway proteins, ERK inhibitor rescue experiment","journal":"Environmental toxicology and pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with inhibitor rescue, multiple biochemical readouts, single lab","pmids":["31404886"],"is_preprint":false},{"year":2019,"finding":"AnxA5 domain specifically recognizes and binds to phosphatidylserine on hypoxia-injured cells; a SDF-1-AnxA5 fusion protein accumulates at infarcted myocardium after peripheral vein injection, attenuates apoptosis, enhances angiogenesis, and improves cardiac function after mouse myocardial infarction, demonstrating ANXA5's PS-targeting function as a delivery anchor for therapeutic cargo.","method":"Receptor competition assay, binding membrane assay, immunofluorescence, mouse myocardial infarction model with fusion protein treatment","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assays and in vivo functional cardiac model, single lab","pmids":["31468674"],"is_preprint":false},{"year":2020,"finding":"miR-506-3p directly binds to ANXA5 mRNA and reduces ANXA5 expression; overexpression of miR-506-3p aggravates DBP-induced testicular oxidative stress in rats by inhibiting the ANXA5/Nrf2/HO-1 signaling pathway, and exogenous recombinant ANXA5 reverses these effects.","method":"miRNA overexpression (agomir), recombinant ANXA5 rescue, Western blot, immunohistochemistry, oxidative stress assays in vivo and in vitro","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA-target interaction with rescue experiment, in vivo and in vitro validation, single lab","pmids":["33354277"],"is_preprint":false},{"year":2020,"finding":"ANXA5 overexpression promotes glucocorticoid (dexamethasone) resistance in B-ALL cells; siRNA-mediated ANXA5 silencing combined with dexamethasone dramatically increases apoptosis and caspase-3/9 cleavage compared to either treatment alone, indicating ANXA5 suppresses caspase-dependent apoptosis to confer glucocorticoid resistance.","method":"siRNA knockdown, flow cytometry apoptosis assay, Western blot for cleaved caspase-3 and -9","journal":"Pediatric hematology and oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined apoptotic readout and pathway component detection, single lab, single study","pmids":["33231128"],"is_preprint":false},{"year":2021,"finding":"In rat pituitary gonadotropes, Anxa5 mRNA is induced by GnRH and rises sequentially after Nr4a3 mRNA peaks at proestrus; the functional relationship between NR4A3 and ANXA5 was established in regulating FSH-beta (Fshb) expression, with GnRH antagonist abolishing Nr4a3 induction, placing ANXA5 downstream of the GnRH/Nr4a3 axis in gonadotropin regulation.","method":"RT-PCR time-course during rat estrous cycle, GnRH antagonist treatment","journal":"The Journal of reproduction and development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mRNA expression timing with pharmacological perturbation, single lab, no direct functional epistasis experiment for ANXA5 specifically","pmids":["33840679"],"is_preprint":false},{"year":2017,"finding":"ANXA5 and TNAP (tissue-nonspecific alkaline phosphatase) are co-incorporated into proteoliposomes mimicking matrix vesicles; AFM imaging revealed that ANXA5 insertion causes minimal surface protrusions (unlike TNAP), and proteoliposomes harboring both proteins show lower affinity for type II collagen fibers than those with AnxA5 alone, demonstrating that AnxA5 modulates membrane structure and collagen-binding properties relevant to biomineralization.","method":"Atomic force microscopy of proteoliposomes, collagen binding assay","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct biophysical reconstitution in membrane mimetics with functional collagen-binding assay, single lab","pmids":["28549727"],"is_preprint":false},{"year":2023,"finding":"FUS (fused in sarcoma) protein directly binds ANXA5 as demonstrated by co-immunoprecipitation; lncRNA MIR4697HG stabilizes FUS, which in turn sustains ANXA5 expression to protect endothelial cells from ox-LDL-induced apoptosis and oxidative stress, placing ANXA5 downstream of the MIR4697HG/FUS axis in atherosclerosis.","method":"RNA pull-down assay (MIR4697HG–FUS), co-immunoprecipitation (FUS–ANXA5), siRNA knockdown rescue experiments, in vivo ApoE-/- mouse atherosclerosis model","journal":"Biochemical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays with functional rescue experiments, single lab","pmids":["38082058"],"is_preprint":false},{"year":2025,"finding":"In healthy skeletal muscle cells, mechanical stress induces upregulation of ANXA5 (and ANXA6), suggesting an adaptive membrane repair response; in DMD patient-derived skeletal muscle cells, this adaptive ANXA5 upregulation is dysregulated, associated with defective membrane resealing capacity demonstrated by shear stress and laser irradiation injury assays.","method":"Shear stress membrane injury assay, laser irradiation assay, Western blot, live-cell imaging of GFP-tagged annexins, immunohistochemistry of DMD patient biopsies","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct membrane repair functional assays in patient-derived cells and biopsies with multiple orthogonal methods; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.09.23.677988"],"is_preprint":true}],"current_model":"ANXA5 is a Ca2+-dependent phospholipid-binding protein (chromosomal locus 4q28-q32) that forms 2D arrays on phosphatidylserine-exposing membranes, thereby inhibiting coagulation and acting as a placental anticoagulant; its promoter M2 haplotype reduces transcription by ~40–60%, lowering ANXA5 surface coverage and increasing thrombotic risk at the fetal-maternal interface; at the cellular level, ANXA5 suppresses caspase-dependent apoptosis, participates in membrane repair responses to mechanical stress, activates the ERK/Nrf2 antioxidant pathway, and influences cancer cell migration and invasion via ERK2/c-Jun/E-cadherin signaling, while FUS directly binds and stabilizes ANXA5 protein in endothelial cells."},"narrative":{"mechanistic_narrative":"ANXA5 is a Ca2+-dependent phospholipid-binding annexin that recognizes surface-exposed phosphatidylserine and assembles into ordered two-dimensional arrays on membranes, a property central to its anticoagulant function at the maternal-fetal interface, where it localizes to placental syncytiotrophoblast microvilli [PMID:2534288, PMID:2148197]. The 2D-array activity is mechanistically required for its anticoagulant action: recombinant ANXA5 that binds phosphatidylserine but cannot form arrays fails to delay coagulation [PMID:27178140]. Its expression is set by transcriptional and post-transcriptional control — the M2 promoter haplotype reduces promoter activity to ~37–42% and lowers allele-specific mRNA in heterozygous placenta, linking reduced ANXA5 to recurrent pregnancy loss, while zinc upregulates and miR-506-3p directly represses ANXA5 [PMID:17339269, PMID:20805002, PMID:29716435, PMID:33354277]. Through its phosphatidylserine-targeting and cytoprotective activities, ANXA5 suppresses caspase-dependent apoptosis to confer glucocorticoid resistance in B-ALL cells and activates the ERK/Nrf2/HO-1 antioxidant pathway [PMID:33231128, PMID:31404886, PMID:33354277]. ANXA5 also drives cancer cell proliferation, migration, and invasion via ERK2/c-Jun/E-cadherin signaling, modulates membrane structure and collagen binding in biomineralizing matrix-vesicle mimetics, and participates in mechanical-stress membrane repair [PMID:27697636, PMID:28549727]. In endothelial cells, FUS directly binds ANXA5 and sustains its expression downstream of a MIR4697HG/FUS axis to protect against ox-LDL-induced apoptosis [PMID:38082058].","teleology":[{"year":1989,"claim":"Establishing ANXA5's chromosomal locus and family membership defined it as a Ca2+-dependent phospholipid-binding annexin, framing all subsequent membrane-based mechanistic work.","evidence":"Somatic cell hybrid Southern blot and in situ chromosome hybridization mapping to 4q28-q32","pmids":["2534288"],"confidence":"Medium","gaps":["Mapping alone establishes no biochemical activity","No functional data in this study"]},{"year":1990,"claim":"Localizing ANXA5 to placental syncytiotrophoblast microvilli grounded its proposed anticoagulant role at the maternal-fetal interface in a specific cellular compartment.","evidence":"Immunoelectron microscopy of placental tissue","pmids":["2148197"],"confidence":"Medium","gaps":["Localization does not demonstrate the anticoagulant mechanism directly","Single study"]},{"year":2007,"claim":"Reporter assays showed the M2 promoter haplotype reduces ANXA5 transcription, providing a mechanistic link between a common variant and reduced expression associated with recurrent pregnancy loss.","evidence":"Luciferase/CAT reporter assays comparing M2 vs wild-type promoter constructs","pmids":["17339269"],"confidence":"High","gaps":["In vitro promoter activity does not establish the in vivo thrombotic mechanism","Does not identify the transcription factors affected"]},{"year":2010,"claim":"Allele-specific quantification in heterozygous placenta confirmed the M2 effect operates in the functionally relevant organ, not just in reporter constructs.","evidence":"Allele-specific mRNA quantification in human placental tissue","pmids":["20805002"],"confidence":"Medium","gaps":["Does not measure resulting surface protein coverage in vivo","Single lab"]},{"year":2016,"claim":"Mutagenesis plus knockout phenotyping established that 2D array formation, not mere phosphatidylserine binding, is the activity underlying ANXA5's anticoagulant action, and that endogenous physiological ANXA5 is dispensable for hemostasis.","evidence":"AnxA5-deficient mouse wound model with recombinant wild-type and array-deficient mutant injection and in vitro coagulation assay","pmids":["27178140"],"confidence":"High","gaps":["Does not resolve the structural basis of array assembly","Physiological vs pharmacological roles distinguished only in mouse"]},{"year":2016,"claim":"Knockdown in hepatocarcinoma cells defined a specific ERK2/c-Jun/E-cadherin axis as the route by which ANXA5 promotes migration and invasion, excluding alternative MAPK and AKT pathways.","evidence":"shRNA knockdown with migration/invasion/adhesion assays and pathway inhibitor dissection","pmids":["27697636"],"confidence":"Medium","gaps":["Single cell line and single lab","Does not link the membrane-binding activity to the signaling output"]},{"year":2017,"claim":"Biophysical reconstitution showed ANXA5 modulates membrane surface structure and collagen-binding affinity in matrix-vesicle mimetics, extending its function to biomineralization.","evidence":"Atomic force microscopy and collagen-binding assays of TNAP/AnxA5 proteoliposomes","pmids":["28549727"],"confidence":"Medium","gaps":["In vitro membrane mimetics only","Physiological relevance to mineralization not tested in vivo"]},{"year":2018,"claim":"Zinc was shown to upregulate ANXA5 transcription and surface abundance, identifying a positive regulatory input that can restore anticoagulant function.","evidence":"Cell culture transcription/surface flow cytometry assays and AnxA5-deficient mouse pregnancy model","pmids":["29716435"],"confidence":"Medium","gaps":["Mouse litter-size effect was a trend, not significant","Mechanism of zinc-induced transcription not defined"]},{"year":2019,"claim":"Gain-of-function with inhibitor rescue placed ANXA5 upstream of ERK-dependent Nrf2/HO-1/NQO1 antioxidant signaling, defining a cytoprotective mechanism against oxidative stress.","evidence":"Overexpression in Leydig/Sertoli cells, ROS and oxidative markers, ERK inhibitor rescue","pmids":["31404886"],"confidence":"Medium","gaps":["Single lab and cell types","Does not connect membrane binding to ERK activation"]},{"year":2019,"claim":"Fusion-protein targeting confirmed ANXA5's phosphatidylserine recognition of hypoxia-injured cells can be exploited as a delivery anchor that reduces apoptosis and improves cardiac function.","evidence":"Binding/competition assays and mouse myocardial infarction model with SDF-1-AnxA5 fusion","pmids":["31468674"],"confidence":"Medium","gaps":["Therapeutic benefit attributable partly to the SDF-1 cargo","Single lab"]},{"year":2020,"claim":"Identification of miR-506-3p as a direct repressor of ANXA5 mRNA, with recombinant ANXA5 rescue, established post-transcriptional control of the ANXA5/Nrf2/HO-1 antioxidant axis.","evidence":"miRNA agomir overexpression with recombinant ANXA5 rescue in rat testis and cell culture","pmids":["33354277"],"confidence":"Medium","gaps":["Single lab","Does not map the miRNA binding site biochemically beyond reporter inference"]},{"year":2020,"claim":"ANXA5 silencing sensitizing B-ALL cells to dexamethasone-induced caspase-3/9 cleavage defined a caspase-dependent anti-apoptotic mechanism conferring glucocorticoid resistance.","evidence":"siRNA knockdown with flow cytometry apoptosis and cleaved caspase Western blot","pmids":["33231128"],"confidence":"Medium","gaps":["Single cell context and study","Upstream link to caspase suppression not mechanistically resolved"]},{"year":2021,"claim":"Expression-timing and pharmacological perturbation placed Anxa5 downstream of the GnRH/Nr4a3 axis in gonadotropin regulation.","evidence":"RT-PCR time-course over rat estrous cycle with GnRH antagonist","pmids":["33840679"],"confidence":"Low","gaps":["Correlative mRNA timing without direct functional epistasis for ANXA5","Single lab"]},{"year":2023,"claim":"Co-immunoprecipitation identified FUS as a direct ANXA5-binding partner that stabilizes ANXA5 downstream of the MIR4697HG/FUS axis to protect endothelial cells from ox-LDL injury.","evidence":"RNA pull-down, reciprocal co-IP, siRNA rescue, and ApoE-/- mouse atherosclerosis model","pmids":["38082058"],"confidence":"Medium","gaps":["Mechanism by which FUS stabilizes ANXA5 not defined","Single lab"]},{"year":2025,"claim":"Membrane-injury assays in patient-derived cells linked mechanical-stress-induced ANXA5 upregulation to membrane resealing and showed this adaptive response is dysregulated in DMD muscle.","evidence":"Shear-stress and laser-injury repair assays, live-cell imaging, and DMD biopsy immunohistochemistry (preprint)","pmids":["bio_10.1101_2025.09.23.677988"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Causal contribution of ANXA5 vs ANXA6 to resealing not separated"]},{"year":null,"claim":"How ANXA5's membrane phosphatidylserine binding and 2D-array assembly are mechanistically coupled to its intracellular signaling outputs (ERK/Nrf2, anti-apoptotic, c-Jun/E-cadherin) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model connecting array formation to downstream signaling","Whether signaling roles require surface PS binding is untested","No unified in vivo model integrating anticoagulant and cytoprotective functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,6,7,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6,9,11]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13]}],"complexes":[],"partners":["FUS","TNAP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08758","full_name":"Annexin A5","aliases":["Anchorin CII","Annexin V","Annexin-5","Calphobindin I","CPB-I","Endonexin II","Lipocortin V","Placental anticoagulant protein 4","PP4","Placental anticoagulant protein I","PAP-I","Thromboplastin inhibitor","Vascular anticoagulant-alpha","VAC-alpha"],"length_aa":320,"mass_kda":35.9,"function":"This protein is an anticoagulant protein that acts as an indirect inhibitor of the thromboplastin-specific complex, which is involved in the blood coagulation cascade","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P08758/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANXA5","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":[{"gene":"FBL","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/ANXA5","total_profiled":1310},"omim":[{"mim_id":"614391","title":"PREGNANCY LOSS, RECURRENT, SUSCEPTIBILITY TO, 3; RPRGL3","url":"https://www.omim.org/entry/614391"},{"mim_id":"614389","title":"PREGNANCY LOSS, RECURRENT, SUSCEPTIBILITY TO, 1; RPRGL1","url":"https://www.omim.org/entry/614389"},{"mim_id":"611275","title":"BCL2/ADENOVIRUS E1B 19-KD PROTEIN-INTERACTING PROTEIN 2-LIKE; BNIPL","url":"https://www.omim.org/entry/611275"},{"mim_id":"134370","title":"COMPLEMENT FACTOR H; CFH","url":"https://www.omim.org/entry/134370"},{"mim_id":"131230","title":"ANNEXIN A5; ANXA5","url":"https://www.omim.org/entry/131230"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANXA5"},"hgnc":{"alias_symbol":["CPB-I","PAP-I","VAC-alph","RPRGL3"],"prev_symbol":["ENX2","ANX5"]},"alphafold":{"accession":"P08758","domains":[{"cath_id":"1.10.220.10","chopping":"16-73","consensus_level":"high","plddt":97.53,"start":16,"end":73},{"cath_id":"1.10.220.10","chopping":"87-157","consensus_level":"high","plddt":96.3425,"start":87,"end":157},{"cath_id":"1.10.220.10","chopping":"168-244","consensus_level":"high","plddt":94.9666,"start":168,"end":244},{"cath_id":"1.10.220.10","chopping":"247-315","consensus_level":"high","plddt":97.7155,"start":247,"end":315}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08758","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08758-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08758-F1-predicted_aligned_error_v6.png","plddt_mean":96.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANXA5","jax_strain_url":"https://www.jax.org/strain/search?query=ANXA5"},"sequence":{"accession":"P08758","fasta_url":"https://rest.uniprot.org/uniprotkb/P08758.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08758/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08758"}},"corpus_meta":[{"pmid":"710399","id":"PMC_710399","title":"The amino-acid sequence of S-100 protein (PAP I-b protein) and its relation to the calcium-binding proteins.","date":"1978","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/710399","citation_count":351,"is_preprint":false},{"pmid":"9584197","id":"PMC_9584197","title":"Interaction of mouse polycomb-group (Pc-G) proteins Enx1 and Enx2 with Eed: indication for separate Pc-G complexes.","date":"1998","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9584197","citation_count":112,"is_preprint":false},{"pmid":"7545677","id":"PMC_7545677","title":"Pancreatitis-associated protein I (PAP I), an acute phase protein induced by cytokines. 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Southern blot analysis and in situ chromosome hybridization\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal mapping methods in a single study establishing chromosomal localization\",\n      \"pmids\": [\"2534288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"ANXA5 (placental anticoagulant protein-I/PAP-I) protein was localized to the microvilli of placental syncytiotrophoblast cells and their cortical cytoplasm beneath the villi, consistent with its anticoagulant function at the maternal-fetal interface.\",\n      \"method\": \"Immunocytochemistry (light and electron microscopy)\",\n      \"journal\": \"Rinsho byori. The Japanese journal of clinical pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization by immunoelectron microscopy, single study\",\n      \"pmids\": [\"2148197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"ANXA5 (CPB-I/calphobindin I) acts as an endogenous inhibitor of protein kinase C; its transcription is markedly suppressed in cervical and endometrial carcinoma cells compared to normal counterparts, as shown by immunohistochemistry, Northern blot, and in situ hybridization.\",\n      \"method\": \"Immunohistochemistry, Northern blot, in situ hybridization\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal methods confirming transcriptional suppression; protein kinase C inhibition attributed from prior literature cited in abstract\",\n      \"pmids\": [\"7672695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The M2 haplotype (four consecutive nucleotide substitutions) in the ANXA5 promoter reduces in vitro ANXA5 promoter activity to 37–42% of normal levels, as demonstrated by reporter gene assays, establishing a mechanistic link between this promoter variant and reduced ANXA5 expression associated with recurrent pregnancy loss.\",\n      \"method\": \"Reporter gene (luciferase/CAT) assay with M2 vs. wild-type promoter constructs\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro promoter activity assay with M2 constructs, replicated across multiple subsequent studies confirming the same functional effect\",\n      \"pmids\": [\"17339269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Anxa5-expressing (Anxa5-LacZ+) perivascular cells isolated from mouse meningeal vasculature express pericyte markers (NG2, desmin, αSMA, PDGFR-β) and Sca-1, stimulate angiogenesis when co-cultured with endothelial cells (increased PECAM expression), and promote vascularization when grafted onto quail chorioallantoic membranes, demonstrating ANXA5 as a marker of pericyte identity with a functional role in angiogenic support.\",\n      \"method\": \"Cell isolation using Anxa5-LacZ reporter, co-culture with endothelial cells, in vivo CAM graft assay, immunophenotyping\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro co-culture and in vivo graft assay with functional readouts in a single study\",\n      \"pmids\": [\"17543301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The M2 allele of ANXA5 in heterozygous placentas results in an average 42% reduction in ANXA5 mRNA levels compared to the normal allele, directly demonstrating allele-specific reduction of ANXA5 expression in the functionally relevant organ.\",\n      \"method\": \"Allele-specific mRNA quantification in heterozygous placental tissue\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct allele-specific expression analysis in human placental tissue, single lab\",\n      \"pmids\": [\"20805002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Exogenous AnxA5 reduces plaque macrophage content in advanced atherosclerotic lesions of apoE-/- mice (59–73% reduction) and inhibits monocyte capture, rolling, adhesion, and transmigration on TNF-α-activated endothelial cells in vitro, demonstrating an anti-inflammatory mechanism through interference with monocyte recruitment via binding to phosphatidylserine on the cell surface.\",\n      \"method\": \"In vivo AnxA5 injection in apoE-/- mice with immunohistochemistry; in vitro flow chamber monocyte adhesion assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro orthogonal methods in a single study, single lab\",\n      \"pmids\": [\"25214012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pharmacological concentrations of AnxA5 (1 µM) inhibit wound hemostasis and delay coagulation pathway activation in vitro; this effect requires AnxA5's ability to form 2D arrays on the cell surface, as an AnxA5 mutant that binds phosphatidylserine but cannot form 2D arrays failed to induce bleeding. Endogenous AnxA5 (at physiological levels) is dispensable for wound healing and hemostasis in AnxA5-deficient mice.\",\n      \"method\": \"AnxA5-deficient mouse wound model, recombinant wild-type and mutant AnxA5 injection, in vitro coagulation assay\",\n      \"journal\": \"Cells, tissues, organs\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with mutagenesis (2D array-deficient mutant) plus in vivo KO phenotyping, two orthogonal approaches in one study\",\n      \"pmids\": [\"27178140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Anxa5 knockdown in murine hepatocarcinoma Hca-F cells reduces proliferation, migration, invasion, and lymph node adhesion; mechanistically, Anxa5 mediates these effects specifically via the ERK2/p-ERK2/c-Jun/p-c-Jun(Ser73) pathway and through regulation of E-cadherin levels, not through p38MAPK/c-Jun, Jnk/c-Jun, or AKT/c-Jun pathways.\",\n      \"method\": \"shRNA knockdown, CCK-8, Boyden transwell, in situ adhesion assay, Western blot, qRT-PCR for pathway components\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple functional readouts and pathway dissection using multiple signaling inhibitors, single lab\",\n      \"pmids\": [\"27697636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Physiological micromolar Zn2+ stimulates ANXA5 transcription, raising ANXA5 protein expression and surface abundance on BeWo and HUVEC cells, resulting in prolonged coagulation times; Zn2+-fed AnxA5-deficient pregnant mice showed a trend toward increased litter size, demonstrating that zinc can upregulate ANXA5 expression to restore anticoagulant function.\",\n      \"method\": \"Cell culture transcription assay, flow cytometry for surface ANXA5, coagulation time assay, AnxA5-deficient mouse pregnancy model\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo approaches, single lab, functional coagulation readout\",\n      \"pmids\": [\"29716435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANXA5 overexpression in mouse Leydig and Sertoli cells activates the Nrf2/HO-1/NQO1 antioxidant pathway and attenuates DBP-induced oxidative stress; this protective effect operates through increased ERK phosphorylation, as ERK inhibition reverses the ANXA5-mediated Nrf2 pathway activation.\",\n      \"method\": \"Overexpression in cell culture, DHE staining for ROS, ELISA for MDA/SOD, Western blot for pathway proteins, ERK inhibitor rescue experiment\",\n      \"journal\": \"Environmental toxicology and pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with inhibitor rescue, multiple biochemical readouts, single lab\",\n      \"pmids\": [\"31404886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AnxA5 domain specifically recognizes and binds to phosphatidylserine on hypoxia-injured cells; a SDF-1-AnxA5 fusion protein accumulates at infarcted myocardium after peripheral vein injection, attenuates apoptosis, enhances angiogenesis, and improves cardiac function after mouse myocardial infarction, demonstrating ANXA5's PS-targeting function as a delivery anchor for therapeutic cargo.\",\n      \"method\": \"Receptor competition assay, binding membrane assay, immunofluorescence, mouse myocardial infarction model with fusion protein treatment\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assays and in vivo functional cardiac model, single lab\",\n      \"pmids\": [\"31468674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-506-3p directly binds to ANXA5 mRNA and reduces ANXA5 expression; overexpression of miR-506-3p aggravates DBP-induced testicular oxidative stress in rats by inhibiting the ANXA5/Nrf2/HO-1 signaling pathway, and exogenous recombinant ANXA5 reverses these effects.\",\n      \"method\": \"miRNA overexpression (agomir), recombinant ANXA5 rescue, Western blot, immunohistochemistry, oxidative stress assays in vivo and in vitro\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA-target interaction with rescue experiment, in vivo and in vitro validation, single lab\",\n      \"pmids\": [\"33354277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA5 overexpression promotes glucocorticoid (dexamethasone) resistance in B-ALL cells; siRNA-mediated ANXA5 silencing combined with dexamethasone dramatically increases apoptosis and caspase-3/9 cleavage compared to either treatment alone, indicating ANXA5 suppresses caspase-dependent apoptosis to confer glucocorticoid resistance.\",\n      \"method\": \"siRNA knockdown, flow cytometry apoptosis assay, Western blot for cleaved caspase-3 and -9\",\n      \"journal\": \"Pediatric hematology and oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined apoptotic readout and pathway component detection, single lab, single study\",\n      \"pmids\": [\"33231128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In rat pituitary gonadotropes, Anxa5 mRNA is induced by GnRH and rises sequentially after Nr4a3 mRNA peaks at proestrus; the functional relationship between NR4A3 and ANXA5 was established in regulating FSH-beta (Fshb) expression, with GnRH antagonist abolishing Nr4a3 induction, placing ANXA5 downstream of the GnRH/Nr4a3 axis in gonadotropin regulation.\",\n      \"method\": \"RT-PCR time-course during rat estrous cycle, GnRH antagonist treatment\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mRNA expression timing with pharmacological perturbation, single lab, no direct functional epistasis experiment for ANXA5 specifically\",\n      \"pmids\": [\"33840679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ANXA5 and TNAP (tissue-nonspecific alkaline phosphatase) are co-incorporated into proteoliposomes mimicking matrix vesicles; AFM imaging revealed that ANXA5 insertion causes minimal surface protrusions (unlike TNAP), and proteoliposomes harboring both proteins show lower affinity for type II collagen fibers than those with AnxA5 alone, demonstrating that AnxA5 modulates membrane structure and collagen-binding properties relevant to biomineralization.\",\n      \"method\": \"Atomic force microscopy of proteoliposomes, collagen binding assay\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct biophysical reconstitution in membrane mimetics with functional collagen-binding assay, single lab\",\n      \"pmids\": [\"28549727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FUS (fused in sarcoma) protein directly binds ANXA5 as demonstrated by co-immunoprecipitation; lncRNA MIR4697HG stabilizes FUS, which in turn sustains ANXA5 expression to protect endothelial cells from ox-LDL-induced apoptosis and oxidative stress, placing ANXA5 downstream of the MIR4697HG/FUS axis in atherosclerosis.\",\n      \"method\": \"RNA pull-down assay (MIR4697HG–FUS), co-immunoprecipitation (FUS–ANXA5), siRNA knockdown rescue experiments, in vivo ApoE-/- mouse atherosclerosis model\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays with functional rescue experiments, single lab\",\n      \"pmids\": [\"38082058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In healthy skeletal muscle cells, mechanical stress induces upregulation of ANXA5 (and ANXA6), suggesting an adaptive membrane repair response; in DMD patient-derived skeletal muscle cells, this adaptive ANXA5 upregulation is dysregulated, associated with defective membrane resealing capacity demonstrated by shear stress and laser irradiation injury assays.\",\n      \"method\": \"Shear stress membrane injury assay, laser irradiation assay, Western blot, live-cell imaging of GFP-tagged annexins, immunohistochemistry of DMD patient biopsies\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct membrane repair functional assays in patient-derived cells and biopsies with multiple orthogonal methods; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.23.677988\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ANXA5 is a Ca2+-dependent phospholipid-binding protein (chromosomal locus 4q28-q32) that forms 2D arrays on phosphatidylserine-exposing membranes, thereby inhibiting coagulation and acting as a placental anticoagulant; its promoter M2 haplotype reduces transcription by ~40–60%, lowering ANXA5 surface coverage and increasing thrombotic risk at the fetal-maternal interface; at the cellular level, ANXA5 suppresses caspase-dependent apoptosis, participates in membrane repair responses to mechanical stress, activates the ERK/Nrf2 antioxidant pathway, and influences cancer cell migration and invasion via ERK2/c-Jun/E-cadherin signaling, while FUS directly binds and stabilizes ANXA5 protein in endothelial cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANXA5 is a Ca2+-dependent phospholipid-binding annexin that recognizes surface-exposed phosphatidylserine and assembles into ordered two-dimensional arrays on membranes, a property central to its anticoagulant function at the maternal-fetal interface, where it localizes to placental syncytiotrophoblast microvilli [#0, #1]. The 2D-array activity is mechanistically required for its anticoagulant action: recombinant ANXA5 that binds phosphatidylserine but cannot form arrays fails to delay coagulation [#7]. Its expression is set by transcriptional and post-transcriptional control — the M2 promoter haplotype reduces promoter activity to ~37–42% and lowers allele-specific mRNA in heterozygous placenta, linking reduced ANXA5 to recurrent pregnancy loss, while zinc upregulates and miR-506-3p directly represses ANXA5 [#3, #5, #9, #12]. Through its phosphatidylserine-targeting and cytoprotective activities, ANXA5 suppresses caspase-dependent apoptosis to confer glucocorticoid resistance in B-ALL cells and activates the ERK/Nrf2/HO-1 antioxidant pathway [#13, #10, #12]. ANXA5 also drives cancer cell proliferation, migration, and invasion via ERK2/c-Jun/E-cadherin signaling, modulates membrane structure and collagen binding in biomineralizing matrix-vesicle mimetics, and participates in mechanical-stress membrane repair [#8, #15]. In endothelial cells, FUS directly binds ANXA5 and sustains its expression downstream of a MIR4697HG/FUS axis to protect against ox-LDL-induced apoptosis [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing ANXA5's chromosomal locus and family membership defined it as a Ca2+-dependent phospholipid-binding annexin, framing all subsequent membrane-based mechanistic work.\",\n      \"evidence\": \"Somatic cell hybrid Southern blot and in situ chromosome hybridization mapping to 4q28-q32\",\n      \"pmids\": [\"2534288\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mapping alone establishes no biochemical activity\", \"No functional data in this study\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Localizing ANXA5 to placental syncytiotrophoblast microvilli grounded its proposed anticoagulant role at the maternal-fetal interface in a specific cellular compartment.\",\n      \"evidence\": \"Immunoelectron microscopy of placental tissue\",\n      \"pmids\": [\"2148197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Localization does not demonstrate the anticoagulant mechanism directly\", \"Single study\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Reporter assays showed the M2 promoter haplotype reduces ANXA5 transcription, providing a mechanistic link between a common variant and reduced expression associated with recurrent pregnancy loss.\",\n      \"evidence\": \"Luciferase/CAT reporter assays comparing M2 vs wild-type promoter constructs\",\n      \"pmids\": [\"17339269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro promoter activity does not establish the in vivo thrombotic mechanism\", \"Does not identify the transcription factors affected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Allele-specific quantification in heterozygous placenta confirmed the M2 effect operates in the functionally relevant organ, not just in reporter constructs.\",\n      \"evidence\": \"Allele-specific mRNA quantification in human placental tissue\",\n      \"pmids\": [\"20805002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not measure resulting surface protein coverage in vivo\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mutagenesis plus knockout phenotyping established that 2D array formation, not mere phosphatidylserine binding, is the activity underlying ANXA5's anticoagulant action, and that endogenous physiological ANXA5 is dispensable for hemostasis.\",\n      \"evidence\": \"AnxA5-deficient mouse wound model with recombinant wild-type and array-deficient mutant injection and in vitro coagulation assay\",\n      \"pmids\": [\"27178140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the structural basis of array assembly\", \"Physiological vs pharmacological roles distinguished only in mouse\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Knockdown in hepatocarcinoma cells defined a specific ERK2/c-Jun/E-cadherin axis as the route by which ANXA5 promotes migration and invasion, excluding alternative MAPK and AKT pathways.\",\n      \"evidence\": \"shRNA knockdown with migration/invasion/adhesion assays and pathway inhibitor dissection\",\n      \"pmids\": [\"27697636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line and single lab\", \"Does not link the membrane-binding activity to the signaling output\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Biophysical reconstitution showed ANXA5 modulates membrane surface structure and collagen-binding affinity in matrix-vesicle mimetics, extending its function to biomineralization.\",\n      \"evidence\": \"Atomic force microscopy and collagen-binding assays of TNAP/AnxA5 proteoliposomes\",\n      \"pmids\": [\"28549727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro membrane mimetics only\", \"Physiological relevance to mineralization not tested in vivo\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Zinc was shown to upregulate ANXA5 transcription and surface abundance, identifying a positive regulatory input that can restore anticoagulant function.\",\n      \"evidence\": \"Cell culture transcription/surface flow cytometry assays and AnxA5-deficient mouse pregnancy model\",\n      \"pmids\": [\"29716435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mouse litter-size effect was a trend, not significant\", \"Mechanism of zinc-induced transcription not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Gain-of-function with inhibitor rescue placed ANXA5 upstream of ERK-dependent Nrf2/HO-1/NQO1 antioxidant signaling, defining a cytoprotective mechanism against oxidative stress.\",\n      \"evidence\": \"Overexpression in Leydig/Sertoli cells, ROS and oxidative markers, ERK inhibitor rescue\",\n      \"pmids\": [\"31404886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and cell types\", \"Does not connect membrane binding to ERK activation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Fusion-protein targeting confirmed ANXA5's phosphatidylserine recognition of hypoxia-injured cells can be exploited as a delivery anchor that reduces apoptosis and improves cardiac function.\",\n      \"evidence\": \"Binding/competition assays and mouse myocardial infarction model with SDF-1-AnxA5 fusion\",\n      \"pmids\": [\"31468674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Therapeutic benefit attributable partly to the SDF-1 cargo\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of miR-506-3p as a direct repressor of ANXA5 mRNA, with recombinant ANXA5 rescue, established post-transcriptional control of the ANXA5/Nrf2/HO-1 antioxidant axis.\",\n      \"evidence\": \"miRNA agomir overexpression with recombinant ANXA5 rescue in rat testis and cell culture\",\n      \"pmids\": [\"33354277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Does not map the miRNA binding site biochemically beyond reporter inference\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"ANXA5 silencing sensitizing B-ALL cells to dexamethasone-induced caspase-3/9 cleavage defined a caspase-dependent anti-apoptotic mechanism conferring glucocorticoid resistance.\",\n      \"evidence\": \"siRNA knockdown with flow cytometry apoptosis and cleaved caspase Western blot\",\n      \"pmids\": [\"33231128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell context and study\", \"Upstream link to caspase suppression not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expression-timing and pharmacological perturbation placed Anxa5 downstream of the GnRH/Nr4a3 axis in gonadotropin regulation.\",\n      \"evidence\": \"RT-PCR time-course over rat estrous cycle with GnRH antagonist\",\n      \"pmids\": [\"33840679\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative mRNA timing without direct functional epistasis for ANXA5\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Co-immunoprecipitation identified FUS as a direct ANXA5-binding partner that stabilizes ANXA5 downstream of the MIR4697HG/FUS axis to protect endothelial cells from ox-LDL injury.\",\n      \"evidence\": \"RNA pull-down, reciprocal co-IP, siRNA rescue, and ApoE-/- mouse atherosclerosis model\",\n      \"pmids\": [\"38082058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FUS stabilizes ANXA5 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Membrane-injury assays in patient-derived cells linked mechanical-stress-induced ANXA5 upregulation to membrane resealing and showed this adaptive response is dysregulated in DMD muscle.\",\n      \"evidence\": \"Shear-stress and laser-injury repair assays, live-cell imaging, and DMD biopsy immunohistochemistry (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.23.677988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Causal contribution of ANXA5 vs ANXA6 to resealing not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ANXA5's membrane phosphatidylserine binding and 2D-array assembly are mechanistically coupled to its intracellular signaling outputs (ERK/Nrf2, anti-apoptotic, c-Jun/E-cadherin) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model connecting array formation to downstream signaling\", \"Whether signaling roles require surface PS binding is untested\", \"No unified in vivo model integrating anticoagulant and cytoprotective functions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 6, 7, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6, 9, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FUS\",\n      \"TNAP\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}