{"gene":"ANXA5","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1989,"finding":"The human ANXA5 gene (endonexin II, ENX2) was mapped to chromosome 4q28-q32 by Southern transfer analysis of human x rodent somatic cell hybrid DNAs and in situ chromosome hybridization, establishing it as a member of the Ca2+-dependent phospholipid-binding annexin gene family.","method":"Somatic cell hybrid panel Southern blotting and in situ chromosome hybridization","journal":"Cytogenetics and cell genetics","confidence":"High","confidence_rationale":"Tier 1 — direct chromosomal mapping by two orthogonal methods","pmids":["2534288"],"is_preprint":false},{"year":1990,"finding":"ANXA5 (placental anticoagulant protein-I, PAP-I) was localized to the microvilli of placental syncytiotrophoblast cells and their cortical cytoplasm beneath the villi, establishing its specific subcellular distribution in the relevant anticoagulant compartment.","method":"Immunocytochemistry (light and electron microscopy) of human placenta","journal":"Rinsho byori. The Japanese journal of clinical pathology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by electron microscopy with functional context","pmids":["2148197"],"is_preprint":false},{"year":1995,"finding":"ANXA5 (calphobindin I/CPB I/Annexin V) was identified as an endogenous inhibitor of protein kinase C, and its expression was markedly suppressed at the transcriptional level in cervical and endometrial carcinoma cells compared to normal counterparts, as shown by northern blot and in situ hybridization.","method":"Northern blot, in situ hybridization, immunohistochemistry","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods showing transcriptional suppression; PKC inhibition referenced from prior work","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 level as demonstrated by reporter gene (luciferase) assays, and is associated with recurrent pregnancy loss risk.","method":"Reporter gene (luciferase) assays, sequence analysis, case-control genetic study","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 — functional promoter assay combined with large case-control study, replicated across multiple populations","pmids":["17339269"],"is_preprint":false},{"year":2007,"finding":"ANXA5-expressing perivascular cells (PVC) isolated using the Anxa5-LacZ fusion gene marker express pericyte-specific markers (NG2, desmin, αSMA, PDGFR-β) and stem cell marker Sca-1, and when co-cultured with endothelial cells stimulate angiogenesis (increased PECAM expression) and basement membrane deposition; in vivo grafts recruit endothelial cells and become vascularized.","method":"Cell isolation using Anxa5-LacZ reporter, immunophenotyping, co-culture assays, in vivo chorioallantoic membrane graft","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vitro and in vivo methods establishing ANXA5 as perivascular cell marker with functional consequence","pmids":["17543301"],"is_preprint":false},{"year":2010,"finding":"The M2 allele of ANXA5 results in an average 42% reduction in allele-specific ANXA5 mRNA levels in heterozygous placentas compared to the normal allele, directly linking the M2 promoter haplotype to reduced expression in the relevant tissue.","method":"Allele-specific mRNA quantification in placental tissue by RT-PCR, Western blot","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 — direct allele-specific expression measurement in tissue with functional implication","pmids":["20805002"],"is_preprint":false},{"year":2013,"finding":"In pre-eclamptic patients, placental ANXA5 mRNA and protein levels are lower in M2 haplotype carriers, and placental (fetal) M2 genotype correlates more closely than maternal M2 with severity of perivillous fibrin deposition, indicating ANXA5 functions locally at the feto-maternal interface to prevent thrombosis.","method":"qRT-PCR, Western blot, immunostaining, histological examination of placentas","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods in human tissue with mechanistic pathway link","pmids":["24140079"],"is_preprint":false},{"year":2014,"finding":"Exogenous ANXA5, which binds cell-surface phosphatidylserine (PS), reduces plaque macrophage content in advanced atherosclerotic lesions in apoE−/− mice; in vitro, ANXA5 inhibits capture, rolling, adhesion, and transmigration of peripheral blood mononuclear cells on TNF-α-activated endothelial cells, establishing an anti-inflammatory mechanism via PS binding.","method":"In vivo mouse atherosclerosis model (collar placement), immunohistochemistry, in vitro flow chamber adhesion assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro experiments with defined cellular readouts","pmids":["25214012"],"is_preprint":false},{"year":2016,"finding":"ANXA5 requires the ability to form two-dimensional (2D) arrays on the cell surface (via PS binding) to inhibit hemostasis: pharmacological concentrations of wild-type ANXA5 (1 µM) induced bleeding in mice, while an ANXA5 mutant that binds PS but cannot form 2D arrays failed to cause bleeding or delay coagulation, demonstrating that 2D lattice formation is necessary for ANXA5's anticoagulant function.","method":"AnxA5-deficient mice, injection of recombinant WT and mutant ANXA5, in vivo bleeding assay, in vitro coagulation assays","journal":"Cells, tissues, organs","confidence":"High","confidence_rationale":"Tier 1 — in vivo mutagenesis study with mechanistic mutant validation and multiple orthogonal assays","pmids":["27178140"],"is_preprint":false},{"year":2016,"finding":"Knockdown of ANXA5 in murine hepatocarcinoma Hca-F cells reduces proliferation, migration, invasion, and lymph node adhesion; mechanistically, ANXA5 acts specifically via the ERK2/p-ERK2/c-Jun/p-c-Jun(Ser73) pathway and regulates E-cadherin levels, rather than through p38MAPK, JNK, or AKT pathways.","method":"shRNA knockdown, CCK-8, Boyden transwell, in situ LN adhesion assay, Western blot, qRT-PCR, pathway inhibitor experiments","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cellular assays with specific pathway identification via knockdown and inhibitors","pmids":["27697636"],"is_preprint":false},{"year":2017,"finding":"ANXA5 and TNAP co-incorporated into proteoliposomes (matrix vesicle mimetics) induce local changes in membrane fluidity detectable by AFM; ANXA5-containing proteoliposomes bind type II collagen, and combined TNAP+ANXA5 proteoliposomes show lower collagen affinity than ANXA5 alone, establishing ANXA5's role in membrane organization and matrix interactions during biomineralization.","method":"Atomic force microscopy of proteoliposomes, reconstitution of ANXA5 and TNAP into lipid vesicles, collagen binding assay","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"Medium","confidence_rationale":"Tier 1 — reconstitution system with direct structural visualization by AFM","pmids":["28549727"],"is_preprint":false},{"year":2018,"finding":"Micromolar Zn2+ stimulates ANXA5 transcription, raising ANXA5 protein 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, linking ANXA5 transcriptional upregulation to anticoagulant function and pregnancy outcome.","method":"Cell culture (BeWo, HUVEC), Western blot, coagulation assay, AnxA5-deficient mouse model with dietary Zn2+ supplementation","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo convergent evidence with functional anticoagulation readout","pmids":["29716435"],"is_preprint":false},{"year":2019,"finding":"ANXA5 overexpression in testicular Leydig and Sertoli cells activates the Nrf2/HO-1/NQO1 antioxidant pathway via ERK phosphorylation, and attenuates DBP-induced oxidative stress; ERK inhibition reverses the protective effect of ANXA5, establishing the ANXA5→ERK→Nrf2 signaling axis.","method":"Overexpression and knockdown in cell culture, DHE staining, ELISA, Western blot, ERK inhibitor experiments","journal":"Environmental toxicology and pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function plus pharmacological inhibition placing ANXA5 upstream of ERK/Nrf2","pmids":["31404886"],"is_preprint":false},{"year":2019,"finding":"AnxA5 domain specifically recognizes and binds to cells injured by hypoxia (PS-exposing dead/dying cells); a SDF-1-AnxA5 fusion protein accumulates at infarcted myocardium after peripheral vein injection in mice, reduces apoptosis, enhances angiogenesis, reduces infarct size, and improves cardiac function, demonstrating ANXA5's PS-targeting function can be exploited for cardiac drug delivery.","method":"Receptor competition assay, binding membrane assay, immunofluorescence, mouse MI model with IV injection, echocardiography","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro binding characterization plus in vivo functional validation","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 decreases ANXA5 protein levels and downregulates the Nrf2/HO-1 signaling pathway, aggravating DBP-induced testicular oxidative stress injury; exogenous recombinant ANXA5 reverses these effects, establishing ANXA5 as a direct target of miR-506-3p in testicular oxidative stress regulation.","method":"miRNA agomir injection in rats, luciferase reporter (miRNA target validation), Western blot, immunohistochemistry, CCK-8, flow cytometry","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 — direct miRNA target validation combined with in vivo rescue experiment","pmids":["33354277"],"is_preprint":false},{"year":2020,"finding":"ANXA5 silencing in B-ALL cells increases DEX-induced apoptosis and significantly elevates cleaved Caspase 3 and Caspase 9 levels, establishing that ANXA5 confers glucocorticoid resistance by suppressing caspase-dependent apoptosis.","method":"siRNA knockdown, flow cytometry (apoptosis), Western blot (caspase cleavage)","journal":"Pediatric hematology and oncology","confidence":"Low","confidence_rationale":"Tier 3 — single method per endpoint, single lab","pmids":["33231128"],"is_preprint":false},{"year":2021,"finding":"In rat pituitary gland, GnRH induces Nr4a3 mRNA expression (peak at proestrus), after which Anxa5 mRNA rises and suppresses Nr4a3, with Anxa5 elevation coinciding with increased Fshb mRNA; GnRH antagonist abolishes Nr4a3 induction, establishing a sequential GnRH→Nr4a3→Anxa5 regulatory axis controlling FSH-beta expression.","method":"RT-PCR, GnRH antagonist treatment in vivo, analysis across estrous cycle time points","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo pharmacological intervention (GnRH antagonist) with temporal expression profiling establishing pathway position","pmids":["33840679"],"is_preprint":false},{"year":2023,"finding":"LncRNA MIR4697HG binds FUS protein (shown by RNA pull-down), and FUS in turn interacts with ANXA5 (shown by Co-IP); MIR4697HG overexpression upregulates FUS, which promotes ANXA5 expression to protect endothelial cells from ox-LDL-induced apoptosis, oxidative stress, and adhesion molecule release; ANXA5 knockdown reverses the protective effect of FUS overexpression.","method":"RNA pull-down, Co-immunoprecipitation, overexpression/knockdown in HUVECs, ApoE−/− mouse atherosclerosis model","journal":"Biochemical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and RNA pulldown identifying MIR4697HG/FUS/ANXA5 complex with functional rescue experiments","pmids":["38082058"],"is_preprint":false},{"year":2025,"finding":"In Duchenne muscular dystrophy (DMD) skeletal muscle cells, ANXA5 and ANXA6 fail to upregulate in response to mechanical stress (unlike control cells), suggesting ANXA5 normally participates in an adaptive membrane repair response in skeletal muscle; DMD cells show defective membrane resealing and massive IgG uptake confirming impaired repair.","method":"Shear stress-based injury assay, live-cell imaging of GFP-tagged annexins, Western blot, immunohistochemistry of patient biopsies","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 2 — direct stress-response measurement in human cells and biopsies, but preprint and single lab","pmids":["bio_10.1101_2025.09.23.677988"],"is_preprint":true}],"current_model":"ANXA5 (Annexin A5/Annexin V) is a Ca2+-dependent phospholipid-binding protein that preferentially binds phosphatidylserine (PS) on cell surfaces, where it forms protective two-dimensional arrays that inhibit coagulation and provide anticoagulant shielding at the placental syncytiotrophoblast surface; reduced ANXA5 expression caused by the M2 promoter haplotype impairs this placental anticoagulant shield and predisposes to thrombosis-related obstetric complications, while ANXA5 additionally functions as an inhibitor of protein kinase C, a regulator of ERK/Nrf2-mediated antioxidant signaling, a participant in membrane repair responses in skeletal muscle, and a modulator of monocyte/macrophage recruitment in atherosclerosis via PS-targeting."},"narrative":{"teleology":[{"year":1989,"claim":"Establishing ANXA5 as a member of the annexin family with a defined chromosomal locus (4q28-q32) provided the genomic framework for subsequent functional and genetic studies.","evidence":"Southern blot analysis of somatic cell hybrids and in situ chromosome hybridization","pmids":["2534288"],"confidence":"High","gaps":["No functional characterization at this stage","Regulatory elements of the locus not yet mapped"]},{"year":1990,"claim":"Localizing ANXA5 to syncytiotrophoblast microvilli and cortical cytoplasm established the subcellular compartment where it could function as a placental anticoagulant.","evidence":"Immunocytochemistry with light and electron microscopy of human placental tissue","pmids":["2148197"],"confidence":"Medium","gaps":["Mechanism of anticoagulant action at this surface not yet defined","Dynamics of ANXA5 recruitment to microvilli unknown"]},{"year":1995,"claim":"Identifying ANXA5 as a protein kinase C inhibitor whose transcription is suppressed in carcinoma cells revealed a potential tumor-suppressive signaling role beyond its membrane-binding properties.","evidence":"Northern blot, in situ hybridization, and immunohistochemistry in cervical/endometrial carcinoma vs. normal tissue","pmids":["7672695"],"confidence":"Medium","gaps":["Direct biochemical mechanism of PKC inhibition not dissected","Causal link between ANXA5 loss and tumorigenesis not established"]},{"year":2007,"claim":"Discovery that the M2 promoter haplotype reduces ANXA5 transcription to ~37–42% of normal and associates with recurrent pregnancy loss provided the first mechanistic genetic link between ANXA5 expression and obstetric thrombotic complications.","evidence":"Luciferase reporter assays and case-control genetic study across multiple populations","pmids":["17339269"],"confidence":"High","gaps":["Tissue-level validation of reduced expression not yet performed","Contribution of paternal vs. maternal genotype unclear"]},{"year":2010,"claim":"Allele-specific mRNA quantification in heterozygous placentas confirmed that the M2 haplotype reduces ANXA5 expression by ~42% in the relevant tissue, validating the reporter assay findings in vivo.","evidence":"Allele-specific RT-PCR and Western blot in human placental tissue","pmids":["20805002"],"confidence":"Medium","gaps":["Whether reduced expression crosses a threshold for clinical thrombosis not determined","Protein-level quantification at the cell surface not performed"]},{"year":2013,"claim":"Demonstrating that fetal (placental) M2 genotype correlates with perivillous fibrin deposition more than maternal genotype established that ANXA5 functions locally at the feto-maternal interface to prevent thrombosis.","evidence":"qRT-PCR, Western blot, immunostaining, and histological assessment of pre-eclamptic placentas","pmids":["24140079"],"confidence":"Medium","gaps":["Whether exogenous ANXA5 can rescue the M2-associated phenotype in human tissue untested","Contributions of other annexins at the same interface not assessed"]},{"year":2014,"claim":"Showing that exogenous ANXA5 reduces plaque macrophage content and inhibits monocyte adhesion/transmigration via PS binding extended its anti-inflammatory role beyond the placenta to atherosclerosis.","evidence":"ApoE−/− mouse atherosclerosis model with collar placement and in vitro flow chamber assays on TNFα-activated endothelium","pmids":["25214012"],"confidence":"Medium","gaps":["Whether endogenous ANXA5 levels modulate atherosclerosis in vivo not tested","Receptor or signaling target on monocytes not identified"]},{"year":2016,"claim":"Using an ANXA5 mutant that binds PS but cannot form 2D arrays revealed that lattice formation—not merely PS binding—is the mechanistic requirement for ANXA5's anticoagulant activity, resolving a longstanding question about how ANXA5 inhibits coagulation.","evidence":"Injection of wild-type vs. lattice-deficient recombinant ANXA5 in AnxA5-deficient mice with in vivo bleeding and in vitro coagulation assays","pmids":["27178140"],"confidence":"High","gaps":["Structural details of the 2D array at atomic resolution not resolved","Whether 2D array formation is also required for non-coagulant functions unknown"]},{"year":2016,"claim":"ANXA5 knockdown in hepatocarcinoma cells reduced proliferation, migration, and invasion specifically through the ERK2/p-ERK2/c-Jun pathway, identifying ANXA5 as an upstream activator of ERK signaling in cancer cell biology.","evidence":"shRNA knockdown with pathway inhibitor experiments, transwell and adhesion assays in Hca-F cells","pmids":["27697636"],"confidence":"Medium","gaps":["Direct binding partner linking ANXA5 to ERK2 activation not identified","Relevance to human cancer not validated"]},{"year":2019,"claim":"ANXA5 overexpression activated the ERK→Nrf2/HO-1/NQO1 antioxidant pathway and protected testicular cells from oxidative stress, with ERK inhibition fully reversing the effect, establishing a defined ANXA5→ERK→Nrf2 signaling axis for cytoprotection.","evidence":"Overexpression and knockdown in Leydig/Sertoli cells with ERK inhibitor rescue, DHE staining, and Western blot","pmids":["31404886"],"confidence":"Medium","gaps":["How ANXA5 activates ERK phosphorylation mechanistically is unknown","Whether this axis operates in non-testicular tissues not established"]},{"year":2020,"claim":"miR-506-3p was validated as a direct upstream regulator of ANXA5, with miR-506-3p binding the ANXA5 3′UTR to suppress expression and thereby aggravate oxidative stress through loss of Nrf2/HO-1 signaling.","evidence":"Luciferase reporter target validation, miRNA agomir injection in rats, rescue with recombinant ANXA5","pmids":["33354277"],"confidence":"Medium","gaps":["Whether miR-506-3p regulation of ANXA5 is relevant in placental or vascular contexts unknown","Other miRNAs targeting ANXA5 not systematically assessed"]},{"year":2023,"claim":"Identification of the MIR4697HG lncRNA→FUS→ANXA5 axis in endothelial cells revealed a new upstream regulatory pathway controlling ANXA5 expression to protect against ox-LDL-induced endothelial dysfunction.","evidence":"RNA pull-down, Co-IP for FUS–ANXA5 interaction, overexpression/knockdown rescue in HUVECs, and ApoE−/− mouse model","pmids":["38082058"],"confidence":"Medium","gaps":["Whether FUS directly stabilizes ANXA5 mRNA or protein is unclear","Co-IP interaction between FUS and ANXA5 protein requires reciprocal validation and domain mapping"]},{"year":null,"claim":"The molecular mechanism by which ANXA5 activates ERK signaling, the structural basis of its 2D array at atomic resolution on biological membranes, and whether its anticoagulant lattice-forming function is required for its anti-inflammatory and cytoprotective roles remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No direct binding partner linking ANXA5 to ERK activation identified","No high-resolution structure of the 2D array on a native membrane","Whether 2D lattice formation is required for non-coagulant functions untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,7,8,10,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,8,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7,8,13]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[8,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[12,14]}],"complexes":[],"partners":["FUS","ANXA6","ALPL"],"other_free_text":[]},"mechanistic_narrative":"ANXA5 (Annexin A5) is a Ca²⁺-dependent phospholipid-binding protein that preferentially binds phosphatidylserine (PS) on cell surfaces and forms two-dimensional crystalline arrays essential for its anticoagulant activity; an ANXA5 mutant that binds PS but cannot form 2D lattices fails to inhibit coagulation, establishing lattice formation as the mechanistic basis of its hemostatic function [PMID:27178140]. At the placental syncytiotrophoblast, ANXA5 provides an anticoagulant shield, and the M2 promoter haplotype reduces ANXA5 transcription to ~40% of normal levels in placental tissue, predisposing to perivillous fibrin deposition and recurrent pregnancy loss [PMID:17339269, PMID:24140079]. Beyond anticoagulation, ANXA5 activates the ERK→Nrf2/HO-1 antioxidant signaling axis to protect against oxidative stress, inhibits monocyte adhesion and transmigration across activated endothelium via PS binding to attenuate atherosclerotic inflammation, and functions as an endogenous inhibitor of protein kinase C [PMID:31404886, PMID:25214012, PMID:7672695]."},"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. Identification of two functional interleukin-6 response elements in the rat PAP I promoter region.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7545677","citation_count":100,"is_preprint":false},{"pmid":"17339269","id":"PMC_17339269","title":"A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss.","date":"2007","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17339269","citation_count":93,"is_preprint":false},{"pmid":"12121700","id":"PMC_12121700","title":"Coordinate regulation of secretory stress proteins (PSP/reg, PAP I, PAP II, and PAP III) in the rat exocrine pancreas during experimental acute pancreatitis.","date":"2002","source":"The Journal of surgical research","url":"https://pubmed.ncbi.nlm.nih.gov/12121700","citation_count":91,"is_preprint":false},{"pmid":"8846772","id":"PMC_8846772","title":"Differential binding of Lrp to two sets of pap DNA binding sites mediated by Pap I regulates Pap phase variation in Escherichia coli.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8846772","citation_count":83,"is_preprint":false},{"pmid":"10403789","id":"PMC_10403789","title":"Pokeweed antiviral protein isoforms PAP-I, PAP-II, and PAP-III depurinate RNA of human immunodeficiency virus (HIV)-1.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10403789","citation_count":67,"is_preprint":false},{"pmid":"19652881","id":"PMC_19652881","title":"Haplotype M2 in the annexin A5 (ANXA5) gene and the occurrence of obstetric complications.","date":"2009","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/19652881","citation_count":56,"is_preprint":false},{"pmid":"11302520","id":"PMC_11302520","title":"Cdx1 promotes cellular growth of epithelial intestinal cells through induction of the secretory protein PAP I.","date":"2001","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11302520","citation_count":45,"is_preprint":false},{"pmid":"20805002","id":"PMC_20805002","title":"Reduced allele specific annexin A5 mRNA levels in placentas carrying the M2/ANXA5 allele.","date":"2010","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/20805002","citation_count":41,"is_preprint":false},{"pmid":"17543301","id":"PMC_17543301","title":"Isolated Anxa5+/Sca-1+ perivascular cells from mouse meningeal vasculature retain their perivascular phenotype in vitro and in vivo.","date":"2007","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/17543301","citation_count":40,"is_preprint":false},{"pmid":"31404886","id":"PMC_31404886","title":"The role of ANXA5 in DBP-induced oxidative stress through ERK/Nrf2 pathway.","date":"2019","source":"Environmental toxicology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31404886","citation_count":31,"is_preprint":false},{"pmid":"28549727","id":"PMC_28549727","title":"Topographic analysis by atomic force microscopy of proteoliposomes matrix vesicle mimetics harboring TNAP and AnxA5.","date":"2017","source":"Biochimica et biophysica acta. Biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/28549727","citation_count":31,"is_preprint":false},{"pmid":"25214012","id":"PMC_25214012","title":"AnxA5 reduces plaque inflammation of advanced atherosclerotic lesions in apoE(-/-) mice.","date":"2014","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25214012","citation_count":31,"is_preprint":false},{"pmid":"31468674","id":"PMC_31468674","title":"The bifunctional SDF-1-AnxA5 fusion protein protects cardiac function after myocardial infarction.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31468674","citation_count":26,"is_preprint":false},{"pmid":"7672695","id":"PMC_7672695","title":"Suppression of calphobindin I (CPB I) production in carcinoma of uterine cervix and endometrium.","date":"1995","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/7672695","citation_count":26,"is_preprint":false},{"pmid":"31744864","id":"PMC_31744864","title":"Nerve Injury-Induced Neuronal PAP-I Maintains Neuropathic Pain by Activating Spinal Microglia.","date":"2019","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31744864","citation_count":25,"is_preprint":false},{"pmid":"24140079","id":"PMC_24140079","title":"Contribution of fetal ANXA5 gene promoter polymorphisms to the onset of pre-eclampsia.","date":"2013","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/24140079","citation_count":24,"is_preprint":false},{"pmid":"23850300","id":"PMC_23850300","title":"Genotyping analyses for polymorphisms of ANXA5 gene in patients with recurrent pregnancy loss.","date":"2013","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/23850300","citation_count":21,"is_preprint":false},{"pmid":"27697636","id":"PMC_27697636","title":"Anxa5 mediates the in vitro malignant behaviours of murine hepatocarcinoma Hca-F cells with high lymph node metastasis potential preferentially via ERK2/p-ERK2/c-Jun/p-c-Jun(Ser73) and E-cadherin.","date":"2016","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/27697636","citation_count":19,"is_preprint":false},{"pmid":"22679123","id":"PMC_22679123","title":"The M2 haplotype in the ANXA5 gene is an independent risk factor for idiopathic small-for-gestational age newborns.","date":"2012","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/22679123","citation_count":16,"is_preprint":false},{"pmid":"8956791","id":"PMC_8956791","title":"Mechanism of PAP I gene induction during hepatocarcinogenesis: clinical implications.","date":"1996","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/8956791","citation_count":14,"is_preprint":false},{"pmid":"33354277","id":"PMC_33354277","title":"Overexpression of miR-506-3p Aggravates DBP-Induced Testicular Oxidative Stress in Rats by Downregulating ANXA5 via Nrf2/HO-1 Signaling Pathway.","date":"2020","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/33354277","citation_count":14,"is_preprint":false},{"pmid":"22870292","id":"PMC_22870292","title":"Combining [11C]-AnxA5 PET imaging with serum biomarkers for improved detection in live mice of modest cell death in human solid tumor xenografts.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22870292","citation_count":14,"is_preprint":false},{"pmid":"11231317","id":"PMC_11231317","title":"Pancreatitis associated protein I (PAP-I) alters adhesion and motility of human melanocytes and melanoma cells.","date":"2001","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/11231317","citation_count":14,"is_preprint":false},{"pmid":"24743186","id":"PMC_24743186","title":"Involvement of ANXA5 and ILKAP in susceptibility to malignant melanoma.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24743186","citation_count":13,"is_preprint":false},{"pmid":"27418639","id":"PMC_27418639","title":"Lessons From the EThIGII Trial: Proper Putative Benefit Assessment of Low-Molecular-Weight Heparin Treatment in M2/ANXA5 Haplotype Carriers.","date":"2016","source":"Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/27418639","citation_count":13,"is_preprint":false},{"pmid":"23498654","id":"PMC_23498654","title":"Independent association of the M2/ANXA5 haplotype with recurrent pregnancy loss (RPL) in PCOS patients.","date":"2013","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/23498654","citation_count":13,"is_preprint":false},{"pmid":"25682309","id":"PMC_25682309","title":"M2/ANXA5 haplotype as a predisposition factor in Malay women and couples experiencing recurrent spontaneous abortion: a pilot study.","date":"2015","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/25682309","citation_count":13,"is_preprint":false},{"pmid":"12600746","id":"PMC_12600746","title":"The Polycomb-group protein ENX-2 interacts with ZAP-70.","date":"2003","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/12600746","citation_count":12,"is_preprint":false},{"pmid":"10662590","id":"PMC_10662590","title":"PAP I interacts with itself, PAP II, PAP III, and lithostathine/regIalpha.","date":"1999","source":"Molecular cell biology research communications : MCBRC","url":"https://pubmed.ncbi.nlm.nih.gov/10662590","citation_count":12,"is_preprint":false},{"pmid":"35964539","id":"PMC_35964539","title":"Research progress on ANXA5 in recurrent pregnancy loss.","date":"2022","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35964539","citation_count":11,"is_preprint":false},{"pmid":"2534288","id":"PMC_2534288","title":"The human endonexin II (ENX2) gene is located at 4q28----q32.","date":"1989","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2534288","citation_count":11,"is_preprint":false},{"pmid":"27178140","id":"PMC_27178140","title":"Skin Wound Repair Is Not Altered in the Absence of Endogenous AnxA1 or AnxA5, but Pharmacological Concentrations of AnxA4 and AnxA5 Inhibit Wound Hemostasis.","date":"2016","source":"Cells, tissues, organs","url":"https://pubmed.ncbi.nlm.nih.gov/27178140","citation_count":11,"is_preprint":false},{"pmid":"22635237","id":"PMC_22635237","title":"The annexin A5 protective shield model revisited: inherited carriage of the M2/ANXA5 haplotype in placenta as a predisposing factor for the development of obstetric antiphospholipid antibodies.","date":"2012","source":"Lupus","url":"https://pubmed.ncbi.nlm.nih.gov/22635237","citation_count":10,"is_preprint":false},{"pmid":"26615672","id":"PMC_26615672","title":"ANXA5 level is linked to in vitro and in vivo tumor malignancy and lymphatic metastasis of murine hepatocarcinoma cell.","date":"2015","source":"Future oncology (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26615672","citation_count":10,"is_preprint":false},{"pmid":"29497952","id":"PMC_29497952","title":"Maternal carriers of the ANXA5 M2 haplotype are exposed to a greater risk for placenta-mediated pregnancy complications.","date":"2018","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29497952","citation_count":9,"is_preprint":false},{"pmid":"34440732","id":"PMC_34440732","title":"Development of Tg(UAS:SEC-Hsa.ANXA5-YFP,myl7:RFP); Casper(roy-/-,nacre-/-) Transparent Transgenic In Vivo Zebrafish Model to Study the Cardiomyocyte Function.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34440732","citation_count":8,"is_preprint":false},{"pmid":"15885230","id":"PMC_15885230","title":"The value of biliary amylase and Hepatocarcinoma-Intestine-Pancreas/Pancreatitis-associated Protein I (HIP/PAP-I) in diagnosing biliary malignancies.","date":"2005","source":"Clinical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15885230","citation_count":8,"is_preprint":false},{"pmid":"34878150","id":"PMC_34878150","title":"Genetic analysis of ANXA5 haplotype and its effect on recurrent pregnancy loss.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/34878150","citation_count":7,"is_preprint":false},{"pmid":"23529182","id":"PMC_23529182","title":"The haplotype M2 of the ANXA5 gene is not associated with antitrophoblast antibodies.","date":"2013","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23529182","citation_count":7,"is_preprint":false},{"pmid":"7487908","id":"PMC_7487908","title":"Identification of a transcriptional regulatory region of the rat pancreatitis-associated protein I (PAP I) gene that confers tissue specificity.","date":"1995","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/7487908","citation_count":7,"is_preprint":false},{"pmid":"38824386","id":"PMC_38824386","title":"ANXA5: A Key Regulator of Immune Cell Infiltration in Hepatocellular Carcinoma.","date":"2024","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/38824386","citation_count":6,"is_preprint":false},{"pmid":"33840679","id":"PMC_33840679","title":"Sequential preovulatory expression of a gonadotropin-releasing hormone-inducible gene, Nr4a3, and its suppressor Anxa5 in the pituitary gland of female rats.","date":"2021","source":"The Journal of reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/33840679","citation_count":6,"is_preprint":false},{"pmid":"40342928","id":"PMC_40342928","title":"ANXA5: related mechanisms of osteogenesis and additional biological functions.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/40342928","citation_count":5,"is_preprint":false},{"pmid":"29716435","id":"PMC_29716435","title":"Micromolar Zinc in Annexin A5 Anticoagulation as a Potential Remedy for RPRGL3-Associated Recurrent Pregnancy Loss.","date":"2018","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/29716435","citation_count":5,"is_preprint":false},{"pmid":"38082058","id":"PMC_38082058","title":"LncRNA MIR4697HG Alleviates Endothelial Cell Injury and Atherosclerosis Progression in Mice via the FUS/ANXA5 Axis.","date":"2023","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38082058","citation_count":5,"is_preprint":false},{"pmid":"33231128","id":"PMC_33231128","title":"Glucocorticoid resistance induced by ANXA5 overexpression in B-cell acute lymphoblastic leukemia.","date":"2020","source":"Pediatric hematology and oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33231128","citation_count":5,"is_preprint":false},{"pmid":"25462330","id":"PMC_25462330","title":"Disruption of murine Tcte3-3 induces tissue specific apoptosis via co-expression of Anxa5 and Pebp1.","date":"2014","source":"Computational biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25462330","citation_count":5,"is_preprint":false},{"pmid":"30196743","id":"PMC_30196743","title":"Correlation of single nucleotide polymorphisms in the promoter region of the ANXA5 (annexin A5) gene with recurrent miscarriages in women of Greek origin.","date":"2018","source":"The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians","url":"https://pubmed.ncbi.nlm.nih.gov/30196743","citation_count":5,"is_preprint":false},{"pmid":"21329657","id":"PMC_21329657","title":"Continuous stress-induced dopamine dysregulation augments PAP-I and PAP-II expression in melanotrophs of the pituitary gland.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21329657","citation_count":5,"is_preprint":false},{"pmid":"9126283","id":"PMC_9126283","title":"Characterization of a silencer regulatory element in the rat PAP I gene which confers tissue-specific expression and is promoter-dependent.","date":"1997","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/9126283","citation_count":5,"is_preprint":false},{"pmid":"29095261","id":"PMC_29095261","title":"The association between annexin A5 (ANXA5) gene polymorphism and left ventricular hypertrophy (LVH) in Chinese endogenous hypertension patients.","date":"2017","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29095261","citation_count":4,"is_preprint":false},{"pmid":"35899914","id":"PMC_35899914","title":"Association between ANXA5 haplotypes and the risk of recurrent pregnancy loss.","date":"2022","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/35899914","citation_count":3,"is_preprint":false},{"pmid":"39857592","id":"PMC_39857592","title":"SSL5-AnxA5 Fusion Protein Constructed Based on Human Atherosclerotic Plaque scRNA-Seq Data Preventing the Binding of Apoptotic Endothelial Cells, Platelets, and Inflammatory Cells.","date":"2024","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/39857592","citation_count":3,"is_preprint":false},{"pmid":"31190166","id":"PMC_31190166","title":"The relevance of ANXA5 genetic variants on male fertility.","date":"2019","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31190166","citation_count":2,"is_preprint":false},{"pmid":"2148197","id":"PMC_2148197","title":"[Morphological detection of placental anticoagulant protein-I (PAP-I) in human placenta].","date":"1990","source":"Rinsho byori. The Japanese journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/2148197","citation_count":2,"is_preprint":false},{"pmid":"30304747","id":"PMC_30304747","title":"Antiphospholipid Antibodies in a General Obstetric Population: Clinical Impact on Pregnancy Outcome and Relationship with the M2 Haplotype in the Annexin A5 (ANXA5) Gene.","date":"2018","source":"Hamostaseologie","url":"https://pubmed.ncbi.nlm.nih.gov/30304747","citation_count":1,"is_preprint":false},{"pmid":"40124374","id":"PMC_40124374","title":"Integrative analysis of single-cell and bulk RNA sequencing reveals the oncogenic role of ANXA5 in gastric cancer and its association with drug resistance.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40124374","citation_count":1,"is_preprint":false},{"pmid":"40438404","id":"PMC_40438404","title":"Identification of functional SNP associated with sperm quality in porcine ANXA5 that contributes to the growth of immature Sertoli cell.","date":"2025","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/40438404","citation_count":1,"is_preprint":false},{"pmid":"10571267","id":"PMC_10571267","title":"Mouse monoclonal antibodies against Phytolacca americana antiviral protein PAP I.","date":"1999","source":"Hybridoma","url":"https://pubmed.ncbi.nlm.nih.gov/10571267","citation_count":1,"is_preprint":false},{"pmid":"39263641","id":"PMC_39263641","title":"ANXA5 and VEGFA Gene Variants in Women with Early Pregnancy Losses from North Macedonia.","date":"2024","source":"Balkan journal of medical genetics : BJMG","url":"https://pubmed.ncbi.nlm.nih.gov/39263641","citation_count":0,"is_preprint":false},{"pmid":"41190166","id":"PMC_41190166","title":"Single nucleotide variations in the ANXA5 promoter regulated piglet weight in the Min pig.","date":"2025","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/41190166","citation_count":0,"is_preprint":false},{"pmid":"41610337","id":"PMC_41610337","title":"Conformation of CD40LG and ANXA5 as Key Events of 2,7-Dibromocarbazole-Induced Cardiotoxicity Using in Vivo and in Vitro Models.","date":"2026","source":"Environmental science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/41610337","citation_count":0,"is_preprint":false},{"pmid":"41815119","id":"PMC_41815119","title":"COL10A1 transcriptional regulation of ANXA5-mediated ferroptosis is involved in malignant progression of head and neck squamous cell carcinoma.","date":"2026","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41815119","citation_count":0,"is_preprint":false},{"pmid":"41411728","id":"PMC_41411728","title":"Remdesivir alleviates inflammation and tissue damage in experimental colitis via AnxA5 Signaling.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41411728","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.23.677988","title":"Duchenne muscular dystrophy is driven by defective membrane repair and annexin-A2 dysregulation in skeletal muscle","date":"2025-09-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.23.677988","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.30.605947","title":"IDENTIFICATION OF IMMUNE RESPONSE AND RNA NETWORK OF RHEUMATOID ARTHRITIS AND MOLECULAR DOCKING OF<i>CELASTRUS PANICULATUS</i>AS POTENTIAL THERAPEUTIC AGENT","date":"2024-08-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.30.605947","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.16.659909","title":"The <i>pcnB</i> gene sustains <i>Shigella flexneri</i> virulence","date":"2025-06-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.16.659909","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36759,"output_tokens":4518,"usd":0.089024},"stage2":{"model":"claude-opus-4-6","input_tokens":8033,"output_tokens":2908,"usd":0.169297},"total_usd":0.258321,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"The human ANXA5 gene (endonexin II, ENX2) was mapped to chromosome 4q28-q32 by Southern transfer analysis of human x rodent somatic cell hybrid DNAs and in situ chromosome hybridization, establishing it as a member of the Ca2+-dependent phospholipid-binding annexin gene family.\",\n      \"method\": \"Somatic cell hybrid panel Southern blotting and in situ chromosome hybridization\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct chromosomal mapping by two orthogonal methods\",\n      \"pmids\": [\"2534288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"ANXA5 (placental anticoagulant protein-I, PAP-I) was localized to the microvilli of placental syncytiotrophoblast cells and their cortical cytoplasm beneath the villi, establishing its specific subcellular distribution in the relevant anticoagulant compartment.\",\n      \"method\": \"Immunocytochemistry (light and electron microscopy) of human placenta\",\n      \"journal\": \"Rinsho byori. The Japanese journal of clinical pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by electron microscopy with functional context\",\n      \"pmids\": [\"2148197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"ANXA5 (calphobindin I/CPB I/Annexin V) was identified as an endogenous inhibitor of protein kinase C, and its expression was markedly suppressed at the transcriptional level in cervical and endometrial carcinoma cells compared to normal counterparts, as shown by northern blot and in situ hybridization.\",\n      \"method\": \"Northern blot, in situ hybridization, immunohistochemistry\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods showing transcriptional suppression; PKC inhibition referenced from prior work\",\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 level as demonstrated by reporter gene (luciferase) assays, and is associated with recurrent pregnancy loss risk.\",\n      \"method\": \"Reporter gene (luciferase) assays, sequence analysis, case-control genetic study\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — functional promoter assay combined with large case-control study, replicated across multiple populations\",\n      \"pmids\": [\"17339269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ANXA5-expressing perivascular cells (PVC) isolated using the Anxa5-LacZ fusion gene marker express pericyte-specific markers (NG2, desmin, αSMA, PDGFR-β) and stem cell marker Sca-1, and when co-cultured with endothelial cells stimulate angiogenesis (increased PECAM expression) and basement membrane deposition; in vivo grafts recruit endothelial cells and become vascularized.\",\n      \"method\": \"Cell isolation using Anxa5-LacZ reporter, immunophenotyping, co-culture assays, in vivo chorioallantoic membrane graft\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo methods establishing ANXA5 as perivascular cell marker with functional consequence\",\n      \"pmids\": [\"17543301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The M2 allele of ANXA5 results in an average 42% reduction in allele-specific ANXA5 mRNA levels in heterozygous placentas compared to the normal allele, directly linking the M2 promoter haplotype to reduced expression in the relevant tissue.\",\n      \"method\": \"Allele-specific mRNA quantification in placental tissue by RT-PCR, Western blot\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct allele-specific expression measurement in tissue with functional implication\",\n      \"pmids\": [\"20805002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In pre-eclamptic patients, placental ANXA5 mRNA and protein levels are lower in M2 haplotype carriers, and placental (fetal) M2 genotype correlates more closely than maternal M2 with severity of perivillous fibrin deposition, indicating ANXA5 functions locally at the feto-maternal interface to prevent thrombosis.\",\n      \"method\": \"qRT-PCR, Western blot, immunostaining, histological examination of placentas\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in human tissue with mechanistic pathway link\",\n      \"pmids\": [\"24140079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Exogenous ANXA5, which binds cell-surface phosphatidylserine (PS), reduces plaque macrophage content in advanced atherosclerotic lesions in apoE−/− mice; in vitro, ANXA5 inhibits capture, rolling, adhesion, and transmigration of peripheral blood mononuclear cells on TNF-α-activated endothelial cells, establishing an anti-inflammatory mechanism via PS binding.\",\n      \"method\": \"In vivo mouse atherosclerosis model (collar placement), immunohistochemistry, in vitro flow chamber adhesion assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro experiments with defined cellular readouts\",\n      \"pmids\": [\"25214012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ANXA5 requires the ability to form two-dimensional (2D) arrays on the cell surface (via PS binding) to inhibit hemostasis: pharmacological concentrations of wild-type ANXA5 (1 µM) induced bleeding in mice, while an ANXA5 mutant that binds PS but cannot form 2D arrays failed to cause bleeding or delay coagulation, demonstrating that 2D lattice formation is necessary for ANXA5's anticoagulant function.\",\n      \"method\": \"AnxA5-deficient mice, injection of recombinant WT and mutant ANXA5, in vivo bleeding assay, in vitro coagulation assays\",\n      \"journal\": \"Cells, tissues, organs\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vivo mutagenesis study with mechanistic mutant validation and multiple orthogonal assays\",\n      \"pmids\": [\"27178140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Knockdown of ANXA5 in murine hepatocarcinoma Hca-F cells reduces proliferation, migration, invasion, and lymph node adhesion; mechanistically, ANXA5 acts specifically via the ERK2/p-ERK2/c-Jun/p-c-Jun(Ser73) pathway and regulates E-cadherin levels, rather than through p38MAPK, JNK, or AKT pathways.\",\n      \"method\": \"shRNA knockdown, CCK-8, Boyden transwell, in situ LN adhesion assay, Western blot, qRT-PCR, pathway inhibitor experiments\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cellular assays with specific pathway identification via knockdown and inhibitors\",\n      \"pmids\": [\"27697636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ANXA5 and TNAP co-incorporated into proteoliposomes (matrix vesicle mimetics) induce local changes in membrane fluidity detectable by AFM; ANXA5-containing proteoliposomes bind type II collagen, and combined TNAP+ANXA5 proteoliposomes show lower collagen affinity than ANXA5 alone, establishing ANXA5's role in membrane organization and matrix interactions during biomineralization.\",\n      \"method\": \"Atomic force microscopy of proteoliposomes, reconstitution of ANXA5 and TNAP into lipid vesicles, collagen binding assay\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution system with direct structural visualization by AFM\",\n      \"pmids\": [\"28549727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Micromolar Zn2+ stimulates ANXA5 transcription, raising ANXA5 protein 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, linking ANXA5 transcriptional upregulation to anticoagulant function and pregnancy outcome.\",\n      \"method\": \"Cell culture (BeWo, HUVEC), Western blot, coagulation assay, AnxA5-deficient mouse model with dietary Zn2+ supplementation\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo convergent evidence with functional anticoagulation readout\",\n      \"pmids\": [\"29716435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANXA5 overexpression in testicular Leydig and Sertoli cells activates the Nrf2/HO-1/NQO1 antioxidant pathway via ERK phosphorylation, and attenuates DBP-induced oxidative stress; ERK inhibition reverses the protective effect of ANXA5, establishing the ANXA5→ERK→Nrf2 signaling axis.\",\n      \"method\": \"Overexpression and knockdown in cell culture, DHE staining, ELISA, Western blot, ERK inhibitor experiments\",\n      \"journal\": \"Environmental toxicology and pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function plus pharmacological inhibition placing ANXA5 upstream of ERK/Nrf2\",\n      \"pmids\": [\"31404886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AnxA5 domain specifically recognizes and binds to cells injured by hypoxia (PS-exposing dead/dying cells); a SDF-1-AnxA5 fusion protein accumulates at infarcted myocardium after peripheral vein injection in mice, reduces apoptosis, enhances angiogenesis, reduces infarct size, and improves cardiac function, demonstrating ANXA5's PS-targeting function can be exploited for cardiac drug delivery.\",\n      \"method\": \"Receptor competition assay, binding membrane assay, immunofluorescence, mouse MI model with IV injection, echocardiography\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro binding characterization plus in vivo functional validation\",\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 decreases ANXA5 protein levels and downregulates the Nrf2/HO-1 signaling pathway, aggravating DBP-induced testicular oxidative stress injury; exogenous recombinant ANXA5 reverses these effects, establishing ANXA5 as a direct target of miR-506-3p in testicular oxidative stress regulation.\",\n      \"method\": \"miRNA agomir injection in rats, luciferase reporter (miRNA target validation), Western blot, immunohistochemistry, CCK-8, flow cytometry\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct miRNA target validation combined with in vivo rescue experiment\",\n      \"pmids\": [\"33354277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA5 silencing in B-ALL cells increases DEX-induced apoptosis and significantly elevates cleaved Caspase 3 and Caspase 9 levels, establishing that ANXA5 confers glucocorticoid resistance by suppressing caspase-dependent apoptosis.\",\n      \"method\": \"siRNA knockdown, flow cytometry (apoptosis), Western blot (caspase cleavage)\",\n      \"journal\": \"Pediatric hematology and oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method per endpoint, single lab\",\n      \"pmids\": [\"33231128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In rat pituitary gland, GnRH induces Nr4a3 mRNA expression (peak at proestrus), after which Anxa5 mRNA rises and suppresses Nr4a3, with Anxa5 elevation coinciding with increased Fshb mRNA; GnRH antagonist abolishes Nr4a3 induction, establishing a sequential GnRH→Nr4a3→Anxa5 regulatory axis controlling FSH-beta expression.\",\n      \"method\": \"RT-PCR, GnRH antagonist treatment in vivo, analysis across estrous cycle time points\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo pharmacological intervention (GnRH antagonist) with temporal expression profiling establishing pathway position\",\n      \"pmids\": [\"33840679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LncRNA MIR4697HG binds FUS protein (shown by RNA pull-down), and FUS in turn interacts with ANXA5 (shown by Co-IP); MIR4697HG overexpression upregulates FUS, which promotes ANXA5 expression to protect endothelial cells from ox-LDL-induced apoptosis, oxidative stress, and adhesion molecule release; ANXA5 knockdown reverses the protective effect of FUS overexpression.\",\n      \"method\": \"RNA pull-down, Co-immunoprecipitation, overexpression/knockdown in HUVECs, ApoE−/− mouse atherosclerosis model\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and RNA pulldown identifying MIR4697HG/FUS/ANXA5 complex with functional rescue experiments\",\n      \"pmids\": [\"38082058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Duchenne muscular dystrophy (DMD) skeletal muscle cells, ANXA5 and ANXA6 fail to upregulate in response to mechanical stress (unlike control cells), suggesting ANXA5 normally participates in an adaptive membrane repair response in skeletal muscle; DMD cells show defective membrane resealing and massive IgG uptake confirming impaired repair.\",\n      \"method\": \"Shear stress-based injury assay, live-cell imaging of GFP-tagged annexins, Western blot, immunohistochemistry of patient biopsies\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 — direct stress-response measurement in human cells and biopsies, but preprint and single lab\",\n      \"pmids\": [\"bio_10.1101_2025.09.23.677988\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ANXA5 (Annexin A5/Annexin V) is a Ca2+-dependent phospholipid-binding protein that preferentially binds phosphatidylserine (PS) on cell surfaces, where it forms protective two-dimensional arrays that inhibit coagulation and provide anticoagulant shielding at the placental syncytiotrophoblast surface; reduced ANXA5 expression caused by the M2 promoter haplotype impairs this placental anticoagulant shield and predisposes to thrombosis-related obstetric complications, while ANXA5 additionally functions as an inhibitor of protein kinase C, a regulator of ERK/Nrf2-mediated antioxidant signaling, a participant in membrane repair responses in skeletal muscle, and a modulator of monocyte/macrophage recruitment in atherosclerosis via PS-targeting.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ANXA5 (Annexin A5) is a Ca²⁺-dependent phospholipid-binding protein that preferentially binds phosphatidylserine (PS) on cell surfaces and forms two-dimensional crystalline arrays essential for its anticoagulant activity; an ANXA5 mutant that binds PS but cannot form 2D lattices fails to inhibit coagulation, establishing lattice formation as the mechanistic basis of its hemostatic function [PMID:27178140]. At the placental syncytiotrophoblast, ANXA5 provides an anticoagulant shield, and the M2 promoter haplotype reduces ANXA5 transcription to ~40% of normal levels in placental tissue, predisposing to perivillous fibrin deposition and recurrent pregnancy loss [PMID:17339269, PMID:24140079]. Beyond anticoagulation, ANXA5 activates the ERK→Nrf2/HO-1 antioxidant signaling axis to protect against oxidative stress, inhibits monocyte adhesion and transmigration across activated endothelium via PS binding to attenuate atherosclerotic inflammation, and functions as an endogenous inhibitor of protein kinase C [PMID:31404886, PMID:25214012, PMID:7672695].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing ANXA5 as a member of the annexin family with a defined chromosomal locus (4q28-q32) provided the genomic framework for subsequent functional and genetic studies.\",\n      \"evidence\": \"Southern blot analysis of somatic cell hybrids and in situ chromosome hybridization\",\n      \"pmids\": [\"2534288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional characterization at this stage\", \"Regulatory elements of the locus not yet mapped\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Localizing ANXA5 to syncytiotrophoblast microvilli and cortical cytoplasm established the subcellular compartment where it could function as a placental anticoagulant.\",\n      \"evidence\": \"Immunocytochemistry with light and electron microscopy of human placental tissue\",\n      \"pmids\": [\"2148197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of anticoagulant action at this surface not yet defined\", \"Dynamics of ANXA5 recruitment to microvilli unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying ANXA5 as a protein kinase C inhibitor whose transcription is suppressed in carcinoma cells revealed a potential tumor-suppressive signaling role beyond its membrane-binding properties.\",\n      \"evidence\": \"Northern blot, in situ hybridization, and immunohistochemistry in cervical/endometrial carcinoma vs. normal tissue\",\n      \"pmids\": [\"7672695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism of PKC inhibition not dissected\", \"Causal link between ANXA5 loss and tumorigenesis not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that the M2 promoter haplotype reduces ANXA5 transcription to ~37–42% of normal and associates with recurrent pregnancy loss provided the first mechanistic genetic link between ANXA5 expression and obstetric thrombotic complications.\",\n      \"evidence\": \"Luciferase reporter assays and case-control genetic study across multiple populations\",\n      \"pmids\": [\"17339269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-level validation of reduced expression not yet performed\", \"Contribution of paternal vs. maternal genotype unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Allele-specific mRNA quantification in heterozygous placentas confirmed that the M2 haplotype reduces ANXA5 expression by ~42% in the relevant tissue, validating the reporter assay findings in vivo.\",\n      \"evidence\": \"Allele-specific RT-PCR and Western blot in human placental tissue\",\n      \"pmids\": [\"20805002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether reduced expression crosses a threshold for clinical thrombosis not determined\", \"Protein-level quantification at the cell surface not performed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that fetal (placental) M2 genotype correlates with perivillous fibrin deposition more than maternal genotype established that ANXA5 functions locally at the feto-maternal interface to prevent thrombosis.\",\n      \"evidence\": \"qRT-PCR, Western blot, immunostaining, and histological assessment of pre-eclamptic placentas\",\n      \"pmids\": [\"24140079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether exogenous ANXA5 can rescue the M2-associated phenotype in human tissue untested\", \"Contributions of other annexins at the same interface not assessed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that exogenous ANXA5 reduces plaque macrophage content and inhibits monocyte adhesion/transmigration via PS binding extended its anti-inflammatory role beyond the placenta to atherosclerosis.\",\n      \"evidence\": \"ApoE−/− mouse atherosclerosis model with collar placement and in vitro flow chamber assays on TNFα-activated endothelium\",\n      \"pmids\": [\"25214012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether endogenous ANXA5 levels modulate atherosclerosis in vivo not tested\", \"Receptor or signaling target on monocytes not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Using an ANXA5 mutant that binds PS but cannot form 2D arrays revealed that lattice formation—not merely PS binding—is the mechanistic requirement for ANXA5's anticoagulant activity, resolving a longstanding question about how ANXA5 inhibits coagulation.\",\n      \"evidence\": \"Injection of wild-type vs. lattice-deficient recombinant ANXA5 in AnxA5-deficient mice with in vivo bleeding and in vitro coagulation assays\",\n      \"pmids\": [\"27178140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of the 2D array at atomic resolution not resolved\", \"Whether 2D array formation is also required for non-coagulant functions unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"ANXA5 knockdown in hepatocarcinoma cells reduced proliferation, migration, and invasion specifically through the ERK2/p-ERK2/c-Jun pathway, identifying ANXA5 as an upstream activator of ERK signaling in cancer cell biology.\",\n      \"evidence\": \"shRNA knockdown with pathway inhibitor experiments, transwell and adhesion assays in Hca-F cells\",\n      \"pmids\": [\"27697636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partner linking ANXA5 to ERK2 activation not identified\", \"Relevance to human cancer not validated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ANXA5 overexpression activated the ERK→Nrf2/HO-1/NQO1 antioxidant pathway and protected testicular cells from oxidative stress, with ERK inhibition fully reversing the effect, establishing a defined ANXA5→ERK→Nrf2 signaling axis for cytoprotection.\",\n      \"evidence\": \"Overexpression and knockdown in Leydig/Sertoli cells with ERK inhibitor rescue, DHE staining, and Western blot\",\n      \"pmids\": [\"31404886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ANXA5 activates ERK phosphorylation mechanistically is unknown\", \"Whether this axis operates in non-testicular tissues not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"miR-506-3p was validated as a direct upstream regulator of ANXA5, with miR-506-3p binding the ANXA5 3′UTR to suppress expression and thereby aggravate oxidative stress through loss of Nrf2/HO-1 signaling.\",\n      \"evidence\": \"Luciferase reporter target validation, miRNA agomir injection in rats, rescue with recombinant ANXA5\",\n      \"pmids\": [\"33354277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether miR-506-3p regulation of ANXA5 is relevant in placental or vascular contexts unknown\", \"Other miRNAs targeting ANXA5 not systematically assessed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of the MIR4697HG lncRNA→FUS→ANXA5 axis in endothelial cells revealed a new upstream regulatory pathway controlling ANXA5 expression to protect against ox-LDL-induced endothelial dysfunction.\",\n      \"evidence\": \"RNA pull-down, Co-IP for FUS–ANXA5 interaction, overexpression/knockdown rescue in HUVECs, and ApoE−/− mouse model\",\n      \"pmids\": [\"38082058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FUS directly stabilizes ANXA5 mRNA or protein is unclear\", \"Co-IP interaction between FUS and ANXA5 protein requires reciprocal validation and domain mapping\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which ANXA5 activates ERK signaling, the structural basis of its 2D array at atomic resolution on biological membranes, and whether its anticoagulant lattice-forming function is required for its anti-inflammatory and cytoprotective roles remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct binding partner linking ANXA5 to ERK activation identified\", \"No high-resolution structure of the 2D array on a native membrane\", \"Whether 2D lattice formation is required for non-coagulant functions untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 7, 8, 10, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 8, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7, 8, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [12, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FUS\",\n      \"ANXA6\",\n      \"ALPL\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}