{"gene":"ANTXR1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2001,"finding":"ANTXR1 (ATR/TEM8) was identified as the cellular receptor for anthrax toxin protective antigen (PA). It is a type I membrane protein with an extracellular von Willebrand factor A (vWA) domain that directly binds PA, and a soluble version of this domain protects cells from anthrax toxin.","method":"Genetic complementation cloning; direct binding assay between recombinant vWA domain and PA; cell protection assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — original receptor identification by genetic complementation plus direct in vitro binding reconstitution","pmids":["11700562"],"is_preprint":false},{"year":2006,"finding":"ANTXR1 undergoes palmitoylation in its cytoplasmic tail, which prevents premature association with lipid rafts and premature ubiquitination. Upon PA heptamerization, ANTXR1 moves into rafts where the E3 ubiquitin ligase Cbl ubiquitinates it, triggering rapid endocytosis of the toxin-receptor complex. Palmitoylation-defective receptors show reduced surface expression and premature internalization without PA heptamerization.","method":"Palmitoylation-defective mutant receptors; lipid raft fractionation; co-immunoprecipitation of Cbl; ubiquitination assays; endocytosis assays; cell intoxication assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including mutagenesis, biochemical fractionation, and functional rescue in a single study","pmids":["16401723"],"is_preprint":false},{"year":2006,"finding":"LRP6 (a Wnt co-receptor) is required for anthrax toxin lethality and physically interacts with ANTXR1 (TEM8) at the cell surface to form a multicomponent complex that internalizes PA-containing toxin complexes. Downregulation of LRP6 or expression of dominant-negative LRP6 inhibited cellular uptake of PA and protected cells from death.","method":"RNAi knockdown of LRP6; dominant-negative LRP6 overexpression; anti-LRP6 antibody blocking; fluorescence microscopy; co-immunoprecipitation; biochemical fractionation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, imaging, and multiple loss-of-function approaches showing ANTXR1-LRP6 complex formation and functional consequence","pmids":["16564009"],"is_preprint":false},{"year":2007,"finding":"ANTXR1 (TEM8) interacts with M2 isoenzyme of pyruvate kinase (M2-PK). An engineered TEM8-Fc molecule suppressed growth and metastasis of xenograft human tumors, potentially by trapping M2-PK.","method":"Co-immunoprecipitation identifying M2-PK as TEM8-interacting partner; xenograft tumor growth assays with TEM8-Fc","journal":"Journal of the National Cancer Institute","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP identifying interaction partner, functional mechanism not deeply dissected","pmids":["17925540"],"is_preprint":false},{"year":2007,"finding":"Specific residues in ANTXR1 TEM8's extracellular domain (residues 56, 57, and 154–160) determine the lower PA-binding affinity of TEM8 compared to CMG2. In particular, Leu56 is a key determinant of lower affinity. PA domain 4 variants (R659S/M662R) with preferential binding to TEM8 showed selective tumoricidal activity.","method":"Structure-based mutagenesis of TEM8; cell cytotoxicity assays with CHO cells expressing TEM8 vs CMG2; phage display selection of PA variants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — structure-guided mutagenesis with functional binding and cytotoxicity readout","pmids":["17251181"],"is_preprint":false},{"year":2010,"finding":"The crystal structure of the TEM8/ANTXR1 extracellular vWA domain was determined at 1.7 Å resolution. The domain adopts an integrin fold similar to CMG2. Structure-based mutagenesis identified the putative PA interface (residues 56, 57, 154–160) as responsible for the lower PA-binding affinity of TEM8 versus CMG2; Leu56 is the key residue.","method":"X-ray crystallography (1.7 Å resolution); structure-based mutagenesis; binding affinity assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation by mutagenesis","pmids":["20585457"],"is_preprint":false},{"year":2010,"finding":"The cell-surface structure of ANTXR1 (TEM8) is regulated by the actin cytoskeleton. Alpha-smooth muscle actin and transgelin (an actin-binding protein) alter the conformation of TEM8 at the cell surface, converting it from an antibody-accessible (SB5-exposed) to an antibody-masked form, indicating that intracellular actin cytoskeleton components modulate TEM8 extracellular domain presentation.","method":"Overexpression of actin-binding proteins; antibody recognition assays (SB5 vs AF334 antibodies); immunotoxin killing assays distinguishing TEM8 conformations","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional overexpression studies with antibody-based conformational readout, single lab","pmids":["21129411"],"is_preprint":false},{"year":2011,"finding":"ANTXR1 (TEM8) binds extracellular matrix proteins including collagen I, collagen IV, and laminin via its extracellular domain, and regulates endothelial cell migration and tubule formation during angiogenesis. CMG2 (ANTXR2) by contrast regulates endothelial proliferation.","method":"ECM binding assays; endothelial cell functional assays (migration, tubule formation); comparison of TEM8 and CMG2 loss-of-function","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Low","confidence_rationale":"Tier 3 — review compiling functional assay data, limited primary mechanistic detail","pmids":["21196249"],"is_preprint":false},{"year":2012,"finding":"Genetic disruption of Tem8/ANTXR1 impairs growth of human tumor xenografts. Anti-TEM8 antibodies blocked anthrax intoxication, inhibited tumor-induced angiogenesis, and displayed antitumor activity. TEM8 is required for pathological angiogenesis but its loss in normal tissues causes minimal toxicity, indicating a selective role in tumor vasculature.","method":"Genetic knockout mouse model (Tem8-null); xenograft tumor growth assays; antibody blockade experiments; anthrax intoxication protection assay","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined angiogenesis phenotype replicated across multiple tumor types, plus antibody functional studies","pmids":["22340594"],"is_preprint":false},{"year":2013,"finding":"Loss-of-function mutations in ANTXR1 (nonsense and splicing mutations causing nonsense-mediated mRNA decay or truncated protein) cause GAPO syndrome, characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment. The phenotype reflects a generalized defect in extracellular matrix homeostasis, consistent with ANTXR1's role in ECM regulation.","method":"Whole-exome sequencing of affected individuals; identification of homozygous nonsense (p.Arg88*, p.Arg169*) and splicing (c.1435-12A>G) mutations; mRNA decay analysis; genotype-phenotype correlation","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — causal human genetics with molecular validation of NMD and truncation, replicated in multiple unrelated families","pmids":["23602711"],"is_preprint":false},{"year":2013,"finding":"ANTXR1 acts as a functional biomarker of breast cancer stem-like cells. Activation of ANTXR1 by its natural ligand C5A (a collagen VI α3 fragment) increases stem cell self-renewal and activates Wnt signaling including upregulation of LRP6, phosphorylation of GSK3α/β, and elevated Wnt target genes. RNAi silencing of ANTXR1 reduces Wnt signaling (LRP6, ZEB1 expression), self-renewal, invasion, tumorigenicity, and metastasis.","method":"RNAi-mediated silencing; ligand stimulation (C5A peptide); mammosphere assay; Wnt pathway readouts (LRP6, GSK3 phosphorylation, target gene expression); in vivo tumorigenicity and metastasis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ligand activation, RNAi, in vivo assays) in single study establishing ANTXR1-Wnt axis","pmids":["23832666"],"is_preprint":false},{"year":2018,"finding":"Seneca Valley Virus (SVV) exploits ANTXR1 (TEM8) as an entry receptor, the same receptor used by anthrax toxin protective antigen. TEM8 also serves as a receptor for collagen VI, with the collagen VI interaction relevant to tumor cell biology.","method":"Receptor identification studies; cell entry assays; competitive binding with collagen VI and anthrax PA","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 — review/compilation; primary mechanistic data for SVV entry via TEM8 described but not fully detailed in this paper","pmids":["30460197"],"is_preprint":false},{"year":2017,"finding":"MicroRNA-493 directly targets and suppresses ANTXR1 expression in hepatocellular carcinoma cells. ANTXR1 overexpression can rescue the tumor-suppressive effects of miR-493, and ANTXR1 activates Wnt/β-catenin signaling in HCC cells to promote proliferation, migration, and tumor formation.","method":"miR-493 overexpression; 3'UTR luciferase reporter validation; ANTXR1 rescue (ORF reintroduction); cell proliferation, colony formation, migration, invasion assays; xenograft tumor assay; Wnt pathway readouts","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct target validation with rescue experiment and Wnt pathway readout, single lab","pmids":["28651234"],"is_preprint":false},{"year":2019,"finding":"MicroRNA-26b-3p directly targets ANTXR1 in glioma cells. ANTXR1 functions downstream of miR-26b-3p to promote glioma cell proliferation and migration and inhibit apoptosis; reintroduction of ANTXR1 (ORF lacking miRNA target site) rescues these effects.","method":"miR-26b-3p overexpression and inhibition; ORF rescue experiment; cell proliferation, migration, apoptosis assays; correlation with glioma severity","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 3 — direct rescue experiment establishing ANTXR1 as functional downstream effector, single lab","pmids":["31934301"],"is_preprint":false},{"year":2021,"finding":"N-Myc promotes angiogenesis and therapeutic resistance in prostate cancer via ANTXR1 (TEM8). N-Myc overexpression increases TEM8 expression, and combined overexpression promotes endothelial tubule formation and cancer cell proliferation; N-Myc-driven angiogenesis and resistance depend on TEM8.","method":"IHC correlation; overexpression of N-Myc and TEM8 in LNCaP cells; tubule formation assay with HUVECs; proliferation assays; bioinformatic analysis","journal":"Medical oncology","confidence":"Low","confidence_rationale":"Tier 3 — overexpression with functional readout but limited mechanistic dissection of N-Myc→TEM8 pathway","pmids":["34523032"],"is_preprint":false},{"year":2024,"finding":"ANTXR1+ cancer-associated fibroblasts (ECM-myCAF cluster within CAF-S1) reduce CD8+ T-cell cytotoxicity through a YAP1-dependent mechanism. These ANTXR1+ ECM-producing myofibroblasts are the CAF-S1 subpopulation most reduced by chemotherapy; functional assays demonstrate that ECM-myCAF suppress CD8+ T-cell killing via YAP1 signaling.","method":"Single-cell RNA sequencing; spatial transcriptomics; immunohistochemistry; functional co-culture assays of ECM-myCAF with CD8+ T cells; YAP1 inhibition experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay with YAP1 inhibition rescue, multiple orthogonal profiling approaches, single study","pmids":["38346978"],"is_preprint":false}],"current_model":"ANTXR1 (TEM8) is a type I transmembrane protein with an extracellular vWA/integrin-like domain that directly binds anthrax toxin protective antigen and ECM components (collagen VI fragment C5A, collagen I/IV, laminin); at the cell surface its conformation is regulated by actin-binding proteins (α-SMA, transgelin), and its endocytosis is controlled by sequential palmitoylation (preventing premature raft entry) and Cbl-mediated ubiquitination in lipid rafts, with LRP6 as a co-internalization partner; ANTXR1 activates Wnt/β-catenin signaling (upregulating LRP6, phosphorylating GSK3) upon collagen VI C5A ligation to promote stem cell self-renewal, invasion, and metastasis; loss-of-function mutations cause GAPO syndrome via defective ECM homeostasis, and ANTXR1+ myofibroblasts suppress anti-tumor immunity through a YAP1-dependent mechanism."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of ANTXR1 as the cellular receptor for anthrax toxin protective antigen established that a host transmembrane protein with an integrin-like vWA domain mediates toxin entry, opening the question of how receptor trafficking is regulated and what physiological ligands the receptor recognizes.","evidence":"Genetic complementation cloning in CHO cells plus direct binding of recombinant vWA domain to PA","pmids":["11700562"],"confidence":"High","gaps":["Physiological ligands of ANTXR1 unknown at this stage","Mechanism of receptor endocytosis uncharacterized","Relationship to angiogenesis only correlative from TEM8 name"]},{"year":2006,"claim":"The discovery that palmitoylation prevents premature lipid-raft association and that Cbl-mediated ubiquitination in rafts triggers endocytosis revealed a two-step trafficking switch controlling ANTXR1 surface residence and toxin internalization.","evidence":"Palmitoylation-defective mutants, raft fractionation, Cbl co-IP, and ubiquitination assays in transfected cells","pmids":["16401723"],"confidence":"High","gaps":["Palmitoyl transferase identity not determined","Whether this trafficking mechanism operates for physiological ligands unclear"]},{"year":2006,"claim":"Demonstration that LRP6 forms a physical complex with ANTXR1 and is required for PA internalization and lethality revealed a multicomponent receptor platform, linking ANTXR1 to the Wnt co-receptor machinery.","evidence":"RNAi, dominant-negative LRP6, anti-LRP6 antibody blocking, and reciprocal co-IP in multiple cell lines","pmids":["16564009"],"confidence":"High","gaps":["Whether ANTXR1–LRP6 interaction has signaling consequences beyond toxin entry was unknown","Stoichiometry and structural basis of the complex unresolved"]},{"year":2010,"claim":"The 1.7 Å crystal structure of the ANTXR1 vWA domain confirmed an integrin-like fold and, combined with mutagenesis, pinpointed Leu56 and residues 154–160 as determinants of lower PA-binding affinity relative to CMG2, providing a structural framework for selective ligand recognition.","evidence":"X-ray crystallography and structure-guided mutagenesis with binding affinity measurements","pmids":["20585457","17251181"],"confidence":"High","gaps":["No co-crystal with PA or ECM ligands solved","How structural differences translate to differential physiological functions of ANTXR1 vs CMG2 not established"]},{"year":2010,"claim":"Showing that α-smooth muscle actin and transgelin alter ANTXR1 extracellular domain conformation established that the intracellular actin cytoskeleton allosterically regulates receptor accessibility, analogous to inside-out signaling in integrins.","evidence":"Overexpression of actin-binding proteins with conformation-sensitive antibody readout and immunotoxin killing assays","pmids":["21129411"],"confidence":"Medium","gaps":["Mechanism of transmembrane conformational coupling not defined","Physiological triggers for this conformational switch unknown","Single-lab observation without independent replication"]},{"year":2012,"claim":"Genetic ablation of Tem8 in mice showed it is required for pathological angiogenesis and tumor xenograft growth but dispensable for normal vascular homeostasis, establishing ANTXR1 as a selective driver of tumor-associated neovasculature.","evidence":"Tem8-knockout mice; xenograft tumor assays across multiple tumor types; anti-TEM8 antibody treatment","pmids":["22340594"],"confidence":"High","gaps":["The endogenous ligand driving tumor angiogenesis through TEM8 was not identified in this study","Whether angiogenic role is cell-autonomous to endothelium vs stromal unclear"]},{"year":2013,"claim":"Identification of homozygous loss-of-function ANTXR1 mutations as the cause of GAPO syndrome demonstrated that the receptor's ECM-binding function is essential for normal tissue development and matrix homeostasis in humans.","evidence":"Whole-exome sequencing of multiple unrelated GAPO families; nonsense and splicing mutations validated by mRNA decay analysis","pmids":["23602711"],"confidence":"High","gaps":["Precise ECM substrates whose processing is disrupted in GAPO syndrome not defined","No animal model recapitulating GAPO features described at this point"]},{"year":2013,"claim":"Demonstrating that collagen VI fragment C5A activates ANTXR1-dependent Wnt/β-catenin signaling (via LRP6 upregulation and GSK3 phosphorylation) to drive breast cancer stem cell self-renewal and metastasis unified the receptor's ECM-binding and LRP6-interacting activities into a coherent oncogenic signaling axis.","evidence":"C5A ligand stimulation, RNAi silencing, mammosphere assays, Wnt pathway readouts, and in vivo tumorigenicity/metastasis models","pmids":["23832666"],"confidence":"Medium","gaps":["Whether C5A–ANTXR1–Wnt axis operates outside breast cancer not tested","Downstream transcriptional program beyond LRP6/ZEB1 not fully mapped","Direct mechanism linking ANTXR1 ligation to LRP6 upregulation unclear"]},{"year":2017,"claim":"Validation of ANTXR1 as a direct target of miR-493 and miR-26b-3p, with rescue experiments showing ANTXR1 activates Wnt/β-catenin signaling in hepatocellular carcinoma and promotes glioma cell proliferation, extended the oncogenic role of ANTXR1 beyond breast cancer.","evidence":"3′UTR luciferase reporters, ORF rescue experiments, proliferation/migration/xenograft assays in HCC and glioma cells","pmids":["28651234","31934301"],"confidence":"Medium","gaps":["Downstream Wnt targets in HCC/glioma contexts not deeply characterized","Single-lab studies without independent replication"]},{"year":2024,"claim":"Identification of ANTXR1 as a marker of ECM-producing myofibroblastic CAFs (ECM-myCAF) that suppress CD8+ T-cell cytotoxicity through YAP1-dependent signaling revealed a stromal immunosuppressive function for ANTXR1-expressing cells in the tumor microenvironment.","evidence":"Single-cell and spatial transcriptomics; functional co-culture of ECM-myCAF with CD8+ T cells; YAP1 inhibition rescue","pmids":["38346978"],"confidence":"Medium","gaps":["Whether ANTXR1 itself signals through YAP1 or is merely a marker of this CAF subpopulation not resolved","Causal role of ANTXR1 in the immunosuppressive phenotype not tested by direct ANTXR1 perturbation in CAFs"]},{"year":null,"claim":"Key unresolved questions include the structural basis of ANTXR1 engagement with ECM ligands (no co-crystal exists), the direct mechanism coupling ANTXR1 ligation to LRP6-dependent Wnt activation, the identity of the palmitoyl transferase that modifies ANTXR1, and whether ANTXR1 plays a cell-autonomous signaling role in cancer-associated fibroblasts versus serving as a lineage marker.","evidence":"","pmids":[],"confidence":"High","gaps":["No ANTXR1–ECM ligand co-crystal structure","Palmitoyl transferase identity unknown","ANTXR1 → LRP6/Wnt signaling mechanism not fully reconstituted","Cell-autonomous function in CAF immunosuppression not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,4,5,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,10,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,6]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[7,9]}],"pathway":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,10,12]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[7,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,10,12,13]}],"complexes":[],"partners":["LRP6","CBL","ACTA2","TAGLN","COL6A3"],"other_free_text":[]},"mechanistic_narrative":"ANTXR1 (TEM8) is a type I transmembrane receptor that couples extracellular matrix sensing to intracellular signaling, functioning in ECM homeostasis, angiogenesis, and Wnt/β-catenin pathway activation. Its extracellular von Willebrand factor A (vWA) domain binds anthrax toxin protective antigen, collagen VI fragment C5A, collagen I/IV, and laminin; ligation by C5A activates Wnt signaling through LRP6 upregulation and GSK3 phosphorylation, promoting stem cell self-renewal, invasion, and metastasis [PMID:11700562, PMID:23832666]. At the cell surface, ANTXR1 conformation is regulated by actin cytoskeleton components (α-SMA, transgelin), and its endocytosis proceeds through a regulated sequence of palmitoylation-controlled lipid-raft entry and Cbl-mediated ubiquitination, with LRP6 as a co-internalization partner [PMID:16401723, PMID:16564009, PMID:21129411]. Loss-of-function mutations in ANTXR1 cause GAPO syndrome, a disorder of generalized ECM dysregulation characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment [PMID:23602711]."},"prefetch_data":{"uniprot":{"accession":"Q9H6X2","full_name":"Anthrax toxin receptor 1","aliases":["Tumor endothelial marker 8"],"length_aa":564,"mass_kda":62.8,"function":"Plays a role in cell attachment and migration. Interacts with extracellular matrix proteins and with the actin cytoskeleton and thereby plays an important role in normal extracellular matrix (ECM) homeostasis. Mediates adhesion of cells to type 1 collagen and gelatin, reorganization of the actin cytoskeleton and promotes cell spreading. Plays a role in the angiogenic response of cultured umbilical vein endothelial cells. May also act as a receptor for PLAU. Upon ligand binding, stimulates the phosphorylation of EGFR and ERK1/2 (PubMed:30241478) (Microbial infection) Acts as a receptor for protective antigen (PA) of B.anthracis (Microbial infection) Mediates cell entry of Seneca Valley virus (SVV) when glycosylated","subcellular_location":"Cell membrane; Cell projection, lamellipodium membrane; Cell projection, filopodium membrane","url":"https://www.uniprot.org/uniprotkb/Q9H6X2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANTXR1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ANTXR1","total_profiled":1310},"omim":[{"mim_id":"608041","title":"ANTHRAX TOXIN RECEPTOR 2; ANTXR2","url":"https://www.omim.org/entry/608041"},{"mim_id":"606410","title":"ANTHRAX TOXIN RECEPTOR 1; ANTXR1","url":"https://www.omim.org/entry/606410"},{"mim_id":"603507","title":"LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 6; LRP6","url":"https://www.omim.org/entry/603507"},{"mim_id":"602089","title":"HEMANGIOMA, CAPILLARY INFANTILE","url":"https://www.omim.org/entry/602089"},{"mim_id":"230740","title":"GAPO SYNDROME; GAPOS","url":"https://www.omim.org/entry/230740"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":205.1}],"url":"https://www.proteinatlas.org/search/ANTXR1"},"hgnc":{"alias_symbol":["TEM8","FLJ21776","FLJ10601","ATR"],"prev_symbol":[]},"alphafold":{"accession":"Q9H6X2","domains":[{"cath_id":"3.40.50.410","chopping":"43-218","consensus_level":"high","plddt":93.3446,"start":43,"end":218},{"cath_id":"2.60.40.10","chopping":"222-314","consensus_level":"high","plddt":87.5657,"start":222,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6X2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6X2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6X2-F1-predicted_aligned_error_v6.png","plddt_mean":72.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANTXR1","jax_strain_url":"https://www.jax.org/strain/search?query=ANTXR1"},"sequence":{"accession":"Q9H6X2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H6X2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H6X2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6X2"}},"corpus_meta":[{"pmid":"24003211","id":"PMC_24003211","title":"DNA damage sensing by the ATM and ATR kinases.","date":"2013","source":"Cold Spring Harbor perspectives in biology","url":"https://pubmed.ncbi.nlm.nih.gov/24003211","citation_count":1143,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10485486","id":"PMC_10485486","title":"Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.","date":"1999","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10485486","citation_count":919,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24267891","id":"PMC_24267891","title":"ATR prohibits replication catastrophe by preventing global exhaustion of RPA.","date":"2013","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/24267891","citation_count":752,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28811666","id":"PMC_28811666","title":"The essential kinase ATR: ensuring faithful duplication of a challenging genome.","date":"2017","source":"Nature reviews. 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fibroblasts.","date":"2001","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11709713","citation_count":107,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40138,"output_tokens":2166,"usd":0.076452},"stage2":{"model":"claude-opus-4-6","input_tokens":5474,"output_tokens":2227,"usd":0.124567},"total_usd":0.483372,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":52280,"output_tokens":4959,"usd":0.115613},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7867,"output_tokens":2873,"usd":0.16674}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"Genetic disruption of Tem8/ANTXR1 in mice impairs growth of human tumor xenografts of diverse origin, and antibodies against the TEM8 extracellular domain block anthrax intoxication and inhibit tumor-induced angiogenesis, demonstrating that TEM8/ANTXR1 plays a functional role in pathological angiogenesis and tumor vasculature.\",\n      \"method\": \"Genetic knockout mouse model (Tem8 disruption), tumor xenograft assays, antibody blockade experiments\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined tumor/angiogenesis phenotype, replicated across multiple tumor types and validated with antibody blockade\",\n      \"pmids\": [\"22340594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Homozygous loss-of-function mutations in ANTXR1 (nonsense and splicing mutations causing nonsense-mediated mRNA decay) cause GAPO syndrome, characterized by growth retardation, alopecia, pseudoanodontia, and visual impairment, recapitulating extracellular matrix accumulation phenotypes seen in Antxr1-mutant mice, establishing ANTXR1 as a regulator of extracellular matrix homeostasis.\",\n      \"method\": \"Human genetics (sequencing of affected individuals), mRNA decay analysis, phenotypic comparison with Antxr1-mutant mouse models\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function with specific molecular and phenotypic readout, consistent with mouse model data\",\n      \"pmids\": [\"23602711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ANTXR1 activation by its natural ligand C5A (a fragment of collagen VI α3) increases cancer stem cell self-renewal and activates Wnt signaling including upregulation of LRP6 expression, phosphorylation of GSK3α/β, and elevated Wnt target gene expression; RNAi-mediated silencing of ANTXR1 reduces LRP6 and ZEB1 expression, self-renewal, invasion, tumorigenicity, and metastasis in breast cancer cells.\",\n      \"method\": \"Ligand stimulation assay, RNAi knockdown, mammosphere assay, Wnt pathway reporter assays, in vivo xenograft and metastasis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in single study linking ANTXR1 to collagen/Wnt signaling axis\",\n      \"pmids\": [\"23832666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TEM8/ANTXR1 cell surface structure is regulated by the actin cytoskeleton; overexpression of alpha-smooth muscle actin or transgelin (an actin-binding protein) converts TEM8 from an antibody-accessible to an antibody-masked form at the cell surface, demonstrating that intracellular actin cytoskeleton components interact with and alter the conformation of TEM8.\",\n      \"method\": \"Overexpression of actin cytoskeleton proteins, antibody binding assays (anti-TEM8 clone SB5), immunotoxin killing assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional antibody discrimination plus overexpression, moderate mechanistic follow-up\",\n      \"pmids\": [\"21129411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the TEM8/ANTXR1 extracellular vWA domain at 1.7 Å resolution reveals a typical integrin fold; structure-based mutagenesis identified residues 56, 57, and 154–160 (particularly Leu56) as responsible for the lower PA-binding affinity of TEM8 compared with CMG2.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, PA-binding affinity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis validation of binding interface\",\n      \"pmids\": [\"20585457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TEM8/ANTXR1 interacts with the M2 isoenzyme of pyruvate kinase (M2-PK); a TEM8-Fc fusion protein bound to protective antigen (PA) in a divalent cation-dependent manner and suppressed tumor growth and metastasis in xenograft models, indicating TEM8 participates in a protein interaction network linked to tumor growth.\",\n      \"method\": \"Engineered TEM8-Fc fusion protein, PA-binding assay, co-immunoprecipitation/interaction assay with M2-PK, in vivo xenograft tumor models\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single study, interaction identified with functional xenograft validation\",\n      \"pmids\": [\"17925540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Phage display selection of protective antigen (PA) variants identified PA domain 4 residues 659 and 662 as key contacts with TEM8/ANTXR1 that discriminate between TEM8 and CMG2 receptors; the PA R659S/M662R variant showed enhanced specificity toward TEM8-overexpressing cells and broad tumoricidal activity.\",\n      \"method\": \"Phage display, cellular cytotoxicity assays with CHO cells expressing TEM8 or CMG2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phage display combined with cellular functional assays defining receptor-binding interface\",\n      \"pmids\": [\"17251181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Seneca Valley Virus (SVV) exploits TEM8/ANTXR1 for cellular entry, the same surface receptor used by anthrax toxin, with collagen VI identified as a native binding partner of TEM8.\",\n      \"method\": \"Viral entry assays, receptor binding studies (reviewed/synthesized from primary experimental work)\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — review of experimental findings, primary data in referenced studies\",\n      \"pmids\": [\"30460197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANTXR1+ cancer-associated fibroblasts (ECM-myCAF cluster) in high-grade serous ovarian cancer reduce CD8+ T-cell cytotoxicity through a YAP1-dependent mechanism, as demonstrated by functional assays with isolated ECM-myCAF cells co-cultured with T cells.\",\n      \"method\": \"Single-cell analysis, spatial transcriptomics, functional co-culture assays with isolated CAF populations, YAP1 pathway inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays with specific CAF subpopulation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"38346978\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANTXR1 (TEM8) is a cell-surface transmembrane protein with an extracellular vWA/integrin-like domain that binds anthrax toxin protective antigen (PA) and collagen VI (C5A fragment); it is required for pathological angiogenesis and tumor vasculature function, regulates extracellular matrix homeostasis (loss causes GAPO syndrome), activates Wnt/LRP6 signaling in cancer stem cells upon collagen ligand binding, and has its cell surface conformation regulated by actin cytoskeleton components including alpha-smooth muscle actin and transgelin.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe vast majority of papers (1-23, 25-29, 31-57, 59, 62-64, 66, 69-71, 73, 75-84, 87-92, 94, 96, 97, 99) are about ATR/ATM kinases — ALIAS COLLISION. The gene queried is ANTXR1 (anthrax toxin receptor 1 / TEM8), not ATR kinase.\n\n**KEEP papers about ANTXR1:**\n- [24] PMID:22340594 — TEM8/ANTXR1 blockade, angiogenesis\n- [30] PMID:23832666 — ANTXR1 in breast cancer stem cells, collagen/Wnt signaling\n- [43] PMID:23602711 — ANTXR1 mutations cause GAPO syndrome\n- [60] PMID:17925540 — TEM8-Fc, antitumor, M2-PK interaction\n- [61] PMID:21196249 — TEM8/ANTXR1 in angiogenesis, ECM binding\n- [65] PMID:21129411 — TEM8 cell surface structure regulated by actin cytoskeleton\n- [67] PMID:38346978 — ANTXR1+ CAF-S1/ECM-myCAF, YAP1, CD8+ T cells\n- [72] PMID:20585457 — Crystal structure of TEM8 extracellular vWA domain\n- [74] PMID:17251181 — PA variants discriminating TEM8 vs CMG2\n- [85] PMID:30460197 — SVV exploits TEM8/ANTXR1 for entry, collagen VI interaction\n- [86] PMID:28651234 — miR-493/ANTXR1/Wnt signaling in HCC\n- [95] PMID:34523032 — N-Myc/TEM8 in prostate cancer angiogenesis\n- [98] PMID:36162918 — TEM8 TriKE, NK cell engagement\n- [100] PMID:31934301 — miR-26b-3p/ANTXR1 in glioma\n\n**gene2pubmed KEEP papers:**\n- [8] PMID:11700562 — Identification of ATR (ANTXR1) as anthrax toxin receptor\n- [11] PMID:12700348 — CMG2 as second anthrax receptor (context for ANTXR1)\n- [21] PMID:16401723 — Receptor palmitoylation/ubiquitination regulate anthrax toxin endocytosis\n- [29] PMID:16564009 — LRP6 interacts with TEM8/ATR for anthrax toxin internalization\n\n**gene2pubmed EXCLUDE:** Papers 1-7, 9-10, 12-20, 22-28, 30 are general proteomics/interactome/cDNA resources not specifically about ANTXR1 mechanism, or are about other genes.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"ANTXR1 (ATR/TEM8) was identified as the cellular receptor for anthrax toxin protective antigen (PA). It is a type I membrane protein with an extracellular von Willebrand factor A (vWA) domain that directly binds PA, and a soluble version of this domain protects cells from anthrax toxin.\",\n      \"method\": \"Genetic complementation cloning; direct binding assay between recombinant vWA domain and PA; cell protection assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original receptor identification by genetic complementation plus direct in vitro binding reconstitution\",\n      \"pmids\": [\"11700562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ANTXR1 undergoes palmitoylation in its cytoplasmic tail, which prevents premature association with lipid rafts and premature ubiquitination. Upon PA heptamerization, ANTXR1 moves into rafts where the E3 ubiquitin ligase Cbl ubiquitinates it, triggering rapid endocytosis of the toxin-receptor complex. Palmitoylation-defective receptors show reduced surface expression and premature internalization without PA heptamerization.\",\n      \"method\": \"Palmitoylation-defective mutant receptors; lipid raft fractionation; co-immunoprecipitation of Cbl; ubiquitination assays; endocytosis assays; cell intoxication assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including mutagenesis, biochemical fractionation, and functional rescue in a single study\",\n      \"pmids\": [\"16401723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LRP6 (a Wnt co-receptor) is required for anthrax toxin lethality and physically interacts with ANTXR1 (TEM8) at the cell surface to form a multicomponent complex that internalizes PA-containing toxin complexes. Downregulation of LRP6 or expression of dominant-negative LRP6 inhibited cellular uptake of PA and protected cells from death.\",\n      \"method\": \"RNAi knockdown of LRP6; dominant-negative LRP6 overexpression; anti-LRP6 antibody blocking; fluorescence microscopy; co-immunoprecipitation; biochemical fractionation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, imaging, and multiple loss-of-function approaches showing ANTXR1-LRP6 complex formation and functional consequence\",\n      \"pmids\": [\"16564009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ANTXR1 (TEM8) interacts with M2 isoenzyme of pyruvate kinase (M2-PK). An engineered TEM8-Fc molecule suppressed growth and metastasis of xenograft human tumors, potentially by trapping M2-PK.\",\n      \"method\": \"Co-immunoprecipitation identifying M2-PK as TEM8-interacting partner; xenograft tumor growth assays with TEM8-Fc\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP identifying interaction partner, functional mechanism not deeply dissected\",\n      \"pmids\": [\"17925540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Specific residues in ANTXR1 TEM8's extracellular domain (residues 56, 57, and 154–160) determine the lower PA-binding affinity of TEM8 compared to CMG2. In particular, Leu56 is a key determinant of lower affinity. PA domain 4 variants (R659S/M662R) with preferential binding to TEM8 showed selective tumoricidal activity.\",\n      \"method\": \"Structure-based mutagenesis of TEM8; cell cytotoxicity assays with CHO cells expressing TEM8 vs CMG2; phage display selection of PA variants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structure-guided mutagenesis with functional binding and cytotoxicity readout\",\n      \"pmids\": [\"17251181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The crystal structure of the TEM8/ANTXR1 extracellular vWA domain was determined at 1.7 Å resolution. The domain adopts an integrin fold similar to CMG2. Structure-based mutagenesis identified the putative PA interface (residues 56, 57, 154–160) as responsible for the lower PA-binding affinity of TEM8 versus CMG2; Leu56 is the key residue.\",\n      \"method\": \"X-ray crystallography (1.7 Å resolution); structure-based mutagenesis; binding affinity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation by mutagenesis\",\n      \"pmids\": [\"20585457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The cell-surface structure of ANTXR1 (TEM8) is regulated by the actin cytoskeleton. Alpha-smooth muscle actin and transgelin (an actin-binding protein) alter the conformation of TEM8 at the cell surface, converting it from an antibody-accessible (SB5-exposed) to an antibody-masked form, indicating that intracellular actin cytoskeleton components modulate TEM8 extracellular domain presentation.\",\n      \"method\": \"Overexpression of actin-binding proteins; antibody recognition assays (SB5 vs AF334 antibodies); immunotoxin killing assays distinguishing TEM8 conformations\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional overexpression studies with antibody-based conformational readout, single lab\",\n      \"pmids\": [\"21129411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ANTXR1 (TEM8) binds extracellular matrix proteins including collagen I, collagen IV, and laminin via its extracellular domain, and regulates endothelial cell migration and tubule formation during angiogenesis. CMG2 (ANTXR2) by contrast regulates endothelial proliferation.\",\n      \"method\": \"ECM binding assays; endothelial cell functional assays (migration, tubule formation); comparison of TEM8 and CMG2 loss-of-function\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — review compiling functional assay data, limited primary mechanistic detail\",\n      \"pmids\": [\"21196249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Genetic disruption of Tem8/ANTXR1 impairs growth of human tumor xenografts. Anti-TEM8 antibodies blocked anthrax intoxication, inhibited tumor-induced angiogenesis, and displayed antitumor activity. TEM8 is required for pathological angiogenesis but its loss in normal tissues causes minimal toxicity, indicating a selective role in tumor vasculature.\",\n      \"method\": \"Genetic knockout mouse model (Tem8-null); xenograft tumor growth assays; antibody blockade experiments; anthrax intoxication protection assay\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined angiogenesis phenotype replicated across multiple tumor types, plus antibody functional studies\",\n      \"pmids\": [\"22340594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function mutations in ANTXR1 (nonsense and splicing mutations causing nonsense-mediated mRNA decay or truncated protein) cause GAPO syndrome, characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment. The phenotype reflects a generalized defect in extracellular matrix homeostasis, consistent with ANTXR1's role in ECM regulation.\",\n      \"method\": \"Whole-exome sequencing of affected individuals; identification of homozygous nonsense (p.Arg88*, p.Arg169*) and splicing (c.1435-12A>G) mutations; mRNA decay analysis; genotype-phenotype correlation\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — causal human genetics with molecular validation of NMD and truncation, replicated in multiple unrelated families\",\n      \"pmids\": [\"23602711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ANTXR1 acts as a functional biomarker of breast cancer stem-like cells. Activation of ANTXR1 by its natural ligand C5A (a collagen VI α3 fragment) increases stem cell self-renewal and activates Wnt signaling including upregulation of LRP6, phosphorylation of GSK3α/β, and elevated Wnt target genes. RNAi silencing of ANTXR1 reduces Wnt signaling (LRP6, ZEB1 expression), self-renewal, invasion, tumorigenicity, and metastasis.\",\n      \"method\": \"RNAi-mediated silencing; ligand stimulation (C5A peptide); mammosphere assay; Wnt pathway readouts (LRP6, GSK3 phosphorylation, target gene expression); in vivo tumorigenicity and metastasis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ligand activation, RNAi, in vivo assays) in single study establishing ANTXR1-Wnt axis\",\n      \"pmids\": [\"23832666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Seneca Valley Virus (SVV) exploits ANTXR1 (TEM8) as an entry receptor, the same receptor used by anthrax toxin protective antigen. TEM8 also serves as a receptor for collagen VI, with the collagen VI interaction relevant to tumor cell biology.\",\n      \"method\": \"Receptor identification studies; cell entry assays; competitive binding with collagen VI and anthrax PA\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — review/compilation; primary mechanistic data for SVV entry via TEM8 described but not fully detailed in this paper\",\n      \"pmids\": [\"30460197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MicroRNA-493 directly targets and suppresses ANTXR1 expression in hepatocellular carcinoma cells. ANTXR1 overexpression can rescue the tumor-suppressive effects of miR-493, and ANTXR1 activates Wnt/β-catenin signaling in HCC cells to promote proliferation, migration, and tumor formation.\",\n      \"method\": \"miR-493 overexpression; 3'UTR luciferase reporter validation; ANTXR1 rescue (ORF reintroduction); cell proliferation, colony formation, migration, invasion assays; xenograft tumor assay; Wnt pathway readouts\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct target validation with rescue experiment and Wnt pathway readout, single lab\",\n      \"pmids\": [\"28651234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MicroRNA-26b-3p directly targets ANTXR1 in glioma cells. ANTXR1 functions downstream of miR-26b-3p to promote glioma cell proliferation and migration and inhibit apoptosis; reintroduction of ANTXR1 (ORF lacking miRNA target site) rescues these effects.\",\n      \"method\": \"miR-26b-3p overexpression and inhibition; ORF rescue experiment; cell proliferation, migration, apoptosis assays; correlation with glioma severity\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct rescue experiment establishing ANTXR1 as functional downstream effector, single lab\",\n      \"pmids\": [\"31934301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"N-Myc promotes angiogenesis and therapeutic resistance in prostate cancer via ANTXR1 (TEM8). N-Myc overexpression increases TEM8 expression, and combined overexpression promotes endothelial tubule formation and cancer cell proliferation; N-Myc-driven angiogenesis and resistance depend on TEM8.\",\n      \"method\": \"IHC correlation; overexpression of N-Myc and TEM8 in LNCaP cells; tubule formation assay with HUVECs; proliferation assays; bioinformatic analysis\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with functional readout but limited mechanistic dissection of N-Myc→TEM8 pathway\",\n      \"pmids\": [\"34523032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANTXR1+ cancer-associated fibroblasts (ECM-myCAF cluster within CAF-S1) reduce CD8+ T-cell cytotoxicity through a YAP1-dependent mechanism. These ANTXR1+ ECM-producing myofibroblasts are the CAF-S1 subpopulation most reduced by chemotherapy; functional assays demonstrate that ECM-myCAF suppress CD8+ T-cell killing via YAP1 signaling.\",\n      \"method\": \"Single-cell RNA sequencing; spatial transcriptomics; immunohistochemistry; functional co-culture assays of ECM-myCAF with CD8+ T cells; YAP1 inhibition experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay with YAP1 inhibition rescue, multiple orthogonal profiling approaches, single study\",\n      \"pmids\": [\"38346978\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANTXR1 (TEM8) is a type I transmembrane protein with an extracellular vWA/integrin-like domain that directly binds anthrax toxin protective antigen and ECM components (collagen VI fragment C5A, collagen I/IV, laminin); at the cell surface its conformation is regulated by actin-binding proteins (α-SMA, transgelin), and its endocytosis is controlled by sequential palmitoylation (preventing premature raft entry) and Cbl-mediated ubiquitination in lipid rafts, with LRP6 as a co-internalization partner; ANTXR1 activates Wnt/β-catenin signaling (upregulating LRP6, phosphorylating GSK3) upon collagen VI C5A ligation to promote stem cell self-renewal, invasion, and metastasis; loss-of-function mutations cause GAPO syndrome via defective ECM homeostasis, and ANTXR1+ myofibroblasts suppress anti-tumor immunity through a YAP1-dependent mechanism.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ANTXR1 (TEM8) is a single-pass transmembrane receptor that functions at the intersection of extracellular matrix homeostasis, pathological angiogenesis, and signaling in tumor biology. Its extracellular von Willebrand factor A (vWA) domain adopts an integrin-like fold that mediates divalent cation-dependent binding to anthrax toxin protective antigen and to collagen VI, with specific residues (Leu56, positions 154–160) determining binding affinity [PMID:20585457, PMID:17251181]. Homozygous loss-of-function mutations in ANTXR1 cause GAPO syndrome—characterized by growth retardation, alopecia, pseudoanodontia, and optic atrophy—establishing ANTXR1 as essential for extracellular matrix turnover, while genetic disruption in mice impairs pathological angiogenesis and tumor xenograft growth [PMID:23602711, PMID:22340594]. Ligand engagement by collagen VI fragment C5A activates Wnt/LRP6 signaling and promotes cancer stem cell self-renewal, invasion, and metastasis, and the receptor's cell-surface conformation is regulated by intracellular actin cytoskeleton components including α-smooth muscle actin and transgelin [PMID:23832666, PMID:21129411].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining the PA–TEM8 binding interface and discovering a novel intracellular interaction partner established that ANTXR1 possesses a specific ligand-discrimination surface in domain 4 of PA and participates in an intracellular protein network including pyruvate kinase M2.\",\n      \"evidence\": \"Phage display mutagenesis of PA domain 4 in CHO cells expressing TEM8 or CMG2; co-immunoprecipitation with M2-PK and xenograft tumor suppression with TEM8-Fc fusion\",\n      \"pmids\": [\"17251181\", \"17925540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological relevance of the TEM8–M2-PK interaction remains untested in endogenous systems\",\n        \"Downstream signaling consequences of PA binding to TEM8 versus CMG2 not delineated\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The 1.7 Å crystal structure of the TEM8 vWA domain revealed an integrin-like fold, and mutagenesis pinpointed Leu56 and residues 154–160 as determinants of its lower PA-binding affinity relative to CMG2, providing a structural basis for receptor selectivity.\",\n      \"evidence\": \"X-ray crystallography and structure-based mutagenesis with PA-binding affinity measurements\",\n      \"pmids\": [\"20585457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of TEM8 in complex with its natural ligand collagen VI\",\n        \"How the transmembrane and cytoplasmic domains contribute to signaling remains structurally unresolved\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The discovery that overexpression of α-smooth muscle actin or transgelin converts TEM8 to an antibody-inaccessible conformation at the cell surface revealed that intracellular cytoskeletal components regulate receptor accessibility from outside the cell.\",\n      \"evidence\": \"Overexpression in cultured cells with anti-TEM8 antibody binding and immunotoxin killing assays\",\n      \"pmids\": [\"21129411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between the TEM8 cytoplasmic tail and actin/transgelin not demonstrated biochemically\",\n        \"Physiological triggers of this conformational switch in vivo unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genetic ablation of Tem8 in mice impaired growth of multiple human tumor xenografts and anti-TEM8 antibodies blocked both anthrax intoxication and tumor angiogenesis, establishing ANTXR1 as a functional requirement for pathological neovascularization.\",\n      \"evidence\": \"Tem8-knockout mouse model, diverse tumor xenograft assays, antibody blockade experiments\",\n      \"pmids\": [\"22340594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous ligand driving TEM8-dependent angiogenesis not identified in this context\",\n        \"Whether TEM8 acts in endothelial cells, pericytes, or both during tumor angiogenesis not resolved\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of homozygous loss-of-function ANTXR1 mutations as the cause of GAPO syndrome, with extracellular matrix accumulation phenotypes matching those of Antxr1-mutant mice, proved ANTXR1 is essential for ECM homeostasis in humans.\",\n      \"evidence\": \"Whole-exome sequencing of affected individuals, mRNA decay analysis, phenotypic comparison with mouse model\",\n      \"pmids\": [\"23602711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which ANTXR1 regulates ECM degradation or remodeling not elucidated\",\n        \"Whether GAPO syndrome phenotypes are driven by matrix accumulation alone or also by impaired signaling is unclear\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that collagen VI fragment C5A activates ANTXR1-dependent Wnt/LRP6 signaling—promoting cancer stem cell self-renewal, invasion, and metastasis—defined a ligand-receptor-pathway axis linking ECM sensing to tumor stemness.\",\n      \"evidence\": \"RNAi knockdown, mammosphere assays, Wnt pathway reporters, in vivo xenograft and metastasis assays in breast cancer models\",\n      \"pmids\": [\"23832666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of signal transduction from ANTXR1 to LRP6/GSK3β not defined at the biochemical level\",\n        \"Whether this signaling axis operates in non-malignant tissues is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ANTXR1 was identified as a marker of ECM-myCAF fibroblasts in ovarian cancer that suppress CD8+ T-cell cytotoxicity via YAP1, extending ANTXR1's tumor-microenvironment role beyond angiogenesis to immune evasion.\",\n      \"evidence\": \"Single-cell RNA-seq, spatial transcriptomics, and functional co-culture assays with isolated CAF populations and YAP1 inhibition in high-grade serous ovarian cancer\",\n      \"pmids\": [\"38346978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ANTXR1 itself drives the immunosuppressive phenotype or is merely a marker of this CAF subtype is unresolved\",\n        \"Relationship between ANTXR1's ECM-regulatory function and YAP1-dependent immune suppression not mechanistically linked\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which ANTXR1 regulates ECM homeostasis—whether through matrix endocytosis, metalloprotease activation, or another route—remains unknown, as does the structural basis of collagen VI engagement and downstream signal transduction to Wnt/LRP6.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of TEM8 in complex with collagen VI or other physiological ligands\",\n        \"Biochemical mechanism connecting ANTXR1 to ECM degradation/remodeling not identified\",\n        \"Signaling intermediates between ANTXR1 cytoplasmic domain and LRP6/GSK3β pathway undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"COL6A3\",\n      \"ACTA2\",\n      \"TAGLN\",\n      \"PKM\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ANTXR1 (TEM8) is a type I transmembrane receptor that couples extracellular matrix sensing to intracellular signaling, functioning in ECM homeostasis, angiogenesis, and Wnt/β-catenin pathway activation. Its extracellular von Willebrand factor A (vWA) domain binds anthrax toxin protective antigen, collagen VI fragment C5A, collagen I/IV, and laminin; ligation by C5A activates Wnt signaling through LRP6 upregulation and GSK3 phosphorylation, promoting stem cell self-renewal, invasion, and metastasis [PMID:11700562, PMID:23832666]. At the cell surface, ANTXR1 conformation is regulated by actin cytoskeleton components (α-SMA, transgelin), and its endocytosis proceeds through a regulated sequence of palmitoylation-controlled lipid-raft entry and Cbl-mediated ubiquitination, with LRP6 as a co-internalization partner [PMID:16401723, PMID:16564009, PMID:21129411]. Loss-of-function mutations in ANTXR1 cause GAPO syndrome, a disorder of generalized ECM dysregulation characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment [PMID:23602711].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of ANTXR1 as the cellular receptor for anthrax toxin protective antigen established that a host transmembrane protein with an integrin-like vWA domain mediates toxin entry, opening the question of how receptor trafficking is regulated and what physiological ligands the receptor recognizes.\",\n      \"evidence\": \"Genetic complementation cloning in CHO cells plus direct binding of recombinant vWA domain to PA\",\n      \"pmids\": [\"11700562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological ligands of ANTXR1 unknown at this stage\", \"Mechanism of receptor endocytosis uncharacterized\", \"Relationship to angiogenesis only correlative from TEM8 name\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The discovery that palmitoylation prevents premature lipid-raft association and that Cbl-mediated ubiquitination in rafts triggers endocytosis revealed a two-step trafficking switch controlling ANTXR1 surface residence and toxin internalization.\",\n      \"evidence\": \"Palmitoylation-defective mutants, raft fractionation, Cbl co-IP, and ubiquitination assays in transfected cells\",\n      \"pmids\": [\"16401723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoyl transferase identity not determined\", \"Whether this trafficking mechanism operates for physiological ligands unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that LRP6 forms a physical complex with ANTXR1 and is required for PA internalization and lethality revealed a multicomponent receptor platform, linking ANTXR1 to the Wnt co-receptor machinery.\",\n      \"evidence\": \"RNAi, dominant-negative LRP6, anti-LRP6 antibody blocking, and reciprocal co-IP in multiple cell lines\",\n      \"pmids\": [\"16564009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ANTXR1–LRP6 interaction has signaling consequences beyond toxin entry was unknown\", \"Stoichiometry and structural basis of the complex unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The 1.7 Å crystal structure of the ANTXR1 vWA domain confirmed an integrin-like fold and, combined with mutagenesis, pinpointed Leu56 and residues 154–160 as determinants of lower PA-binding affinity relative to CMG2, providing a structural framework for selective ligand recognition.\",\n      \"evidence\": \"X-ray crystallography and structure-guided mutagenesis with binding affinity measurements\",\n      \"pmids\": [\"20585457\", \"17251181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal with PA or ECM ligands solved\", \"How structural differences translate to differential physiological functions of ANTXR1 vs CMG2 not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that α-smooth muscle actin and transgelin alter ANTXR1 extracellular domain conformation established that the intracellular actin cytoskeleton allosterically regulates receptor accessibility, analogous to inside-out signaling in integrins.\",\n      \"evidence\": \"Overexpression of actin-binding proteins with conformation-sensitive antibody readout and immunotoxin killing assays\",\n      \"pmids\": [\"21129411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of transmembrane conformational coupling not defined\", \"Physiological triggers for this conformational switch unknown\", \"Single-lab observation without independent replication\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genetic ablation of Tem8 in mice showed it is required for pathological angiogenesis and tumor xenograft growth but dispensable for normal vascular homeostasis, establishing ANTXR1 as a selective driver of tumor-associated neovasculature.\",\n      \"evidence\": \"Tem8-knockout mice; xenograft tumor assays across multiple tumor types; anti-TEM8 antibody treatment\",\n      \"pmids\": [\"22340594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The endogenous ligand driving tumor angiogenesis through TEM8 was not identified in this study\", \"Whether angiogenic role is cell-autonomous to endothelium vs stromal unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of homozygous loss-of-function ANTXR1 mutations as the cause of GAPO syndrome demonstrated that the receptor's ECM-binding function is essential for normal tissue development and matrix homeostasis in humans.\",\n      \"evidence\": \"Whole-exome sequencing of multiple unrelated GAPO families; nonsense and splicing mutations validated by mRNA decay analysis\",\n      \"pmids\": [\"23602711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise ECM substrates whose processing is disrupted in GAPO syndrome not defined\", \"No animal model recapitulating GAPO features described at this point\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that collagen VI fragment C5A activates ANTXR1-dependent Wnt/β-catenin signaling (via LRP6 upregulation and GSK3 phosphorylation) to drive breast cancer stem cell self-renewal and metastasis unified the receptor's ECM-binding and LRP6-interacting activities into a coherent oncogenic signaling axis.\",\n      \"evidence\": \"C5A ligand stimulation, RNAi silencing, mammosphere assays, Wnt pathway readouts, and in vivo tumorigenicity/metastasis models\",\n      \"pmids\": [\"23832666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether C5A–ANTXR1–Wnt axis operates outside breast cancer not tested\", \"Downstream transcriptional program beyond LRP6/ZEB1 not fully mapped\", \"Direct mechanism linking ANTXR1 ligation to LRP6 upregulation unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Validation of ANTXR1 as a direct target of miR-493 and miR-26b-3p, with rescue experiments showing ANTXR1 activates Wnt/β-catenin signaling in hepatocellular carcinoma and promotes glioma cell proliferation, extended the oncogenic role of ANTXR1 beyond breast cancer.\",\n      \"evidence\": \"3′UTR luciferase reporters, ORF rescue experiments, proliferation/migration/xenograft assays in HCC and glioma cells\",\n      \"pmids\": [\"28651234\", \"31934301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream Wnt targets in HCC/glioma contexts not deeply characterized\", \"Single-lab studies without independent replication\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of ANTXR1 as a marker of ECM-producing myofibroblastic CAFs (ECM-myCAF) that suppress CD8+ T-cell cytotoxicity through YAP1-dependent signaling revealed a stromal immunosuppressive function for ANTXR1-expressing cells in the tumor microenvironment.\",\n      \"evidence\": \"Single-cell and spatial transcriptomics; functional co-culture of ECM-myCAF with CD8+ T cells; YAP1 inhibition rescue\",\n      \"pmids\": [\"38346978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ANTXR1 itself signals through YAP1 or is merely a marker of this CAF subpopulation not resolved\", \"Causal role of ANTXR1 in the immunosuppressive phenotype not tested by direct ANTXR1 perturbation in CAFs\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of ANTXR1 engagement with ECM ligands (no co-crystal exists), the direct mechanism coupling ANTXR1 ligation to LRP6-dependent Wnt activation, the identity of the palmitoyl transferase that modifies ANTXR1, and whether ANTXR1 plays a cell-autonomous signaling role in cancer-associated fibroblasts versus serving as a lineage marker.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ANTXR1–ECM ligand co-crystal structure\", \"Palmitoyl transferase identity unknown\", \"ANTXR1 → LRP6/Wnt signaling mechanism not fully reconstituted\", \"Cell-autonomous function in CAF immunosuppression not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 4, 5, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 10, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 6]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 10, 12]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 10, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LRP6\", \"CBL\", \"ACTA2\", \"TAGLN\", \"COL6A3\"],\n    \"other_free_text\": []\n  }\n}\n```"}