{"gene":"ANTXR1","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2004,"finding":"TEM8/ANTXR1 extracellular domain binds the C5 domain of collagen alpha 3(VI); the TEM8-interacting region was mapped to the COOH-terminal C5 domain of collagen alpha 3(VI) using the extracellular domain of TEM8 as bait to identify ligands.","method":"Pulldown/ligand identification using TEM8 extracellular domain as bait","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab pulldown with domain-mapping follow-up; binding partner confirmed by direct interaction assay","pmids":["14871805"],"is_preprint":false},{"year":2005,"finding":"TEM8 overexpression in endothelial cells enhances cell adhesion to collagen 3-fold and increases migration 3-fold; the recombinant TEM8 extracellular domain (TEM8-ED) binds preferentially to collagen and acts as a dominant-negative inhibitor of endogenous TEM8, blocking both adhesion and migration without affecting beta1 integrin activation. TEM8 protein expression is upregulated 5-fold upon initiation of tube formation in HUVEC.","method":"Overexpression in endothelial cells; dominant-negative extracellular domain inhibition; adhesion and migration assays (denudation, Boyden chamber); tube formation assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (adhesion, migration, tube formation) in a single lab with dominant-negative approach","pmids":["15777794"],"is_preprint":false},{"year":2005,"finding":"The vWA domain together with the transmembrane domain of TEM8 is required for tubule formation; knockdown of TEM8 via ribozyme transgene significantly reduced microvessel formation and migration in HECV endothelial cells. CHO cells expressing only the vWA+TM domains of TEM8 formed tubule-like structures, whereas other isolated domains did not.","method":"Ribozyme-mediated knockdown; domain deletion constructs transfected into CHO cells; microtubule/tube formation assay; migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype and domain dissection using multiple constructs, single lab","pmids":["15993844"],"is_preprint":false},{"year":2007,"finding":"TEM8 interacts with the M2 isoenzyme of pyruvate kinase (M2-PK); TEM8-Fc fusion protein (extracellular domain of TEM8 linked to Fc) trapped M2-PK and suppressed tumor growth and metastasis in xenograft models.","method":"Co-interaction/pulldown implied by TEM8-Fc trapping of M2-PK; in vivo xenograft tumor growth assays","journal":"Journal of the National Cancer Institute","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, interaction with M2-PK inferred from TEM8-Fc trapping with limited mechanistic validation in the abstract","pmids":["17925540"],"is_preprint":false},{"year":2007,"finding":"Phage display selection identified PA domain 4 (residues 605-729) as the principal region contacting TEM8; substitutions R659S and M662R in PA enhanced specificity toward TEM8-overexpressing cells over CMG2-expressing cells, and N657Q significantly reduced toxicity on TEM8 but not CMG2 cells, demonstrating distinct residue-level determinants of PA binding to TEM8.","method":"Phage display selection; cellular cytotoxicity assays with CHO cells expressing TEM8 or CMG2","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with functional cytotoxicity assays defining receptor-binding interface, single lab","pmids":["17251181"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the TEM8 extracellular vWA domain resolved at 1.7 Å reveals a typical integrin fold; structure-based mutagenesis identified residues 56, 57, and 154-160 as the PA-binding interface, with Leu56 being a key determinant of lower PA-binding affinity relative to CMG2. An L56A TEM8 variant showed increased affinity for PA.","method":"X-ray crystallography (1.7 Å); structure-based mutagenesis; PA binding affinity assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional binding validation in a single study","pmids":["20585457"],"is_preprint":false},{"year":2010,"finding":"The cell surface conformation of TEM8 is regulated by the actin cytoskeleton; overexpression of alpha-smooth muscle actin or transgelin (an actin-binding protein) converted TEM8 from an antibody-accessible (SB5-exposed) to an SB5-masked form on the cell surface, demonstrating that intracellular actin components alter TEM8 extracellular domain structure.","method":"Overexpression of actin-binding proteins; differential antibody recognition of cell surface TEM8; immunotoxin killing assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression coupled with antibody-based conformational readout and immunotoxin assay, single lab","pmids":["21129411"],"is_preprint":false},{"year":2012,"finding":"Genetic disruption of Tem8 impairs growth of human tumor xenografts (melanoma, breast, colon, lung); antibodies against the TEM8 extracellular domain blocked anthrax intoxication, inhibited tumor-induced angiogenesis, and showed broad antitumor activity in vivo, establishing TEM8 as required for pathological angiogenesis.","method":"Genetic knockout (Tem8-/- mice); xenograft tumor growth assays; anti-TEM8 antibody blocking experiments","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic disruption combined with antibody blockade across multiple tumor models, replicated across cancer types in one rigorous study","pmids":["22340594"],"is_preprint":false},{"year":2013,"finding":"ANTXR1 activation by its natural ligand C5A (a collagen VI alpha3 fragment) increases cancer stem cell self-renewal (mammosphere assay) and activates Wnt signaling including upregulation of LRP6, phosphorylation of GSK3alpha/beta, and expression of Wnt target genes. RNAi silencing of ANTXR1 reduced LRP6 and ZEB1 expression, self-renewal, invasion, tumorigenicity, and metastasis.","method":"Ligand stimulation with C5A; RNAi knockdown; mammosphere assay; Western blot for Wnt pathway components; in vivo tumorigenicity/metastasis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ligand stimulation, RNAi, in vivo), single lab","pmids":["23832666"],"is_preprint":false},{"year":2013,"finding":"Loss-of-function mutations in ANTXR1 (nonsense, splicing) cause GAPO syndrome; nonsense mutations trigger nonsense-mediated mRNA decay resulting in loss of ANTXR1, and the major GAPO phenotypes (dental abnormalities, extracellular matrix accumulation) recapitulate Antxr1-mutant mouse phenotypes, establishing ANTXR1 as required for extracellular matrix homeostasis.","method":"Whole exome sequencing; identification of homozygous mutations; comparison to Antxr1-mutant mouse phenotype","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics with functional validation via mouse model comparison; nonsense-mediated decay mechanism experimentally supported","pmids":["23602711"],"is_preprint":false},{"year":2016,"finding":"In Antxr1-deficient primary fibroblasts, increased collagen type I (Col1a1) and fibronectin (Fn1) expression occurs via a cell-autonomous ANTXR1-dependent mechanism partly mediated through CTGF; VEGF signaling acts in parallel. Re-expression of the longest ANTXR1 isoform (sv1) in mutant fibroblasts decreased Ctgf, Col1a1, and Fn1 transcripts but had no effect on VEGF expression, demonstrating ANTXR1 regulation of ECM via a CTGF-dependent pathway.","method":"Primary fibroblasts from Antxr1+/+ and Antxr1-/- mice; shRNA knockdown of VEGF; rescue by ANTXR1 sv1 re-expression; VEGF neutralizing antibody; qRT-PCR/Western blot","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function/rescue with multiple orthogonal approaches (shRNA, antibody, isoform re-expression), single lab","pmids":["28011198"],"is_preprint":false},{"year":2016,"finding":"TEM8 N-glycosylation is required for proper folding and trafficking to the cell surface; absence of N-linked glycans on either the vWA or Ig-like extracellular domains leads to misfolding and retention by ER quality control machinery, preventing surface expression.","method":"N-glycosylation mutants; cell surface trafficking assays; ER quality control assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis of glycosylation sites with trafficking and folding readouts, single lab","pmids":["25781883"],"is_preprint":false},{"year":2018,"finding":"TEM8 functions as a receptor for urokinase plasminogen activator (uPA); uPA binding stimulates phosphorylation of TEM8 and augments EGFR and ERK1/2 phosphorylation. TEM8-Fc abrogated the TEM8-uPA interaction, blocked uPA-induced HepG2 cell migration in vitro, and inhibited MCF-7 xenograft growth and metastasis in vivo.","method":"Co-immunoprecipitation/pulldown; phosphorylation assays (Western blot); TEM8-Fc blocking; migration assay; xenograft mouse model","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction plus functional blocking with in vitro and in vivo validation, single lab","pmids":["30241478"],"is_preprint":false},{"year":2020,"finding":"ANTXR1 positively regulates RANKL-induced osteoclast differentiation and bone resorption; gain- and loss-of-function studies showed ANTXR1 affects phosphorylation of JNK, Akt, IkappaB, and PLCgamma2 and subsequently alters c-Fos and NFATc1 levels. ANTXR1 manipulation in bone marrow macrophages also modulated HUVECs tube formation via secretion of MMP-9 and VEGF-A, with no effect on osteoblast differentiation.","method":"Gain- and loss-of-function in bone marrow macrophages; osteoclast differentiation assay; phosphorylation Western blots; HUVEC tube formation assay; bone resorption assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss of function with defined signaling readouts, multiple orthogonal assays, single lab","pmids":["30686531"],"is_preprint":false},{"year":2020,"finding":"TEM8 overexpression in ovarian cancer cells activates Rac1/Cdc42/JNK and MEK/ERK/STAT3 signaling pathways, promoting proliferation, G0/G1 transition, migration, and invasion while suppressing apoptosis. Pharmacological inhibition of RAC1 (EHop-016) or MEK (PD98059) suppressed malignant behaviors in TEM8-overexpressing cells. Transcription factor GATA2 binds the TEM8 promoter region (TATTAGTTATCTTT site) and regulates TEM8 expression.","method":"Overexpression; pathway inhibitor treatment; Western blot for phosphorylated signaling components; promoter binding assay (ChIP/luciferase implied); proliferation, apoptosis, migration, invasion assays","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with pathway-inhibitor rescue and transcription factor binding, multiple readouts, single lab","pmids":["32774719"],"is_preprint":false},{"year":2020,"finding":"Antxr1 is a direct transcriptional target of Runx2 in chondrocytes; Antxr1 deletion in mice results in shorter limbs from E16.5 due to reduced chondrocyte proliferation. Chondrocyte-specific Antxr1 transgenic overexpression also caused shortened limbs with increased BrdU uptake and apoptosis, accompanied by matrix mineralization, showing dose-sensitive roles in chondrocyte proliferation and apoptosis.","method":"Antxr1-/- mouse; chondrocyte-specific transgenic overexpression; BrdU incorporation assay; apoptosis assay; Runx2 target gene analysis; histological analysis of growth plates","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic loss-of-function and gain-of-function with defined cellular phenotypes and direct transcriptional regulation by Runx2","pmids":["32244499"],"is_preprint":false},{"year":2021,"finding":"TEM8 increases active RhoC levels and induces ROCK1-mediated phosphorylation of SMAD5, a signaling cascade essential for promoting cancer cell stemness and vasculogenic mimicry capacity in TNBC. ASB10, an ERalpha trans-activated E3 ligase, ubiquitylates TEM8 for proteasomal degradation; ASB10 deficiency in TNBC results in elevated TEM8 levels.","method":"Mechanistic dissection by overexpression/knockdown; Western blot for RhoC, ROCK1, pSMAD5; ubiquitylation assay; co-immunoprecipitation for ASB10-TEM8 interaction; vasculogenic mimicry assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods defining upstream E3 ligase and downstream RhoC/ROCK1/SMAD5 pathway, single rigorous study","pmids":["34285210"],"is_preprint":false},{"year":2021,"finding":"In vivo imaging assay using LFn-NLS-Cre chimaeric protein with PA shows that TEM8 is required for anthrax toxin intoxication in the kidney and spleen, while CMG2 is dominant in liver, heart, and leukocytes; combined loss of both receptors completely abolishes intoxication, demonstrating organ-specific receptor utilization.","method":"Transgenic Cre-reporter mice; chimeric LFn-NLS-Cre protein + PA co-administration; confocal microscopy; flow cytometry; TEM8- and CMG2-deficient mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo single-cell resolution imaging with genetic receptor knockouts providing epistatic evidence for organ-specific receptor utilization","pmids":["34871548"],"is_preprint":false},{"year":2022,"finding":"ANTXR1 interacts with LRP6 to promote nuclear entry of beta-catenin and activate Wnt/beta-catenin signaling, thereby repressing gamma-globin (HBG) expression. Overexpression of ANTXR1 decreased gamma-globin; knockdown increased it. The regulatory effect was reversed by XAV939 (Wnt inhibitor) and LiCl (GSK3beta inhibitor). ANTXR1 overexpression also increased c-Jun-mediated SOX6 transcription, which silences gamma-globin.","method":"Overexpression and knockdown in K562, CD34+ cord blood, HUDEP-2 cells; Co-IP for ANTXR1-LRP6 interaction; pharmacological modulation of Wnt pathway; ChIP/promoter analysis for SOX6","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for LRP6 interaction, pharmacological rescue, gain/loss-of-function with defined transcriptional readout, single lab","pmids":["35942209"],"is_preprint":false},{"year":2024,"finding":"ANTXR1 deficiency in human fibroblasts induces a senescent phenotype associated with defects in nuclear architecture and actin dynamics, proposing GAPO syndrome as a progeroid disorder.","method":"ANTXR1 knockdown/deficiency in human fibroblasts; senescence assays; nuclear architecture imaging; actin dynamics assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple cellular phenotype readouts (senescence, nuclear architecture, actin), single lab","pmids":["38653789"],"is_preprint":false},{"year":2024,"finding":"ANTXR1 mediates collagen turnover in the heart; genetic disruption of Antxr1 or treatment with neutralizing antibodies prevented cardiac deterioration after acute myocardial infarction and improved function in pressure overload and obesity-induced heart failure models. Mechanistic studies revealed ANTXR1 antibody blockade improved post-infarct scar formation and attenuated late-stage chronic TGFbeta-mediated extracellular matrix remodeling.","method":"Antxr1 genetic knockout; neutralizing antibody treatment; multiple heart failure mouse models (MI, pressure overload, obesity-induced HFpEF); functional cardiac measurements; histological scar analysis; TGFbeta pathway assessment","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus pharmacological blockade across multiple independent disease models with mechanistic pathway (TGFbeta/ECM) identification","pmids":["41039173"],"is_preprint":false},{"year":2025,"finding":"CALCR (a G-protein-coupled receptor) physically interacts with ANTXR1 as shown by co-immunoprecipitation; CALCR knockdown decreased AKT phosphorylation, linking the CALCR-ANTXR1 complex to AKT signaling in gastric cancer.","method":"Co-immunoprecipitation; CALCR knockdown; Western blot for AKT phosphorylation; xenograft mouse model","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP experiment with limited mechanistic follow-up on ANTXR1-specific contribution, single lab","pmids":["40195530"],"is_preprint":false},{"year":2025,"finding":"CAF-derived lactate promotes ANTXR1 transcription via histone lactylation and induces ANTXR1 lactylation at lysine 453. ANTXR1 K453 lactylation promotes protein stability and activates the RhoC/ROCK1/SMAD5 signaling pathway, driving colorectal cancer stemness and oxaliplatin resistance.","method":"Histone lactylation ChIP on ANTXR1 promoter; site-specific lactylation at K453 identified by mass spectrometry; gain/loss-of-function; Western blot for RhoC/ROCK1/SMAD5; CDX/PDX xenograft models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific PTM identification (K453 lactylation) with downstream pathway validation and in vivo rescue, single lab","pmids":["40683418"],"is_preprint":false},{"year":2024,"finding":"TEM8 overexpression in glioblastoma activates the Src/PI3K/AKT/GSK-3beta/beta-catenin pathway, leading to beta-catenin stabilization and activation of its transcriptional program; TEM8 overexpression promotes proliferation, invasion, migration, and chemo-radioresistance, while knockdown reverses these effects.","method":"Overexpression and knockdown; Western blot for Src, PI3K, AKT, GSK3beta, beta-catenin; proliferation, invasion, migration assays; DNA methylation array correlation","journal":"Cancer genomics & proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with signaling pathway validation, multiple functional readouts, single lab","pmids":["39191501"],"is_preprint":false},{"year":2006,"finding":"PA-induced cytotoxicity in macrophages overexpressing ANTXR1 requires direct interaction with ANTXR1, oligomerization of PA, channel formation, and endosomal acidification, but is independent of the ANTXR1 cytoplasmic tail. Overexpression of ANTXR1 extends PA-oligomer half-life and sensitizes cells to lethal toxin. PA-alone cytotoxicity proceeds via caspase-3 activation, DNA fragmentation, PARP cleavage, and Bid activation (apoptosis).","method":"ANTXR1 overexpression in RAW 264.7 macrophages; PA oligomerization assay; endosomal acidification inhibition; cytoplasmic tail deletion mutants; caspase activation assays; apoptosis markers","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic dissection experiments (domain deletion, chemical inhibitors, apoptosis markers) in a single lab","pmids":["16882031"],"is_preprint":false},{"year":2010,"finding":"ANTXR1 is dynamically expressed in chick embryo and FGF signaling is sufficient (but not necessary) to induce ANTXR1 expression in facial mesenchyme; in vitro, ANTXR1 can link ECM components with the actin cytoskeleton to promote cell adhesion and spreading.","method":"Suppression subtractive hybridization screen; FGF gain-of-function/loss-of-function in chick embryo; cell adhesion assays","journal":"Developmental dynamics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single experimental system, cell adhesion/actin linkage inferred from in vitro assay cited in passing, single lab","pmids":["20034073"],"is_preprint":false}],"current_model":"ANTXR1/TEM8 is a type I transmembrane protein with an integrin-like vWA domain that binds collagen VI (C5 domain), uPA, and the anthrax toxin protective antigen (PA) via a defined interface (Leu56, residues 154-160); it links the extracellular matrix to the actin cytoskeleton, regulates ECM homeostasis (collagen I, fibronectin, CTGF) and is required for pathological angiogenesis. Its cell-surface conformation is modulated by actin-binding proteins (alpha-SMA, transgelin), its protein stability is controlled by ASB10-mediated ubiquitylation and lactylation at K453, and it signals through multiple downstream pathways including RhoC/ROCK1/SMAD5 (stemness/vasculogenic mimicry), Rac1/Cdc42/JNK and MEK/ERK/STAT3 (proliferation/invasion), PI3K/AKT/GSK3beta/beta-catenin, and Wnt/LRP6 (gamma-globin regulation and stemness); in vivo, ANTXR1 is required for anthrax toxin entry in kidney/spleen, drives maladaptive cardiac ECM remodeling via TGFbeta, and regulates chondrocyte proliferation downstream of Runx2, while loss-of-function mutations cause GAPO syndrome through defective ECM homeostasis and fibroblast senescence."},"narrative":{"mechanistic_narrative":"ANTXR1 (TEM8) is a type I transmembrane receptor with an integrin-like vWA domain that couples the extracellular matrix to the actin cytoskeleton and governs ECM homeostasis and pathological angiogenesis [PMID:22340594, PMID:23602711]. Its extracellular vWA domain adopts an integrin fold and binds the C5 domain of collagen VI alpha3, the urokinase plasminogen activator (uPA), and the anthrax toxin protective antigen (PA) through a defined interface at residues 56-57 and 154-160, with Leu56 setting its lower PA affinity relative to CMG2 [PMID:14871805, PMID:20585457, PMID:30241478]. Engagement of collagen drives endothelial adhesion, migration, and tube formation, requiring the vWA plus transmembrane domains, and TEM8 is essential for tumor-induced angiogenesis and xenograft growth [PMID:15777794, PMID:15993844, PMID:22340594]. ANTXR1 surface availability is gated by N-glycosylation-dependent folding and ER quality control, by actin-binding proteins (alpha-smooth muscle actin, transgelin) that mask its extracellular epitope, and by post-translational control through ASB10-mediated ubiquitylation and K453 lactylation [PMID:25781883, PMID:21129411, PMID:34285210, PMID:40683418]. Downstream, ANTXR1 activates a RhoC/ROCK1/SMAD5 axis driving cancer stemness and vasculogenic mimicry, and engages Wnt signaling via LRP6 and GSK3beta/beta-catenin to control self-renewal and gamma-globin repression [PMID:34285210, PMID:23832666, PMID:35942209]. In vivo, ANTXR1 is required for anthrax toxin entry in kidney and spleen, acts downstream of Runx2 to set chondrocyte proliferation, and drives maladaptive cardiac collagen remodeling through TGFbeta [PMID:34871548, PMID:32244499, PMID:41039173]. Loss-of-function mutations in ANTXR1 cause GAPO syndrome through defective ECM homeostasis [PMID:23602711].","teleology":[{"year":2004,"claim":"Establishing that the TEM8 ectodomain recognizes a specific ECM ligand answered what this orphan tumor-endothelial marker physically binds, anchoring it to the extracellular matrix.","evidence":"Pulldown using the TEM8 extracellular domain as bait, with domain mapping to collagen alpha3(VI) C5","pmids":["14871805"],"confidence":"Medium","gaps":["Binding affinity and stoichiometry not quantified","Functional consequence of the collagen VI interaction not yet established"]},{"year":2005,"claim":"Functional assays showed TEM8 is not merely a binder but an active mediator of endothelial adhesion, migration, and tube formation, defining its role in vessel morphogenesis.","evidence":"Overexpression, dominant-negative ectodomain, ribozyme knockdown, and domain-deletion constructs in endothelial and CHO cells","pmids":["15777794","15993844"],"confidence":"Medium","gaps":["Did not identify the intracellular effectors linking TEM8 to the cytoskeleton","vWA+TM sufficiency for tubule formation tested only in CHO surrogate cells"]},{"year":2006,"claim":"Dissecting the anthrax intoxication pathway clarified which steps require ANTXR1 and showed the cytoplasmic tail is dispensable for toxin entry, defining the receptor's mechanistic contribution.","evidence":"ANTXR1 overexpression in RAW 264.7 macrophages with PA oligomerization, acidification inhibition, tail-deletion mutants, and apoptosis markers","pmids":["16882031"],"confidence":"Medium","gaps":["Performed in overexpression macrophage model","Did not address physiological receptor levels"]},{"year":2007,"claim":"Mutagenesis of PA defined residue-level determinants distinguishing TEM8 from the related receptor CMG2, providing the basis for receptor-selective toxin targeting.","evidence":"Phage display selection and cytotoxicity assays in CHO cells expressing TEM8 or CMG2","pmids":["17251181"],"confidence":"Medium","gaps":["Mapped the PA side of the interface but not yet the TEM8 side","Selectivity tested only in engineered CHO cells"]},{"year":2010,"claim":"The crystal structure plus structure-guided mutagenesis revealed an integrin fold and pinpointed the TEM8 PA-binding interface, explaining its lower toxin affinity relative to CMG2 and how the cytoskeleton can remodel its surface conformation.","evidence":"1.7 A X-ray structure of the vWA domain with mutagenesis; separately, actin-binding protein overexpression with conformation-sensitive antibody readout","pmids":["20585457","21129411"],"confidence":"High","gaps":["Structure limited to the isolated vWA domain","Mechanism linking intracellular actin proteins to ectodomain conformation not resolved at atomic level"]},{"year":2012,"claim":"Genetic knockout combined with antibody blockade established TEM8 as required for pathological angiogenesis and a therapeutic target across multiple tumor types.","evidence":"Tem8-/- mice, xenograft models of melanoma/breast/colon/lung, and anti-TEM8 ectodomain antibodies","pmids":["22340594"],"confidence":"High","gaps":["Downstream signaling driving the angiogenic requirement not defined here","Distinction between tumor-cell-intrinsic and stromal roles incomplete"]},{"year":2013,"claim":"Human genetics tied ANTXR1 loss to GAPO syndrome and to ECM accumulation, while ligand stimulation linked the receptor to Wnt-driven cancer stemness, establishing its dual roles in ECM homeostasis and self-renewal.","evidence":"Whole-exome sequencing with NMD analysis and mouse phenotype comparison; C5A ligand stimulation, RNAi, mammosphere and in vivo metastasis assays","pmids":["23602711","23832666"],"confidence":"High","gaps":["How loss of an ECM receptor causes excess ECM accumulation not mechanistically resolved in 2013","Direct biochemical link between ANTXR1 and LRP6/Wnt not yet shown"]},{"year":2016,"claim":"Rescue experiments defined ANTXR1 as a cell-autonomous, CTGF-dependent suppressor of collagen I and fibronectin, and showed surface delivery depends on N-glycosylation, mechanistically connecting receptor loss to ECM accumulation.","evidence":"Antxr1-/- primary fibroblasts with isoform re-expression and VEGF perturbation; N-glycosylation mutants with trafficking/ER quality control assays","pmids":["28011198","25781883"],"confidence":"Medium","gaps":["The signaling intermediate between ANTXR1 and CTGF not identified","Relative contributions of CTGF versus VEGF arms not quantified in vivo"]},{"year":2020,"claim":"In vivo genetics and signaling profiling placed ANTXR1 in tissue-specific programs: a Runx2-driven role in chondrocyte proliferation, a RANKL-coupled role in osteoclast differentiation, and ovarian-cancer Rac1/JNK and MEK/ERK/STAT3 cascades under GATA2 transcriptional control.","evidence":"Antxr1 knockout and chondrocyte-specific transgenic mice; gain/loss-of-function in bone marrow macrophages; overexpression with pathway inhibitors and promoter binding in ovarian cancer cells","pmids":["32244499","30686531","32774719"],"confidence":"High","gaps":["Whether the same downstream effectors operate across these tissues unknown","Dose sensitivity of chondrocyte phenotypes not mechanistically explained"]},{"year":2021,"claim":"Identification of the RhoC/ROCK1/SMAD5 cascade and the ASB10 E3 ligase defined both a stemness-driving downstream pathway and an upstream determinant of ANTXR1 protein abundance, and organ-resolved imaging clarified receptor utilization for anthrax toxin.","evidence":"Overexpression/knockdown with RhoC/ROCK1/pSMAD5 readouts, ubiquitylation and ASB10 co-IP in TNBC; LFn-NLS-Cre + PA in vivo imaging with TEM8/CMG2 knockout mice","pmids":["34285210","34871548"],"confidence":"High","gaps":["How ANTXR1 activates RhoC at the membrane not defined","Trigger for ASB10-mediated turnover beyond ERalpha context unclear"]},{"year":2022,"claim":"Demonstrating a direct ANTXR1-LRP6 interaction provided the biochemical basis for ANTXR1 activation of Wnt/beta-catenin, extending its signaling role to gamma-globin repression.","evidence":"Co-IP for ANTXR1-LRP6, gain/loss-of-function and Wnt/GSK3beta pharmacological rescue in K562, CD34+, and HUDEP-2 cells","pmids":["35942209"],"confidence":"Medium","gaps":["Single co-IP for the LRP6 interaction without structural mapping","Direct versus indirect control of SOX6 not fully separated"]},{"year":2024,"claim":"Multiple disease-model studies established ANTXR1 as a driver of maladaptive cardiac ECM remodeling and as a determinant of fibroblast senescence, reframing GAPO as a progeroid disorder and ANTXR1 as a cardiac therapeutic target.","evidence":"Antxr1 knockout and neutralizing antibodies across MI, pressure-overload, and HFpEF mouse models with TGFbeta pathway analysis; ANTXR1-deficient human fibroblasts with senescence, nuclear architecture, and actin assays; glioblastoma Src/PI3K/AKT/GSK3beta/beta-catenin profiling","pmids":["41039173","38653789","39191501"],"confidence":"High","gaps":["How ANTXR1 loss accelerates senescence mechanistically not resolved","Connection between cardiac TGFbeta remodeling and the fibroblast ECM program not directly tested"]},{"year":2025,"claim":"Identification of K453 lactylation linked the tumor metabolic microenvironment to ANTXR1 stability and the RhoC/ROCK1/SMAD5 axis, and a CALCR interaction was reported to couple ANTXR1 to AKT signaling.","evidence":"Histone lactylation ChIP, mass-spec site mapping of K453, and gain/loss-of-function with xenografts; CALCR co-IP and knockdown with AKT readout in gastric cancer","pmids":["40683418","40195530"],"confidence":"Medium","gaps":["CALCR-ANTXR1 link rests on a single co-IP with limited ANTXR1-specific follow-up","Enzyme depositing K453 lactylation not identified"]},{"year":null,"claim":"The molecular events converting ANTXR1 ligand engagement into its divergent intracellular outputs (RhoC, Wnt/LRP6, MEK/ERK, AKT) and the unifying mechanism by which receptor loss produces ECM accumulation and senescence remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the full-length receptor or ligand-bound complexes beyond the vWA domain","Tissue-specific selection among downstream pathways unexplained","Direct cytoskeletal effectors of the cytoplasmic tail not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[4,5,17,24]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8,12,16,18]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,0,25]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6,25]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,11,24]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[9,10,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,16,18,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,17,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[15,13,25]}],"complexes":[],"partners":["COL6A3","PLAU","LRP6","ASB10","CALCR"],"other_free_text":[]}},"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. 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review.","date":"2024","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38423276","citation_count":1,"is_preprint":false},{"pmid":"40970092","id":"PMC_40970092","title":"The mechanosensitive protein ANTXR1 is involved in maintaining cartilage homeostasis in post-traumatic osteoarthritis.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/40970092","citation_count":0,"is_preprint":false},{"pmid":"41505341","id":"PMC_41505341","title":"Expression and clinical significance of TEM8 protein in triple-negative breast cancer.","date":"2026","source":"Science progress","url":"https://pubmed.ncbi.nlm.nih.gov/41505341","citation_count":0,"is_preprint":false},{"pmid":"42061011","id":"PMC_42061011","title":"The genomic, transcriptomic, and immunologic landscape of TEM8 (ANTXR1) in neuroendocrine neoplasms (NENs) including small-cell lung cancer (SCLC).","date":"2026","source":"Cancer treatment and research communications","url":"https://pubmed.ncbi.nlm.nih.gov/42061011","citation_count":0,"is_preprint":false},{"pmid":"42143941","id":"PMC_42143941","title":"Identification of the target ANTXR1 and covalent acylation mechanism of 8-esterified cycloberberines against cancer.","date":"2026","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42143941","citation_count":0,"is_preprint":false},{"pmid":"42251445","id":"PMC_42251445","title":"Comprehensive multi-omics pan-cancer analysis revealed that ANTXR1 is a potential biomarker for diagnosis and immunotherapy.","date":"2026","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/42251445","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.05.626996","title":"Engineering an Anthrax Toxin inspired protein-ligand for Nanoparticle-Mediated Treatment of Malignant Melanoma","date":"2024-12-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.05.626996","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38783,"output_tokens":6962,"usd":0.11039,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16027,"output_tokens":4923,"usd":0.101605,"stage2_stop_reason":"end_turn"},"total_usd":0.211995,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"TEM8/ANTXR1 extracellular domain binds the C5 domain of collagen alpha 3(VI); the TEM8-interacting region was mapped to the COOH-terminal C5 domain of collagen alpha 3(VI) using the extracellular domain of TEM8 as bait to identify ligands.\",\n      \"method\": \"Pulldown/ligand identification using TEM8 extracellular domain as bait\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab pulldown with domain-mapping follow-up; binding partner confirmed by direct interaction assay\",\n      \"pmids\": [\"14871805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TEM8 overexpression in endothelial cells enhances cell adhesion to collagen 3-fold and increases migration 3-fold; the recombinant TEM8 extracellular domain (TEM8-ED) binds preferentially to collagen and acts as a dominant-negative inhibitor of endogenous TEM8, blocking both adhesion and migration without affecting beta1 integrin activation. TEM8 protein expression is upregulated 5-fold upon initiation of tube formation in HUVEC.\",\n      \"method\": \"Overexpression in endothelial cells; dominant-negative extracellular domain inhibition; adhesion and migration assays (denudation, Boyden chamber); tube formation assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (adhesion, migration, tube formation) in a single lab with dominant-negative approach\",\n      \"pmids\": [\"15777794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The vWA domain together with the transmembrane domain of TEM8 is required for tubule formation; knockdown of TEM8 via ribozyme transgene significantly reduced microvessel formation and migration in HECV endothelial cells. CHO cells expressing only the vWA+TM domains of TEM8 formed tubule-like structures, whereas other isolated domains did not.\",\n      \"method\": \"Ribozyme-mediated knockdown; domain deletion constructs transfected into CHO cells; microtubule/tube formation assay; migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype and domain dissection using multiple constructs, single lab\",\n      \"pmids\": [\"15993844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TEM8 interacts with the M2 isoenzyme of pyruvate kinase (M2-PK); TEM8-Fc fusion protein (extracellular domain of TEM8 linked to Fc) trapped M2-PK and suppressed tumor growth and metastasis in xenograft models.\",\n      \"method\": \"Co-interaction/pulldown implied by TEM8-Fc trapping of M2-PK; in vivo xenograft tumor growth assays\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, interaction with M2-PK inferred from TEM8-Fc trapping with limited mechanistic validation in the abstract\",\n      \"pmids\": [\"17925540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Phage display selection identified PA domain 4 (residues 605-729) as the principal region contacting TEM8; substitutions R659S and M662R in PA enhanced specificity toward TEM8-overexpressing cells over CMG2-expressing cells, and N657Q significantly reduced toxicity on TEM8 but not CMG2 cells, demonstrating distinct residue-level determinants of PA binding to TEM8.\",\n      \"method\": \"Phage display selection; cellular cytotoxicity assays with CHO cells expressing TEM8 or CMG2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with functional cytotoxicity assays defining receptor-binding interface, single lab\",\n      \"pmids\": [\"17251181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the TEM8 extracellular vWA domain resolved at 1.7 Å reveals a typical integrin fold; structure-based mutagenesis identified residues 56, 57, and 154-160 as the PA-binding interface, with Leu56 being a key determinant of lower PA-binding affinity relative to CMG2. An L56A TEM8 variant showed increased affinity for PA.\",\n      \"method\": \"X-ray crystallography (1.7 Å); structure-based mutagenesis; PA binding affinity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional binding validation in a single study\",\n      \"pmids\": [\"20585457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The cell surface conformation of TEM8 is regulated by the actin cytoskeleton; overexpression of alpha-smooth muscle actin or transgelin (an actin-binding protein) converted TEM8 from an antibody-accessible (SB5-exposed) to an SB5-masked form on the cell surface, demonstrating that intracellular actin components alter TEM8 extracellular domain structure.\",\n      \"method\": \"Overexpression of actin-binding proteins; differential antibody recognition of cell surface TEM8; immunotoxin killing assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression coupled with antibody-based conformational readout and immunotoxin assay, single lab\",\n      \"pmids\": [\"21129411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Genetic disruption of Tem8 impairs growth of human tumor xenografts (melanoma, breast, colon, lung); antibodies against the TEM8 extracellular domain blocked anthrax intoxication, inhibited tumor-induced angiogenesis, and showed broad antitumor activity in vivo, establishing TEM8 as required for pathological angiogenesis.\",\n      \"method\": \"Genetic knockout (Tem8-/- mice); xenograft tumor growth assays; anti-TEM8 antibody blocking experiments\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic disruption combined with antibody blockade across multiple tumor models, replicated across cancer types in one rigorous study\",\n      \"pmids\": [\"22340594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ANTXR1 activation by its natural ligand C5A (a collagen VI alpha3 fragment) increases cancer stem cell self-renewal (mammosphere assay) and activates Wnt signaling including upregulation of LRP6, phosphorylation of GSK3alpha/beta, and expression of Wnt target genes. RNAi silencing of ANTXR1 reduced LRP6 and ZEB1 expression, self-renewal, invasion, tumorigenicity, and metastasis.\",\n      \"method\": \"Ligand stimulation with C5A; RNAi knockdown; mammosphere assay; Western blot for Wnt pathway components; in vivo tumorigenicity/metastasis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ligand stimulation, RNAi, in vivo), single lab\",\n      \"pmids\": [\"23832666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function mutations in ANTXR1 (nonsense, splicing) cause GAPO syndrome; nonsense mutations trigger nonsense-mediated mRNA decay resulting in loss of ANTXR1, and the major GAPO phenotypes (dental abnormalities, extracellular matrix accumulation) recapitulate Antxr1-mutant mouse phenotypes, establishing ANTXR1 as required for extracellular matrix homeostasis.\",\n      \"method\": \"Whole exome sequencing; identification of homozygous mutations; comparison to Antxr1-mutant mouse phenotype\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics with functional validation via mouse model comparison; nonsense-mediated decay mechanism experimentally supported\",\n      \"pmids\": [\"23602711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Antxr1-deficient primary fibroblasts, increased collagen type I (Col1a1) and fibronectin (Fn1) expression occurs via a cell-autonomous ANTXR1-dependent mechanism partly mediated through CTGF; VEGF signaling acts in parallel. Re-expression of the longest ANTXR1 isoform (sv1) in mutant fibroblasts decreased Ctgf, Col1a1, and Fn1 transcripts but had no effect on VEGF expression, demonstrating ANTXR1 regulation of ECM via a CTGF-dependent pathway.\",\n      \"method\": \"Primary fibroblasts from Antxr1+/+ and Antxr1-/- mice; shRNA knockdown of VEGF; rescue by ANTXR1 sv1 re-expression; VEGF neutralizing antibody; qRT-PCR/Western blot\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function/rescue with multiple orthogonal approaches (shRNA, antibody, isoform re-expression), single lab\",\n      \"pmids\": [\"28011198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TEM8 N-glycosylation is required for proper folding and trafficking to the cell surface; absence of N-linked glycans on either the vWA or Ig-like extracellular domains leads to misfolding and retention by ER quality control machinery, preventing surface expression.\",\n      \"method\": \"N-glycosylation mutants; cell surface trafficking assays; ER quality control assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis of glycosylation sites with trafficking and folding readouts, single lab\",\n      \"pmids\": [\"25781883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TEM8 functions as a receptor for urokinase plasminogen activator (uPA); uPA binding stimulates phosphorylation of TEM8 and augments EGFR and ERK1/2 phosphorylation. TEM8-Fc abrogated the TEM8-uPA interaction, blocked uPA-induced HepG2 cell migration in vitro, and inhibited MCF-7 xenograft growth and metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation/pulldown; phosphorylation assays (Western blot); TEM8-Fc blocking; migration assay; xenograft mouse model\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction plus functional blocking with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"30241478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANTXR1 positively regulates RANKL-induced osteoclast differentiation and bone resorption; gain- and loss-of-function studies showed ANTXR1 affects phosphorylation of JNK, Akt, IkappaB, and PLCgamma2 and subsequently alters c-Fos and NFATc1 levels. ANTXR1 manipulation in bone marrow macrophages also modulated HUVECs tube formation via secretion of MMP-9 and VEGF-A, with no effect on osteoblast differentiation.\",\n      \"method\": \"Gain- and loss-of-function in bone marrow macrophages; osteoclast differentiation assay; phosphorylation Western blots; HUVEC tube formation assay; bone resorption assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss of function with defined signaling readouts, multiple orthogonal assays, single lab\",\n      \"pmids\": [\"30686531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TEM8 overexpression in ovarian cancer cells activates Rac1/Cdc42/JNK and MEK/ERK/STAT3 signaling pathways, promoting proliferation, G0/G1 transition, migration, and invasion while suppressing apoptosis. Pharmacological inhibition of RAC1 (EHop-016) or MEK (PD98059) suppressed malignant behaviors in TEM8-overexpressing cells. Transcription factor GATA2 binds the TEM8 promoter region (TATTAGTTATCTTT site) and regulates TEM8 expression.\",\n      \"method\": \"Overexpression; pathway inhibitor treatment; Western blot for phosphorylated signaling components; promoter binding assay (ChIP/luciferase implied); proliferation, apoptosis, migration, invasion assays\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with pathway-inhibitor rescue and transcription factor binding, multiple readouts, single lab\",\n      \"pmids\": [\"32774719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Antxr1 is a direct transcriptional target of Runx2 in chondrocytes; Antxr1 deletion in mice results in shorter limbs from E16.5 due to reduced chondrocyte proliferation. Chondrocyte-specific Antxr1 transgenic overexpression also caused shortened limbs with increased BrdU uptake and apoptosis, accompanied by matrix mineralization, showing dose-sensitive roles in chondrocyte proliferation and apoptosis.\",\n      \"method\": \"Antxr1-/- mouse; chondrocyte-specific transgenic overexpression; BrdU incorporation assay; apoptosis assay; Runx2 target gene analysis; histological analysis of growth plates\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic loss-of-function and gain-of-function with defined cellular phenotypes and direct transcriptional regulation by Runx2\",\n      \"pmids\": [\"32244499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TEM8 increases active RhoC levels and induces ROCK1-mediated phosphorylation of SMAD5, a signaling cascade essential for promoting cancer cell stemness and vasculogenic mimicry capacity in TNBC. ASB10, an ERalpha trans-activated E3 ligase, ubiquitylates TEM8 for proteasomal degradation; ASB10 deficiency in TNBC results in elevated TEM8 levels.\",\n      \"method\": \"Mechanistic dissection by overexpression/knockdown; Western blot for RhoC, ROCK1, pSMAD5; ubiquitylation assay; co-immunoprecipitation for ASB10-TEM8 interaction; vasculogenic mimicry assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods defining upstream E3 ligase and downstream RhoC/ROCK1/SMAD5 pathway, single rigorous study\",\n      \"pmids\": [\"34285210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In vivo imaging assay using LFn-NLS-Cre chimaeric protein with PA shows that TEM8 is required for anthrax toxin intoxication in the kidney and spleen, while CMG2 is dominant in liver, heart, and leukocytes; combined loss of both receptors completely abolishes intoxication, demonstrating organ-specific receptor utilization.\",\n      \"method\": \"Transgenic Cre-reporter mice; chimeric LFn-NLS-Cre protein + PA co-administration; confocal microscopy; flow cytometry; TEM8- and CMG2-deficient mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo single-cell resolution imaging with genetic receptor knockouts providing epistatic evidence for organ-specific receptor utilization\",\n      \"pmids\": [\"34871548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANTXR1 interacts with LRP6 to promote nuclear entry of beta-catenin and activate Wnt/beta-catenin signaling, thereby repressing gamma-globin (HBG) expression. Overexpression of ANTXR1 decreased gamma-globin; knockdown increased it. The regulatory effect was reversed by XAV939 (Wnt inhibitor) and LiCl (GSK3beta inhibitor). ANTXR1 overexpression also increased c-Jun-mediated SOX6 transcription, which silences gamma-globin.\",\n      \"method\": \"Overexpression and knockdown in K562, CD34+ cord blood, HUDEP-2 cells; Co-IP for ANTXR1-LRP6 interaction; pharmacological modulation of Wnt pathway; ChIP/promoter analysis for SOX6\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for LRP6 interaction, pharmacological rescue, gain/loss-of-function with defined transcriptional readout, single lab\",\n      \"pmids\": [\"35942209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANTXR1 deficiency in human fibroblasts induces a senescent phenotype associated with defects in nuclear architecture and actin dynamics, proposing GAPO syndrome as a progeroid disorder.\",\n      \"method\": \"ANTXR1 knockdown/deficiency in human fibroblasts; senescence assays; nuclear architecture imaging; actin dynamics assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple cellular phenotype readouts (senescence, nuclear architecture, actin), single lab\",\n      \"pmids\": [\"38653789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANTXR1 mediates collagen turnover in the heart; genetic disruption of Antxr1 or treatment with neutralizing antibodies prevented cardiac deterioration after acute myocardial infarction and improved function in pressure overload and obesity-induced heart failure models. Mechanistic studies revealed ANTXR1 antibody blockade improved post-infarct scar formation and attenuated late-stage chronic TGFbeta-mediated extracellular matrix remodeling.\",\n      \"method\": \"Antxr1 genetic knockout; neutralizing antibody treatment; multiple heart failure mouse models (MI, pressure overload, obesity-induced HFpEF); functional cardiac measurements; histological scar analysis; TGFbeta pathway assessment\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus pharmacological blockade across multiple independent disease models with mechanistic pathway (TGFbeta/ECM) identification\",\n      \"pmids\": [\"41039173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CALCR (a G-protein-coupled receptor) physically interacts with ANTXR1 as shown by co-immunoprecipitation; CALCR knockdown decreased AKT phosphorylation, linking the CALCR-ANTXR1 complex to AKT signaling in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation; CALCR knockdown; Western blot for AKT phosphorylation; xenograft mouse model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP experiment with limited mechanistic follow-up on ANTXR1-specific contribution, single lab\",\n      \"pmids\": [\"40195530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAF-derived lactate promotes ANTXR1 transcription via histone lactylation and induces ANTXR1 lactylation at lysine 453. ANTXR1 K453 lactylation promotes protein stability and activates the RhoC/ROCK1/SMAD5 signaling pathway, driving colorectal cancer stemness and oxaliplatin resistance.\",\n      \"method\": \"Histone lactylation ChIP on ANTXR1 promoter; site-specific lactylation at K453 identified by mass spectrometry; gain/loss-of-function; Western blot for RhoC/ROCK1/SMAD5; CDX/PDX xenograft models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific PTM identification (K453 lactylation) with downstream pathway validation and in vivo rescue, single lab\",\n      \"pmids\": [\"40683418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEM8 overexpression in glioblastoma activates the Src/PI3K/AKT/GSK-3beta/beta-catenin pathway, leading to beta-catenin stabilization and activation of its transcriptional program; TEM8 overexpression promotes proliferation, invasion, migration, and chemo-radioresistance, while knockdown reverses these effects.\",\n      \"method\": \"Overexpression and knockdown; Western blot for Src, PI3K, AKT, GSK3beta, beta-catenin; proliferation, invasion, migration assays; DNA methylation array correlation\",\n      \"journal\": \"Cancer genomics & proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with signaling pathway validation, multiple functional readouts, single lab\",\n      \"pmids\": [\"39191501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PA-induced cytotoxicity in macrophages overexpressing ANTXR1 requires direct interaction with ANTXR1, oligomerization of PA, channel formation, and endosomal acidification, but is independent of the ANTXR1 cytoplasmic tail. Overexpression of ANTXR1 extends PA-oligomer half-life and sensitizes cells to lethal toxin. PA-alone cytotoxicity proceeds via caspase-3 activation, DNA fragmentation, PARP cleavage, and Bid activation (apoptosis).\",\n      \"method\": \"ANTXR1 overexpression in RAW 264.7 macrophages; PA oligomerization assay; endosomal acidification inhibition; cytoplasmic tail deletion mutants; caspase activation assays; apoptosis markers\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic dissection experiments (domain deletion, chemical inhibitors, apoptosis markers) in a single lab\",\n      \"pmids\": [\"16882031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ANTXR1 is dynamically expressed in chick embryo and FGF signaling is sufficient (but not necessary) to induce ANTXR1 expression in facial mesenchyme; in vitro, ANTXR1 can link ECM components with the actin cytoskeleton to promote cell adhesion and spreading.\",\n      \"method\": \"Suppression subtractive hybridization screen; FGF gain-of-function/loss-of-function in chick embryo; cell adhesion assays\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single experimental system, cell adhesion/actin linkage inferred from in vitro assay cited in passing, single lab\",\n      \"pmids\": [\"20034073\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANTXR1/TEM8 is a type I transmembrane protein with an integrin-like vWA domain that binds collagen VI (C5 domain), uPA, and the anthrax toxin protective antigen (PA) via a defined interface (Leu56, residues 154-160); it links the extracellular matrix to the actin cytoskeleton, regulates ECM homeostasis (collagen I, fibronectin, CTGF) and is required for pathological angiogenesis. Its cell-surface conformation is modulated by actin-binding proteins (alpha-SMA, transgelin), its protein stability is controlled by ASB10-mediated ubiquitylation and lactylation at K453, and it signals through multiple downstream pathways including RhoC/ROCK1/SMAD5 (stemness/vasculogenic mimicry), Rac1/Cdc42/JNK and MEK/ERK/STAT3 (proliferation/invasion), PI3K/AKT/GSK3beta/beta-catenin, and Wnt/LRP6 (gamma-globin regulation and stemness); in vivo, ANTXR1 is required for anthrax toxin entry in kidney/spleen, drives maladaptive cardiac ECM remodeling via TGFbeta, and regulates chondrocyte proliferation downstream of Runx2, while loss-of-function mutations cause GAPO syndrome through defective ECM homeostasis and fibroblast senescence.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANTXR1 (TEM8) is a type I transmembrane receptor with an integrin-like vWA domain that couples the extracellular matrix to the actin cytoskeleton and governs ECM homeostasis and pathological angiogenesis [#7, #9]. Its extracellular vWA domain adopts an integrin fold and binds the C5 domain of collagen VI alpha3, the urokinase plasminogen activator (uPA), and the anthrax toxin protective antigen (PA) through a defined interface at residues 56-57 and 154-160, with Leu56 setting its lower PA affinity relative to CMG2 [#0, #5, #12]. Engagement of collagen drives endothelial adhesion, migration, and tube formation, requiring the vWA plus transmembrane domains, and TEM8 is essential for tumor-induced angiogenesis and xenograft growth [#1, #2, #7]. ANTXR1 surface availability is gated by N-glycosylation-dependent folding and ER quality control, by actin-binding proteins (alpha-smooth muscle actin, transgelin) that mask its extracellular epitope, and by post-translational control through ASB10-mediated ubiquitylation and K453 lactylation [#11, #6, #16, #22]. Downstream, ANTXR1 activates a RhoC/ROCK1/SMAD5 axis driving cancer stemness and vasculogenic mimicry, and engages Wnt signaling via LRP6 and GSK3beta/beta-catenin to control self-renewal and gamma-globin repression [#16, #8, #18]. In vivo, ANTXR1 is required for anthrax toxin entry in kidney and spleen, acts downstream of Runx2 to set chondrocyte proliferation, and drives maladaptive cardiac collagen remodeling through TGFbeta [#17, #15, #20]. Loss-of-function mutations in ANTXR1 cause GAPO syndrome through defective ECM homeostasis [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that the TEM8 ectodomain recognizes a specific ECM ligand answered what this orphan tumor-endothelial marker physically binds, anchoring it to the extracellular matrix.\",\n      \"evidence\": \"Pulldown using the TEM8 extracellular domain as bait, with domain mapping to collagen alpha3(VI) C5\",\n      \"pmids\": [\"14871805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding affinity and stoichiometry not quantified\", \"Functional consequence of the collagen VI interaction not yet established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Functional assays showed TEM8 is not merely a binder but an active mediator of endothelial adhesion, migration, and tube formation, defining its role in vessel morphogenesis.\",\n      \"evidence\": \"Overexpression, dominant-negative ectodomain, ribozyme knockdown, and domain-deletion constructs in endothelial and CHO cells\",\n      \"pmids\": [\"15777794\", \"15993844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the intracellular effectors linking TEM8 to the cytoskeleton\", \"vWA+TM sufficiency for tubule formation tested only in CHO surrogate cells\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Dissecting the anthrax intoxication pathway clarified which steps require ANTXR1 and showed the cytoplasmic tail is dispensable for toxin entry, defining the receptor's mechanistic contribution.\",\n      \"evidence\": \"ANTXR1 overexpression in RAW 264.7 macrophages with PA oligomerization, acidification inhibition, tail-deletion mutants, and apoptosis markers\",\n      \"pmids\": [\"16882031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed in overexpression macrophage model\", \"Did not address physiological receptor levels\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mutagenesis of PA defined residue-level determinants distinguishing TEM8 from the related receptor CMG2, providing the basis for receptor-selective toxin targeting.\",\n      \"evidence\": \"Phage display selection and cytotoxicity assays in CHO cells expressing TEM8 or CMG2\",\n      \"pmids\": [\"17251181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mapped the PA side of the interface but not yet the TEM8 side\", \"Selectivity tested only in engineered CHO cells\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The crystal structure plus structure-guided mutagenesis revealed an integrin fold and pinpointed the TEM8 PA-binding interface, explaining its lower toxin affinity relative to CMG2 and how the cytoskeleton can remodel its surface conformation.\",\n      \"evidence\": \"1.7 A X-ray structure of the vWA domain with mutagenesis; separately, actin-binding protein overexpression with conformation-sensitive antibody readout\",\n      \"pmids\": [\"20585457\", \"21129411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure limited to the isolated vWA domain\", \"Mechanism linking intracellular actin proteins to ectodomain conformation not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genetic knockout combined with antibody blockade established TEM8 as required for pathological angiogenesis and a therapeutic target across multiple tumor types.\",\n      \"evidence\": \"Tem8-/- mice, xenograft models of melanoma/breast/colon/lung, and anti-TEM8 ectodomain antibodies\",\n      \"pmids\": [\"22340594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling driving the angiogenic requirement not defined here\", \"Distinction between tumor-cell-intrinsic and stromal roles incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Human genetics tied ANTXR1 loss to GAPO syndrome and to ECM accumulation, while ligand stimulation linked the receptor to Wnt-driven cancer stemness, establishing its dual roles in ECM homeostasis and self-renewal.\",\n      \"evidence\": \"Whole-exome sequencing with NMD analysis and mouse phenotype comparison; C5A ligand stimulation, RNAi, mammosphere and in vivo metastasis assays\",\n      \"pmids\": [\"23602711\", \"23832666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How loss of an ECM receptor causes excess ECM accumulation not mechanistically resolved in 2013\", \"Direct biochemical link between ANTXR1 and LRP6/Wnt not yet shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Rescue experiments defined ANTXR1 as a cell-autonomous, CTGF-dependent suppressor of collagen I and fibronectin, and showed surface delivery depends on N-glycosylation, mechanistically connecting receptor loss to ECM accumulation.\",\n      \"evidence\": \"Antxr1-/- primary fibroblasts with isoform re-expression and VEGF perturbation; N-glycosylation mutants with trafficking/ER quality control assays\",\n      \"pmids\": [\"28011198\", \"25781883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The signaling intermediate between ANTXR1 and CTGF not identified\", \"Relative contributions of CTGF versus VEGF arms not quantified in vivo\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In vivo genetics and signaling profiling placed ANTXR1 in tissue-specific programs: a Runx2-driven role in chondrocyte proliferation, a RANKL-coupled role in osteoclast differentiation, and ovarian-cancer Rac1/JNK and MEK/ERK/STAT3 cascades under GATA2 transcriptional control.\",\n      \"evidence\": \"Antxr1 knockout and chondrocyte-specific transgenic mice; gain/loss-of-function in bone marrow macrophages; overexpression with pathway inhibitors and promoter binding in ovarian cancer cells\",\n      \"pmids\": [\"32244499\", \"30686531\", \"32774719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same downstream effectors operate across these tissues unknown\", \"Dose sensitivity of chondrocyte phenotypes not mechanistically explained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of the RhoC/ROCK1/SMAD5 cascade and the ASB10 E3 ligase defined both a stemness-driving downstream pathway and an upstream determinant of ANTXR1 protein abundance, and organ-resolved imaging clarified receptor utilization for anthrax toxin.\",\n      \"evidence\": \"Overexpression/knockdown with RhoC/ROCK1/pSMAD5 readouts, ubiquitylation and ASB10 co-IP in TNBC; LFn-NLS-Cre + PA in vivo imaging with TEM8/CMG2 knockout mice\",\n      \"pmids\": [\"34285210\", \"34871548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ANTXR1 activates RhoC at the membrane not defined\", \"Trigger for ASB10-mediated turnover beyond ERalpha context unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating a direct ANTXR1-LRP6 interaction provided the biochemical basis for ANTXR1 activation of Wnt/beta-catenin, extending its signaling role to gamma-globin repression.\",\n      \"evidence\": \"Co-IP for ANTXR1-LRP6, gain/loss-of-function and Wnt/GSK3beta pharmacological rescue in K562, CD34+, and HUDEP-2 cells\",\n      \"pmids\": [\"35942209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP for the LRP6 interaction without structural mapping\", \"Direct versus indirect control of SOX6 not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple disease-model studies established ANTXR1 as a driver of maladaptive cardiac ECM remodeling and as a determinant of fibroblast senescence, reframing GAPO as a progeroid disorder and ANTXR1 as a cardiac therapeutic target.\",\n      \"evidence\": \"Antxr1 knockout and neutralizing antibodies across MI, pressure-overload, and HFpEF mouse models with TGFbeta pathway analysis; ANTXR1-deficient human fibroblasts with senescence, nuclear architecture, and actin assays; glioblastoma Src/PI3K/AKT/GSK3beta/beta-catenin profiling\",\n      \"pmids\": [\"41039173\", \"38653789\", \"39191501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ANTXR1 loss accelerates senescence mechanistically not resolved\", \"Connection between cardiac TGFbeta remodeling and the fibroblast ECM program not directly tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of K453 lactylation linked the tumor metabolic microenvironment to ANTXR1 stability and the RhoC/ROCK1/SMAD5 axis, and a CALCR interaction was reported to couple ANTXR1 to AKT signaling.\",\n      \"evidence\": \"Histone lactylation ChIP, mass-spec site mapping of K453, and gain/loss-of-function with xenografts; CALCR co-IP and knockdown with AKT readout in gastric cancer\",\n      \"pmids\": [\"40683418\", \"40195530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CALCR-ANTXR1 link rests on a single co-IP with limited ANTXR1-specific follow-up\", \"Enzyme depositing K453 lactylation not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular events converting ANTXR1 ligand engagement into its divergent intracellular outputs (RhoC, Wnt/LRP6, MEK/ERK, AKT) and the unifying mechanism by which receptor loss produces ECM accumulation and senescence remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the full-length receptor or ligand-bound complexes beyond the vWA domain\", \"Tissue-specific selection among downstream pathways unexplained\", \"Direct cytoskeletal effectors of the cytoplasmic tail not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [4, 5, 17, 24]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 12, 16, 18]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 0, 25]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 11, 24]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [9, 10, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 16, 18, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 17, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [15, 13, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"COL6A3\", \"PLAU\", \"LRP6\", \"ASB10\", \"CALCR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}