{"gene":"PLXDC1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2014,"finding":"PLXDC1 (TEM7) and PLXDC2 were identified as cell-surface transmembrane receptors for the secreted factor PEDF (Pigment Epithelium Derived Factor). Loss-of-function and gain-of-function studies in distinct cellular models demonstrated cell type-specific receptor activities. PEDF receptors form homooligomers under basal conditions, and PEDF dissociates the homooligomer to activate the receptors. Mutations in the intracellular domain profoundly affect receptor activities.","method":"Loss-of-function and gain-of-function cellular assays, receptor binding studies, mutagenesis of intracellular domain","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function in distinct cellular models with mutagenesis, single lab but multiple orthogonal approaches","pmids":["25535841"],"is_preprint":false},{"year":2004,"finding":"Cortactin was identified as a binding partner for the extracellular region of TEM7 (PLXDC1) and its homologue TEM7R. The binding domain of cortactin was mapped to a unique nine-amino acid region in its plexin-like domain. TEM7 protein (membrane-bound form) was confirmed to be overexpressed on the endothelium of various tumor types.","method":"Affinity purification, protein binding assay, antibody-based cell surface detection, domain mapping","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification with domain mapping, single lab, two orthogonal methods (pulldown + antibody confirmation)","pmids":["15574754"],"is_preprint":false},{"year":2015,"finding":"The gain-of-function transcription factor TGLI1 directly binds to the TEM7 (PLXDC1) gene promoter to upregulate its expression. Conditioned medium from TGLI1-expressing GBM cells induced tubule formation of brain microvascular endothelial cells, and this induction was prevented by TEM7 knockdown, establishing TEM7 as a downstream effector of TGLI1-mediated angiogenesis.","method":"Promoter binding assay (chromatin immunoprecipitation implied), gene expression profiling, siRNA knockdown, tubule formation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding plus functional rescue by knockdown, single lab, two orthogonal methods","pmids":["26093087"],"is_preprint":false},{"year":2018,"finding":"Bevacizumab (anti-VEGF) treatment triggers upregulation of PLXDC1 in glioblastoma cells via epithelial-to-mesenchymal transition. Enforced expression of PLXDC1 in U87MG cells promoted perivascular brain infiltration, while PLXDC1 inhibition prevented perivascular infiltration and significantly increased survival of bevacizumab-treated rats.","method":"In vivo xenograft models, lentiviral overexpression, PLXDC1 inhibition, survival analysis in rat models","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in vivo with survival readout, single lab, multiple orthogonal approaches","pmids":["30414187"],"is_preprint":false},{"year":2011,"finding":"TEM7 (PLXDC1) protein expression on tumor endothelial cells was confirmed by flow cytometry and RT-PCR. TEM7 expression was absent from normal microvascular endothelial cells (HMVEC) and HUVEC but was induced in endothelial precursor/progenitor cells by phorbol ester PMA. An anti-TEM7 antibody mediated antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis in TEM7-expressing cancer cell lines.","method":"RT-PCR, flow cytometry, ADCC assay, phagocytosis assay, adenoviral TEM7 expression","journal":"Microvascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional ADCC assay plus expression characterization, single lab, multiple orthogonal methods","pmids":["21958527"],"is_preprint":false},{"year":2018,"finding":"Silencing of PLXDC1 using siRNA delivered via CD44-targeted chitosan nanoparticles significantly inhibited tumor growth, cell proliferation, and microvessel density while increasing apoptosis in A2780 ovarian tumor-bearing mice, establishing PLXDC1 as functionally required for tumor angiogenesis.","method":"siRNA knockdown in vivo (mouse xenograft), nanoparticle delivery, tumor growth measurement, microvessel density quantification, apoptosis assay","journal":"Drug delivery","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo loss-of-function with multiple phenotypic readouts, single lab","pmids":["29890852"],"is_preprint":false},{"year":2008,"finding":"TEM7/PLXDC1 membrane-bound protein was localized to the luminal surfaces of vascular endothelial cells in fibrovascular membranes from patients with proliferative diabetic retinopathy, colocalizing with the endothelial marker CD34, as shown by immunoelectron microscopy.","method":"Immunohistochemistry, immunoelectron microscopy, in situ hybridization, RT-PCR","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular localization by immunoelectron microscopy confirmed at protein level with multiple methods, single lab","pmids":["18316703"],"is_preprint":false}],"current_model":"PLXDC1 (TEM7) is a transmembrane cell-surface receptor for PEDF that forms homooligomers dissociated by ligand binding to activate downstream signaling; it is expressed on tumor and angiogenic endothelium, binds cortactin via its extracellular domain, is transcriptionally regulated by TGLI1 through direct promoter binding, and functionally promotes angiogenesis and perivascular tumor infiltration, with its inhibition reducing tumor growth and increasing survival in preclinical models."},"narrative":{"mechanistic_narrative":"PLXDC1 (TEM7) is a single-pass transmembrane cell-surface receptor that functions in tumor and angiogenic endothelium to promote angiogenesis and tumor progression [PMID:25535841, PMID:29890852]. Together with PLXDC2, it serves as a receptor for the secreted factor PEDF: the receptors form homooligomers under basal conditions that PEDF binding dissociates to activate downstream signaling, and mutations in the intracellular domain alter receptor activity [PMID:25535841]. Its extracellular region binds cortactin through a discrete nine-amino-acid segment in the cortactin plexin-like domain [PMID:15574754]. PLXDC1 is selectively displayed on the luminal surface of tumor and pathological vascular endothelium and on endothelial progenitor cells, being absent from normal mature endothelium [PMID:15574754, PMID:21958527, PMID:18316703]; this restricted expression is exploited by anti-TEM7 antibodies that drive antibody-dependent cellular cytotoxicity and phagocytosis of TEM7-positive cells [PMID:21958527]. Expression is driven transcriptionally by direct promoter binding of the gain-of-function transcription factor TGLI1, with PLXDC1 acting as a required downstream effector of TGLI1-induced endothelial tubule formation [PMID:26093087]. Functionally, PLXDC1 is required for tumor angiogenesis and growth—its silencing reduces tumor growth, proliferation, and microvessel density while increasing apoptosis [PMID:29890852]—and it is induced by anti-VEGF (bevacizumab) therapy via epithelial-to-mesenchymal transition to drive perivascular brain tumor infiltration, with PLXDC1 inhibition preventing infiltration and prolonging survival [PMID:30414187].","teleology":[{"year":2004,"claim":"Established the first molecular interaction partner of PLXDC1, linking its extracellular domain to the actin-regulatory adaptor cortactin and confirming tumor-endothelial expression.","evidence":"Affinity purification, domain mapping, and antibody-based cell-surface detection in tumor endothelium","pmids":["15574754"],"confidence":"Medium","gaps":["Functional consequence of the cortactin interaction not established","No reciprocal validation or signaling readout","Mechanism connecting extracellular receptor to intracellular cortactin unresolved"]},{"year":2008,"claim":"Localized PLXDC1 protein to the luminal endothelial surface in pathological neovasculature, defining where the receptor acts in disease.","evidence":"Immunoelectron microscopy, immunohistochemistry, in situ hybridization, and RT-PCR in proliferative diabetic retinopathy membranes","pmids":["18316703"],"confidence":"Medium","gaps":["Descriptive localization without functional perturbation","Does not establish signaling role at this site"]},{"year":2011,"claim":"Demonstrated PLXDC1 is restricted to tumor/progenitor endothelium and absent from normal vasculature, validating it as a targetable tumor-vascular marker.","evidence":"Flow cytometry, RT-PCR, PMA induction in endothelial precursors, and ADCC/phagocytosis assays with anti-TEM7 antibody","pmids":["21958527"],"confidence":"Medium","gaps":["Mechanism of expression induction by PMA not defined","Antibody efficacy not tested in vivo here"]},{"year":2014,"claim":"Defined PLXDC1 as a ligand-activated PEDF receptor with a homooligomer-dissociation activation mechanism and an intracellular signaling domain, answering how the receptor transduces a signal.","evidence":"Reciprocal gain- and loss-of-function cellular assays, receptor binding, and intracellular-domain mutagenesis","pmids":["25535841"],"confidence":"High","gaps":["Downstream signaling effectors not identified","Structural basis of homooligomer dissociation unresolved","Cell-type-specific receptor activities not mechanistically explained"]},{"year":2015,"claim":"Placed PLXDC1 within a transcriptional axis as a direct TGLI1 target required for tumor-induced angiogenesis, connecting upstream regulation to functional output.","evidence":"Promoter binding assay, expression profiling, siRNA knockdown, and endothelial tubule formation assay in glioblastoma models","pmids":["26093087"],"confidence":"Medium","gaps":["Direct promoter occupancy by ChIP only implied","Does not connect TGLI1-driven expression to PEDF receptor signaling"]},{"year":2018,"claim":"Demonstrated PLXDC1 is functionally required for tumor angiogenesis and growth in vivo, moving beyond correlation to causal requirement.","evidence":"In vivo siRNA silencing via CD44-targeted nanoparticles in ovarian tumor xenografts with tumor growth, microvessel, and apoptosis readouts","pmids":["29890852"],"confidence":"Medium","gaps":["Single tumor model","Molecular mechanism downstream of knockdown not dissected"]},{"year":2018,"claim":"Linked PLXDC1 to therapy resistance, showing anti-VEGF treatment induces PLXDC1 via EMT to drive perivascular tumor infiltration and that inhibition improves survival.","evidence":"In vivo xenograft models with lentiviral overexpression, PLXDC1 inhibition, and survival analysis in bevacizumab-treated rats","pmids":["30414187"],"confidence":"Medium","gaps":["Mechanism coupling PLXDC1 to invasive phenotype not defined","EMT-to-PLXDC1 regulatory link not molecularly mapped"]},{"year":null,"claim":"The intracellular signaling cascade triggered by PEDF-induced PLXDC1 activation and how it mechanistically drives angiogenesis and tumor infiltration remain undefined.","evidence":"No downstream effector or pathway has been identified in the available corpus","pmids":[],"confidence":"Low","gaps":["No downstream signaling effectors identified","Relationship between PEDF receptor signaling and cortactin binding unknown","No structural model of the receptor or its activation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4,6]}],"pathway":[],"complexes":[],"partners":["PEDF","SERPINF1","CTTN","PLXDC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IUK5","full_name":"Plexin domain-containing protein 1","aliases":["Tumor endothelial marker 3","Tumor endothelial marker 7"],"length_aa":500,"mass_kda":55.8,"function":"Plays a critical role in endothelial cell capillary morphogenesis","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8IUK5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXDC1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLXDC1","total_profiled":1310},"omim":[{"mim_id":"606827","title":"PLEXIN DOMAIN-CONTAINING PROTEIN 2; PLXDC2","url":"https://www.omim.org/entry/606827"},{"mim_id":"606826","title":"PLEXIN DOMAIN-CONTAINING PROTEIN 1; PLXDC1","url":"https://www.omim.org/entry/606826"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":44.9}],"url":"https://www.proteinatlas.org/search/PLXDC1"},"hgnc":{"alias_symbol":["TEM3","TEM7"],"prev_symbol":[]},"alphafold":{"accession":"Q8IUK5","domains":[{"cath_id":"-","chopping":"85-302","consensus_level":"high","plddt":91.5569,"start":85,"end":302},{"cath_id":"3.30.1680","chopping":"306-356","consensus_level":"high","plddt":87.2292,"start":306,"end":356}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUK5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUK5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUK5-F1-predicted_aligned_error_v6.png","plddt_mean":72.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLXDC1","jax_strain_url":"https://www.jax.org/strain/search?query=PLXDC1"},"sequence":{"accession":"Q8IUK5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IUK5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IUK5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUK5"}},"corpus_meta":[{"pmid":"3055178","id":"PMC_3055178","title":"Plasmid-mediated beta-lactamase (TEM-7) involved in resistance to ceftazidime and aztreonam.","date":"1988","source":"Reviews of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/3055178","citation_count":105,"is_preprint":false},{"pmid":"25535841","id":"PMC_25535841","title":"Identification of PLXDC1 and PLXDC2 as the transmembrane receptors for the multifunctional factor PEDF.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25535841","citation_count":72,"is_preprint":false},{"pmid":"2327769","id":"PMC_2327769","title":"Molecular epidemiology of TEM-3 (CTX-1) beta-lactamase.","date":"1990","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/2327769","citation_count":62,"is_preprint":false},{"pmid":"29890852","id":"PMC_29890852","title":"Selective delivery of PLXDC1 small interfering RNA to endothelial cells for anti-angiogenesis tumor therapy using CD44-targeted chitosan nanoparticles for epithelial ovarian cancer.","date":"2018","source":"Drug delivery","url":"https://pubmed.ncbi.nlm.nih.gov/29890852","citation_count":54,"is_preprint":false},{"pmid":"2506109","id":"PMC_2506109","title":"Substitution of serine for arginine in position 162 of TEM-type beta-lactamases extends the substrate profile of mutant enzymes, TEM-7 and TEM-101, to ceftazidime and aztreonam.","date":"1989","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/2506109","citation_count":51,"is_preprint":false},{"pmid":"26093087","id":"PMC_26093087","title":"The gain-of-function GLI1 transcription factor TGLI1 enhances expression of VEGF-C and TEM7 to promote glioblastoma angiogenesis.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26093087","citation_count":46,"is_preprint":false},{"pmid":"1331747","id":"PMC_1331747","title":"A new example of physical linkage between Tn1 and Tn21: the antibiotic multiple-resistance region of plasmid pCFF04 encoding extended-spectrum beta-lactamase TEM-3.","date":"1992","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/1331747","citation_count":46,"is_preprint":false},{"pmid":"15574754","id":"PMC_15574754","title":"Identification of a binding partner for the endothelial cell surface proteins TEM7 and TEM7R.","date":"2004","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15574754","citation_count":42,"is_preprint":false},{"pmid":"18316703","id":"PMC_18316703","title":"TEM7 (PLXDC1) in neovascular endothelial cells of fibrovascular membranes from patients with proliferative diabetic retinopathy.","date":"2008","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/18316703","citation_count":42,"is_preprint":false},{"pmid":"8192442","id":"PMC_8192442","title":"Different ratios of the piperacillin-tazobactam combination for treatment of experimental meningitis due to Klebsiella pneumoniae producing the TEM-3 extended-spectrum beta-lactamase.","date":"1994","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/8192442","citation_count":34,"is_preprint":false},{"pmid":"1856122","id":"PMC_1856122","title":"Possible in-vivo transfer of beta-lactamase TEM-3 from Klebsiella pneumoniae to Salmonella kedougou.","date":"1991","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/1856122","citation_count":33,"is_preprint":false},{"pmid":"17031559","id":"PMC_17031559","title":"PLXDC1 (TEM7) is identified in a genome-wide expression screen of glioblastoma endothelium.","date":"2006","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17031559","citation_count":30,"is_preprint":false},{"pmid":"30414187","id":"PMC_30414187","title":"Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1.","date":"2018","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30414187","citation_count":28,"is_preprint":false},{"pmid":"21958527","id":"PMC_21958527","title":"Tumor endothelial marker 7 (TEM-7): a novel target for antiangiogenic therapy.","date":"2011","source":"Microvascular research","url":"https://pubmed.ncbi.nlm.nih.gov/21958527","citation_count":25,"is_preprint":false},{"pmid":"8849221","id":"PMC_8849221","title":"Survey of Klebsiella pneumoniae producing extended-spectrum beta-lactamases: prevalence of TEM-3 and first identification of TEM-26 in France.","date":"1996","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/8849221","citation_count":22,"is_preprint":false},{"pmid":"11709345","id":"PMC_11709345","title":"TEM-89 beta-lactamase produced by a Proteus mirabilis clinical isolate: new complex mutant (CMT 3) with mutations in both TEM-59 (IRT-17) and TEM-3.","date":"2001","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/11709345","citation_count":21,"is_preprint":false},{"pmid":"40091495","id":"PMC_40091495","title":"PLXDC1+ Tumor-Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40091495","citation_count":15,"is_preprint":false},{"pmid":"8195610","id":"PMC_8195610","title":"Activity of isepamicin and selection of permeability mutants to beta-lactams during aminoglycoside therapy of experimental endocarditis due to Klebsiella pneumoniae CF104 producing an aminoglycoside acetyltransferase 6' modifying enzyme and a TEM-3 beta-lactamase.","date":"1994","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/8195610","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10728,"output_tokens":1804,"usd":0.029622,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8669,"output_tokens":2575,"usd":0.05386,"stage2_stop_reason":"end_turn"},"total_usd":0.083482,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"PLXDC1 (TEM7) and PLXDC2 were identified as cell-surface transmembrane receptors for the secreted factor PEDF (Pigment Epithelium Derived Factor). Loss-of-function and gain-of-function studies in distinct cellular models demonstrated cell type-specific receptor activities. PEDF receptors form homooligomers under basal conditions, and PEDF dissociates the homooligomer to activate the receptors. Mutations in the intracellular domain profoundly affect receptor activities.\",\n      \"method\": \"Loss-of-function and gain-of-function cellular assays, receptor binding studies, mutagenesis of intracellular domain\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function in distinct cellular models with mutagenesis, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"25535841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cortactin was identified as a binding partner for the extracellular region of TEM7 (PLXDC1) and its homologue TEM7R. The binding domain of cortactin was mapped to a unique nine-amino acid region in its plexin-like domain. TEM7 protein (membrane-bound form) was confirmed to be overexpressed on the endothelium of various tumor types.\",\n      \"method\": \"Affinity purification, protein binding assay, antibody-based cell surface detection, domain mapping\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification with domain mapping, single lab, two orthogonal methods (pulldown + antibody confirmation)\",\n      \"pmids\": [\"15574754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The gain-of-function transcription factor TGLI1 directly binds to the TEM7 (PLXDC1) gene promoter to upregulate its expression. Conditioned medium from TGLI1-expressing GBM cells induced tubule formation of brain microvascular endothelial cells, and this induction was prevented by TEM7 knockdown, establishing TEM7 as a downstream effector of TGLI1-mediated angiogenesis.\",\n      \"method\": \"Promoter binding assay (chromatin immunoprecipitation implied), gene expression profiling, siRNA knockdown, tubule formation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding plus functional rescue by knockdown, single lab, two orthogonal methods\",\n      \"pmids\": [\"26093087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Bevacizumab (anti-VEGF) treatment triggers upregulation of PLXDC1 in glioblastoma cells via epithelial-to-mesenchymal transition. Enforced expression of PLXDC1 in U87MG cells promoted perivascular brain infiltration, while PLXDC1 inhibition prevented perivascular infiltration and significantly increased survival of bevacizumab-treated rats.\",\n      \"method\": \"In vivo xenograft models, lentiviral overexpression, PLXDC1 inhibition, survival analysis in rat models\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in vivo with survival readout, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"30414187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TEM7 (PLXDC1) protein expression on tumor endothelial cells was confirmed by flow cytometry and RT-PCR. TEM7 expression was absent from normal microvascular endothelial cells (HMVEC) and HUVEC but was induced in endothelial precursor/progenitor cells by phorbol ester PMA. An anti-TEM7 antibody mediated antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis in TEM7-expressing cancer cell lines.\",\n      \"method\": \"RT-PCR, flow cytometry, ADCC assay, phagocytosis assay, adenoviral TEM7 expression\",\n      \"journal\": \"Microvascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ADCC assay plus expression characterization, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21958527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Silencing of PLXDC1 using siRNA delivered via CD44-targeted chitosan nanoparticles significantly inhibited tumor growth, cell proliferation, and microvessel density while increasing apoptosis in A2780 ovarian tumor-bearing mice, establishing PLXDC1 as functionally required for tumor angiogenesis.\",\n      \"method\": \"siRNA knockdown in vivo (mouse xenograft), nanoparticle delivery, tumor growth measurement, microvessel density quantification, apoptosis assay\",\n      \"journal\": \"Drug delivery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo loss-of-function with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"29890852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TEM7/PLXDC1 membrane-bound protein was localized to the luminal surfaces of vascular endothelial cells in fibrovascular membranes from patients with proliferative diabetic retinopathy, colocalizing with the endothelial marker CD34, as shown by immunoelectron microscopy.\",\n      \"method\": \"Immunohistochemistry, immunoelectron microscopy, in situ hybridization, RT-PCR\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular localization by immunoelectron microscopy confirmed at protein level with multiple methods, single lab\",\n      \"pmids\": [\"18316703\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLXDC1 (TEM7) is a transmembrane cell-surface receptor for PEDF that forms homooligomers dissociated by ligand binding to activate downstream signaling; it is expressed on tumor and angiogenic endothelium, binds cortactin via its extracellular domain, is transcriptionally regulated by TGLI1 through direct promoter binding, and functionally promotes angiogenesis and perivascular tumor infiltration, with its inhibition reducing tumor growth and increasing survival in preclinical models.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLXDC1 (TEM7) is a single-pass transmembrane cell-surface receptor that functions in tumor and angiogenic endothelium to promote angiogenesis and tumor progression [#0, #5]. Together with PLXDC2, it serves as a receptor for the secreted factor PEDF: the receptors form homooligomers under basal conditions that PEDF binding dissociates to activate downstream signaling, and mutations in the intracellular domain alter receptor activity [#0]. Its extracellular region binds cortactin through a discrete nine-amino-acid segment in the cortactin plexin-like domain [#1]. PLXDC1 is selectively displayed on the luminal surface of tumor and pathological vascular endothelium and on endothelial progenitor cells, being absent from normal mature endothelium [#1, #4, #6]; this restricted expression is exploited by anti-TEM7 antibodies that drive antibody-dependent cellular cytotoxicity and phagocytosis of TEM7-positive cells [#4]. Expression is driven transcriptionally by direct promoter binding of the gain-of-function transcription factor TGLI1, with PLXDC1 acting as a required downstream effector of TGLI1-induced endothelial tubule formation [#2]. Functionally, PLXDC1 is required for tumor angiogenesis and growth—its silencing reduces tumor growth, proliferation, and microvessel density while increasing apoptosis [#5]—and it is induced by anti-VEGF (bevacizumab) therapy via epithelial-to-mesenchymal transition to drive perivascular brain tumor infiltration, with PLXDC1 inhibition preventing infiltration and prolonging survival [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the first molecular interaction partner of PLXDC1, linking its extracellular domain to the actin-regulatory adaptor cortactin and confirming tumor-endothelial expression.\",\n      \"evidence\": \"Affinity purification, domain mapping, and antibody-based cell-surface detection in tumor endothelium\",\n      \"pmids\": [\"15574754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the cortactin interaction not established\", \"No reciprocal validation or signaling readout\", \"Mechanism connecting extracellular receptor to intracellular cortactin unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Localized PLXDC1 protein to the luminal endothelial surface in pathological neovasculature, defining where the receptor acts in disease.\",\n      \"evidence\": \"Immunoelectron microscopy, immunohistochemistry, in situ hybridization, and RT-PCR in proliferative diabetic retinopathy membranes\",\n      \"pmids\": [\"18316703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Descriptive localization without functional perturbation\", \"Does not establish signaling role at this site\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated PLXDC1 is restricted to tumor/progenitor endothelium and absent from normal vasculature, validating it as a targetable tumor-vascular marker.\",\n      \"evidence\": \"Flow cytometry, RT-PCR, PMA induction in endothelial precursors, and ADCC/phagocytosis assays with anti-TEM7 antibody\",\n      \"pmids\": [\"21958527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of expression induction by PMA not defined\", \"Antibody efficacy not tested in vivo here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined PLXDC1 as a ligand-activated PEDF receptor with a homooligomer-dissociation activation mechanism and an intracellular signaling domain, answering how the receptor transduces a signal.\",\n      \"evidence\": \"Reciprocal gain- and loss-of-function cellular assays, receptor binding, and intracellular-domain mutagenesis\",\n      \"pmids\": [\"25535841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling effectors not identified\", \"Structural basis of homooligomer dissociation unresolved\", \"Cell-type-specific receptor activities not mechanistically explained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed PLXDC1 within a transcriptional axis as a direct TGLI1 target required for tumor-induced angiogenesis, connecting upstream regulation to functional output.\",\n      \"evidence\": \"Promoter binding assay, expression profiling, siRNA knockdown, and endothelial tubule formation assay in glioblastoma models\",\n      \"pmids\": [\"26093087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy by ChIP only implied\", \"Does not connect TGLI1-driven expression to PEDF receptor signaling\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated PLXDC1 is functionally required for tumor angiogenesis and growth in vivo, moving beyond correlation to causal requirement.\",\n      \"evidence\": \"In vivo siRNA silencing via CD44-targeted nanoparticles in ovarian tumor xenografts with tumor growth, microvessel, and apoptosis readouts\",\n      \"pmids\": [\"29890852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single tumor model\", \"Molecular mechanism downstream of knockdown not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked PLXDC1 to therapy resistance, showing anti-VEGF treatment induces PLXDC1 via EMT to drive perivascular tumor infiltration and that inhibition improves survival.\",\n      \"evidence\": \"In vivo xenograft models with lentiviral overexpression, PLXDC1 inhibition, and survival analysis in bevacizumab-treated rats\",\n      \"pmids\": [\"30414187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling PLXDC1 to invasive phenotype not defined\", \"EMT-to-PLXDC1 regulatory link not molecularly mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling cascade triggered by PEDF-induced PLXDC1 activation and how it mechanistically drives angiogenesis and tumor infiltration remain undefined.\",\n      \"evidence\": \"No downstream effector or pathway has been identified in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No downstream signaling effectors identified\", \"Relationship between PEDF receptor signaling and cortactin binding unknown\", \"No structural model of the receptor or its activation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0001525\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PEDF\",\n      \"SERPINF1\",\n      \"CTTN\",\n      \"PLXDC2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}