{"gene":"PLXDC2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2014,"finding":"PLXDC1 and PLXDC2 are identified as cell-surface transmembrane receptors for PEDF (Pigment Epithelium Derived Factor). PEDF receptors form homooligomers under basal conditions, and PEDF binding dissociates the homooligomer to activate the receptors. Mutations in the intracellular domain profoundly affect receptor activities.","method":"Loss-of-function and gain-of-function studies in distinct cellular models; receptor oligomerization assays; intracellular domain mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal loss- and gain-of-function across multiple cellular models, mutagenesis of intracellular domain, oligomerization assays; single lab but multiple orthogonal methods","pmids":["25535841"],"is_preprint":false},{"year":2004,"finding":"Cortactin binds to the extracellular region of PLXDC2 (TEM7R). The binding domain of cortactin was mapped to a unique nine-amino acid region in its plexin-like domain.","method":"Affinity purification strategy (pulldown) followed by binding domain mapping","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — affinity pulldown with domain mapping, single lab, replicated for both TEM7 and TEM7R","pmids":["15574754"],"is_preprint":false},{"year":2011,"finding":"PLXDC2 acts as a mitogen for neural progenitors in a cell non-autonomous manner. Expression of the extracellular domain alone (which can be cleaved and shed in vivo) is sufficient to induce proliferation in embryonic neuroepithelial cells, indicating the activity resides in the extracellular domain.","method":"In ovo electroporation (misexpression in chick neural tube), in vitro cultures of mouse embryonic neuroepithelial cells, extracellular domain expression constructs","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo misexpression and in vitro functional assay, domain dissection; single lab but two orthogonal experimental systems","pmids":["21283688"],"is_preprint":false},{"year":2022,"finding":"PLXDC2 promotes invadopodium formation and gastric cancer invasion by physically interacting with PTP1B (protein tyrosine phosphatase 1B), preventing PTP1B from dephosphorylating phospho-Cortactin, thereby maintaining elevated p-Cortactin levels that drive invadopodia assembly.","method":"Co-immunoprecipitation (physical interaction with PTP1B), knockdown/overexpression with invasion/metastasis assays, phospho-Cortactin level measurement","journal":"Clinical & experimental metastasis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for interaction, KD/OE with defined cellular phenotype and mechanistic readout; single lab, moderate methodological breadth","pmids":["35661947"],"is_preprint":false},{"year":2023,"finding":"Radioresistance-induced upregulation of c-Met promotes PLXDC2 expression through activation of ERK1/2-ELK1 signaling. PLXDC2 in turn modulates cancer cell plasticity via EMT induction and enrichment of the cancer stem cell subpopulation, leading to radioresistance in HNSCC. Depletion of PLXDC2 reverses EMT and blunts CSC self-renewal.","method":"Proteome profiler antibody arrays (c-Met phosphorylation), genetic knockdown, pharmacologic inhibition of c-Met (SU11274), ERK1/2-ELK1 pathway analysis, EMT and CSC functional assays, orthotopic mouse model","journal":"Cancer research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by KD and pathway inhibition with multiple functional readouts; single lab","pmids":["37089864"],"is_preprint":false},{"year":2024,"finding":"Extracellular (secreted) PTEN binds PLXDC2 on macrophages, triggering activation of JAK2-STAT1 signaling, which switches tumor-associated macrophages from an immunosuppressive to an inflammatory phenotype, leading to enhanced CD8+ T and NK cell activation and tumor suppression.","method":"Binding assay (extracellular PTEN to PLXDC2), intratumoral PTEN protein injection in mice, JAK2-STAT1 pathway analysis, macrophage phenotype switching assays, co-culture with T/NK cells, anti-PD-1 combination treatment","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding established, downstream signaling pathway identified (JAK2-STAT1), phenotypic rescue in vivo, multiple orthogonal methods including patient-derived primary cells","pmids":["39197453"],"is_preprint":false},{"year":2019,"finding":"siRNA-mediated knockdown of PLXDC2 in human hepatocellular carcinoma cells modulates Factor V (F5) gene expression, and also influences F2 and F10 coagulation factor gene expression, establishing PLXDC2 as a regulator of coagulation factor gene expression.","method":"siRNA knockdown in human hepatocellular carcinoma cell line with mRNA expression readout for F5, F2, F10","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA knockdown experiment, single cell line, single lab, no mechanistic pathway defined","pmids":["31271701"],"is_preprint":false},{"year":2025,"finding":"Loss of Plxdc2 in microglia exacerbates neuroinflammation after ischemic stroke. Plxdc2 maintains microglial homeostatic state by facilitating activation of PPARγ, which in turn modulates NF-κB p65 signaling and lipid metabolism. AAV-mediated overexpression of Plxdc2 in microglia in vivo protects against ischemic brain injury.","method":"AAV overexpression and lentivirus-mediated knockdown of Plxdc2 in microglia in vivo; in vitro microglial activation assays; NF-κB p65 and PPARγ pathway analysis","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV/lentivirus gain/loss-of-function with defined pathway readouts (NF-κB, PPARγ); single lab, two orthogonal in vivo and in vitro systems","pmids":["40345569"],"is_preprint":false},{"year":2025,"finding":"PLXDC2 overexpression in BV2 microglial cells impairs Aβ uptake (phagocytosis) and suppresses pro-inflammatory cytokines IL-6 and IL-1β, without altering lipid droplet formation.","method":"Overexpression in BV2 microglial cell line; functional Aβ phagocytosis assay; cytokine measurement; lipid droplet assay","journal":"Biomolecules & therapeutics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment in cell line, single lab, no upstream/downstream pathway defined","pmids":["41126775"],"is_preprint":false},{"year":2025,"finding":"PLXDC2 is expressed on the surface of hematopoietic stem cells (HSCs) and marks both mouse and human HSCs with long-term multilineage reconstitution ability. Plxdc2-GFP+ CD150+ cells demonstrated 1-in-2.8 long-term multilineage reconstitution in transplantation; human PLXDC2+ HSCs outperformed PLXDC2- HSCs in xenograft reconstitution.","method":"GFP knock-in reporter mouse (Plxdc2-GFP); transplantation assays; novel anti-human PLXDC2 antibody; xenograft model","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic reporter knock-in with functional transplantation readout in two species (mouse and human); single lab but direct functional validation","pmids":["41372396"],"is_preprint":false}],"current_model":"PLXDC2 is a type I transmembrane receptor that serves as a cell-surface receptor for PEDF (forming dissociable homooligomers) and secreted PTEN (activating JAK2-STAT1 in macrophages), binds cortactin and PTP1B through its extracellular and intracellular domains respectively to regulate invadopodium formation and cancer cell invasion, acts as a cell-non-autonomous mitogen for neural progenitors via its shed extracellular domain, modulates microglial homeostasis through PPARγ-NF-κB signaling, marks hematopoietic stem cells, and is transcriptionally regulated downstream of c-Met/ERK1/2-ELK1 signaling to drive EMT and cancer stem cell plasticity."},"narrative":{"mechanistic_narrative":"PLXDC2 is a type I transmembrane cell-surface receptor that transduces extracellular ligand cues into intracellular signaling to control cell proliferation, immune phenotype, and cancer cell behavior [PMID:25535841, PMID:39197453]. It functions as a receptor for PEDF, forming dissociable homooligomers under basal conditions that are activated when PEDF binding disrupts the oligomer, with intracellular-domain residues being critical for receptor activity [PMID:25535841]. A second ligand, secreted extracellular PTEN, binds PLXDC2 on macrophages and triggers JAK2-STAT1 signaling that reprograms tumor-associated macrophages from an immunosuppressive to an inflammatory state, enhancing CD8+ T and NK cell activation [PMID:39197453]. In cancer, PLXDC2 promotes invadopodium formation and invasion by binding PTP1B through its intracellular region and binding cortactin through its extracellular region, sustaining elevated phospho-cortactin by preventing its dephosphorylation [PMID:15574754, PMID:35661947]; PLXDC2 is itself induced downstream of c-Met/ERK1/2-ELK1 signaling to drive EMT and cancer stem cell plasticity [PMID:37089864]. Its shed extracellular domain acts as a cell-non-autonomous mitogen for embryonic neural progenitors [PMID:21283688], and in microglia PLXDC2 maintains a homeostatic state via PPARγ–NF-κB signaling to limit neuroinflammation [PMID:40345569]. PLXDC2 also marks hematopoietic stem cells with long-term multilineage reconstitution capacity [PMID:41372396].","teleology":[{"year":2004,"claim":"Identifying the first physical partner of PLXDC2 established that its extracellular region engages the actin-regulatory protein cortactin, hinting at a role in cytoskeletal/invasive processes.","evidence":"Affinity pulldown and binding-domain mapping for TEM7R (PLXDC2)","pmids":["15574754"],"confidence":"Medium","gaps":["Functional consequence of the cortactin interaction not tested here","Single lab, no reciprocal in vivo validation"]},{"year":2011,"claim":"Showed PLXDC2 acts cell-non-autonomously as a mitogen, localizing the proliferative activity to a cleaved/shed extracellular domain rather than full-length receptor signaling.","evidence":"In ovo electroporation in chick neural tube plus mouse neuroepithelial cultures with extracellular-domain constructs","pmids":["21283688"],"confidence":"Medium","gaps":["Receptor/partner mediating the mitogenic effect on progenitors unidentified","Protease responsible for ectodomain shedding unknown"]},{"year":2014,"claim":"Defined PLXDC2 as a bona fide PEDF receptor with a regulatory mechanism—homooligomers dissociated by ligand binding—answering how the receptor is activated.","evidence":"Reciprocal loss/gain-of-function across cellular models, oligomerization assays, intracellular-domain mutagenesis","pmids":["25535841"],"confidence":"High","gaps":["Downstream effectors of PEDF–PLXDC2 signaling not delineated","Structural basis of oligomer dissociation not resolved"]},{"year":2019,"claim":"First link of PLXDC2 to coagulation-factor gene expression, suggesting a transcriptional/regulatory role beyond surface receptor function.","evidence":"siRNA knockdown in a hepatocellular carcinoma cell line with F5/F2/F10 mRNA readout","pmids":["31271701"],"confidence":"Low","gaps":["Single siRNA, single cell line, not independently confirmed","No mechanistic pathway connecting PLXDC2 to coagulation factor transcription"]},{"year":2022,"claim":"Provided a mechanism for PLXDC2-driven cancer invasion by showing it sequesters PTP1B to protect phospho-cortactin, connecting the earlier cortactin interaction to invadopodia.","evidence":"Co-IP with PTP1B, knockdown/overexpression invasion assays, phospho-cortactin measurement in gastric cancer cells","pmids":["35661947"],"confidence":"Medium","gaps":["Co-IP not reciprocally validated structurally","Whether PEDF/PTEN ligand engagement modulates the PTP1B interaction untested"]},{"year":2023,"claim":"Placed PLXDC2 downstream of c-Met/ERK1/2-ELK1 signaling and showed it drives EMT and cancer stem cell plasticity, explaining a route to radioresistance.","evidence":"Phospho-antibody arrays, knockdown, c-Met inhibition (SU11274), EMT/CSC assays, orthotopic HNSCC model","pmids":["37089864"],"confidence":"Medium","gaps":["Direct ELK1 occupancy of the PLXDC2 promoter not shown","Effectors mediating PLXDC2-induced EMT undefined"]},{"year":2024,"claim":"Identified secreted PTEN as a second PLXDC2 ligand and mapped a JAK2-STAT1 axis that reprograms tumor-associated macrophages, establishing an immunomodulatory receptor function.","evidence":"Binding assays, intratumoral PTEN injection in mice, JAK2-STAT1 analysis, macrophage/T/NK co-cultures, anti-PD-1 combination","pmids":["39197453"],"confidence":"High","gaps":["How a normally intracellular phosphatase becomes a secreted ligand not fully resolved","Relationship between PTEN and PEDF binding sites on PLXDC2 unknown"]},{"year":2025,"claim":"Demonstrated PLXDC2 maintains microglial homeostasis via PPARγ–NF-κB signaling, defining a neuroprotective role in ischemic injury, while a complementary study linked it to Aβ phagocytosis and cytokine control.","evidence":"In vivo AAV overexpression/lentivirus knockdown in microglia with PPARγ/NF-κB readouts (stroke); BV2 overexpression with Aβ phagocytosis and cytokine assays (Alzheimer model)","pmids":["40345569","41126775"],"confidence":"Medium","gaps":["Ligand driving microglial PLXDC2 signaling not identified","BV2 phagocytosis study is single overexpression in one cell line","Mechanism connecting PLXDC2 to PPARγ activation unresolved"]},{"year":2025,"claim":"Established PLXDC2 as a surface marker of long-term reconstituting hematopoietic stem cells in both mouse and human, extending its biology to stem cell identity.","evidence":"Plxdc2-GFP knock-in reporter, transplantation assays, anti-human PLXDC2 antibody, xenograft reconstitution","pmids":["41372396"],"confidence":"Medium","gaps":["Functional requirement of PLXDC2 for HSC maintenance vs. correlation as a marker not separated","Ligand/signaling in HSCs undefined"]},{"year":null,"claim":"How a single receptor reconciles distinct ligands (PEDF, secreted PTEN), an ectodomain-shedding mitogen activity, and tissue-specific signaling outputs (JAK2-STAT1, PPARγ-NF-κB, PTP1B/cortactin) into a unified mechanism remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of PLXDC2 with any ligand","Intracellular signaling effectors of the full-length receptor incompletely mapped","Whether the same domain mediates PEDF vs PTEN binding unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,9]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["PEDF","PTEN","PTP1B","CTTN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UX71","full_name":"Plexin domain-containing protein 2","aliases":["Tumor endothelial marker 7-related protein"],"length_aa":529,"mass_kda":59.6,"function":"May play a role in tumor angiogenesis","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q6UX71/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXDC2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLXDC2","total_profiled":1310},"omim":[{"mim_id":"606827","title":"PLEXIN DOMAIN-CONTAINING PROTEIN 2; PLXDC2","url":"https://www.omim.org/entry/606827"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PLXDC2"},"hgnc":{"alias_symbol":["TEM7R","FLJ14623","PLXDC2-OT"],"prev_symbol":[]},"alphafold":{"accession":"Q6UX71","domains":[{"cath_id":"-","chopping":"109-326","consensus_level":"high","plddt":91.2699,"start":109,"end":326},{"cath_id":"-","chopping":"330-374","consensus_level":"high","plddt":90.8609,"start":330,"end":374}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UX71","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UX71-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UX71-F1-predicted_aligned_error_v6.png","plddt_mean":69.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLXDC2","jax_strain_url":"https://www.jax.org/strain/search?query=PLXDC2"},"sequence":{"accession":"Q6UX71","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UX71.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UX71/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UX71"}},"corpus_meta":[{"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":"21283688","id":"PMC_21283688","title":"Plxdc2 is a mitogen for neural progenitors.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21283688","citation_count":43,"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":"17280871","id":"PMC_17280871","title":"Expression of Plxdc2/TEM7R in the developing nervous system of the mouse.","date":"2006","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/17280871","citation_count":38,"is_preprint":false},{"pmid":"34124056","id":"PMC_34124056","title":"Overexpression of PLXDC2 in Stromal Cell-Associated M2 Macrophages Is Related to EMT and the Progression of Gastric Cancer.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34124056","citation_count":30,"is_preprint":false},{"pmid":"39197453","id":"PMC_39197453","title":"Secreted PTEN binds PLXDC2 on macrophages to drive antitumor immunity and tumor suppression.","date":"2024","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/39197453","citation_count":24,"is_preprint":false},{"pmid":"33684230","id":"PMC_33684230","title":"LncRNA, PLXDC2-OT promoted the osteogenesis potentials of MSCs by inhibiting the deacetylation function of RBM6/SIRT7 complex and OSX specific isoform.","date":"2021","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/33684230","citation_count":21,"is_preprint":false},{"pmid":"37089864","id":"PMC_37089864","title":"Adaptive c-Met-PLXDC2 Signaling Axis Mediates Cancer Stem Cell Plasticity to Confer Radioresistance-associated Aggressiveness in Head and Neck Cancer.","date":"2023","source":"Cancer research communications","url":"https://pubmed.ncbi.nlm.nih.gov/37089864","citation_count":14,"is_preprint":false},{"pmid":"29378261","id":"PMC_29378261","title":"Improving the quality of a recombinant rabbit monoclonal antibody against PLXDC2 by optimizing transient expression conditions and purification method.","date":"2018","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/29378261","citation_count":13,"is_preprint":false},{"pmid":"35661947","id":"PMC_35661947","title":"PLXDC2 enhances invadopodium formation to promote invasion and metastasis of gastric cancer cells via interacting with PTP1B.","date":"2022","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/35661947","citation_count":11,"is_preprint":false},{"pmid":"31271701","id":"PMC_31271701","title":"A Genome Wide Association Study on plasma FV levels identified PLXDC2 as a new modifier of the coagulation process.","date":"2019","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/31271701","citation_count":9,"is_preprint":false},{"pmid":"30326957","id":"PMC_30326957","title":"Plexin domain containing 2 (PLXDC2) gene polymorphism rs7081455 may not influence POAG risk in a Saudi cohort.","date":"2018","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/30326957","citation_count":6,"is_preprint":false},{"pmid":"28930887","id":"PMC_28930887","title":"Genetic Variant Near PLXDC2 Influences the Risk of Primary Open-angle Glaucoma by Increasing Intraocular Pressure in the Japanese Population.","date":"2017","source":"Journal of glaucoma","url":"https://pubmed.ncbi.nlm.nih.gov/28930887","citation_count":6,"is_preprint":false},{"pmid":"40345569","id":"PMC_40345569","title":"Loss of Plxdc2 exacerbates microglia-mediated neuroinflammation and ischemic brain injury.","date":"2025","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40345569","citation_count":5,"is_preprint":false},{"pmid":"41126775","id":"PMC_41126775","title":"Microglial PLXDC2 Modulates Aβ Phagocytosis and Inflammatory Responses.","date":"2025","source":"Biomolecules & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/41126775","citation_count":2,"is_preprint":false},{"pmid":"41372396","id":"PMC_41372396","title":"Prospective isolation of mouse and human hematopoietic stem cells using PLXDC2.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41372396","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.05.25339596","title":"Genome-wide association study reveals two novel genetic loci associated with chronic lung allograft dysfunction","date":"2025-11-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.05.25339596","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.19.629410","title":"Genome-wide association analyses in dairy heifers highlight genes overlapping with mouse and human fertility and human health traits","date":"2024-12-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.19.629410","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11278,"output_tokens":2621,"usd":0.036575,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9812,"output_tokens":3294,"usd":0.065705,"stage2_stop_reason":"end_turn"},"total_usd":0.10228,"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 and PLXDC2 are identified as cell-surface transmembrane receptors for PEDF (Pigment Epithelium Derived Factor). PEDF receptors form homooligomers under basal conditions, and PEDF binding 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 studies in distinct cellular models; receptor oligomerization assays; intracellular domain mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal loss- and gain-of-function across multiple cellular models, mutagenesis of intracellular domain, oligomerization assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25535841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cortactin binds to the extracellular region of PLXDC2 (TEM7R). The binding domain of cortactin was mapped to a unique nine-amino acid region in its plexin-like domain.\",\n      \"method\": \"Affinity purification strategy (pulldown) followed by binding domain mapping\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — affinity pulldown with domain mapping, single lab, replicated for both TEM7 and TEM7R\",\n      \"pmids\": [\"15574754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PLXDC2 acts as a mitogen for neural progenitors in a cell non-autonomous manner. Expression of the extracellular domain alone (which can be cleaved and shed in vivo) is sufficient to induce proliferation in embryonic neuroepithelial cells, indicating the activity resides in the extracellular domain.\",\n      \"method\": \"In ovo electroporation (misexpression in chick neural tube), in vitro cultures of mouse embryonic neuroepithelial cells, extracellular domain expression constructs\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo misexpression and in vitro functional assay, domain dissection; single lab but two orthogonal experimental systems\",\n      \"pmids\": [\"21283688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PLXDC2 promotes invadopodium formation and gastric cancer invasion by physically interacting with PTP1B (protein tyrosine phosphatase 1B), preventing PTP1B from dephosphorylating phospho-Cortactin, thereby maintaining elevated p-Cortactin levels that drive invadopodia assembly.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction with PTP1B), knockdown/overexpression with invasion/metastasis assays, phospho-Cortactin level measurement\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for interaction, KD/OE with defined cellular phenotype and mechanistic readout; single lab, moderate methodological breadth\",\n      \"pmids\": [\"35661947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Radioresistance-induced upregulation of c-Met promotes PLXDC2 expression through activation of ERK1/2-ELK1 signaling. PLXDC2 in turn modulates cancer cell plasticity via EMT induction and enrichment of the cancer stem cell subpopulation, leading to radioresistance in HNSCC. Depletion of PLXDC2 reverses EMT and blunts CSC self-renewal.\",\n      \"method\": \"Proteome profiler antibody arrays (c-Met phosphorylation), genetic knockdown, pharmacologic inhibition of c-Met (SU11274), ERK1/2-ELK1 pathway analysis, EMT and CSC functional assays, orthotopic mouse model\",\n      \"journal\": \"Cancer research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by KD and pathway inhibition with multiple functional readouts; single lab\",\n      \"pmids\": [\"37089864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Extracellular (secreted) PTEN binds PLXDC2 on macrophages, triggering activation of JAK2-STAT1 signaling, which switches tumor-associated macrophages from an immunosuppressive to an inflammatory phenotype, leading to enhanced CD8+ T and NK cell activation and tumor suppression.\",\n      \"method\": \"Binding assay (extracellular PTEN to PLXDC2), intratumoral PTEN protein injection in mice, JAK2-STAT1 pathway analysis, macrophage phenotype switching assays, co-culture with T/NK cells, anti-PD-1 combination treatment\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding established, downstream signaling pathway identified (JAK2-STAT1), phenotypic rescue in vivo, multiple orthogonal methods including patient-derived primary cells\",\n      \"pmids\": [\"39197453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"siRNA-mediated knockdown of PLXDC2 in human hepatocellular carcinoma cells modulates Factor V (F5) gene expression, and also influences F2 and F10 coagulation factor gene expression, establishing PLXDC2 as a regulator of coagulation factor gene expression.\",\n      \"method\": \"siRNA knockdown in human hepatocellular carcinoma cell line with mRNA expression readout for F5, F2, F10\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA knockdown experiment, single cell line, single lab, no mechanistic pathway defined\",\n      \"pmids\": [\"31271701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of Plxdc2 in microglia exacerbates neuroinflammation after ischemic stroke. Plxdc2 maintains microglial homeostatic state by facilitating activation of PPARγ, which in turn modulates NF-κB p65 signaling and lipid metabolism. AAV-mediated overexpression of Plxdc2 in microglia in vivo protects against ischemic brain injury.\",\n      \"method\": \"AAV overexpression and lentivirus-mediated knockdown of Plxdc2 in microglia in vivo; in vitro microglial activation assays; NF-κB p65 and PPARγ pathway analysis\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV/lentivirus gain/loss-of-function with defined pathway readouts (NF-κB, PPARγ); single lab, two orthogonal in vivo and in vitro systems\",\n      \"pmids\": [\"40345569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PLXDC2 overexpression in BV2 microglial cells impairs Aβ uptake (phagocytosis) and suppresses pro-inflammatory cytokines IL-6 and IL-1β, without altering lipid droplet formation.\",\n      \"method\": \"Overexpression in BV2 microglial cell line; functional Aβ phagocytosis assay; cytokine measurement; lipid droplet assay\",\n      \"journal\": \"Biomolecules & therapeutics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment in cell line, single lab, no upstream/downstream pathway defined\",\n      \"pmids\": [\"41126775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PLXDC2 is expressed on the surface of hematopoietic stem cells (HSCs) and marks both mouse and human HSCs with long-term multilineage reconstitution ability. Plxdc2-GFP+ CD150+ cells demonstrated 1-in-2.8 long-term multilineage reconstitution in transplantation; human PLXDC2+ HSCs outperformed PLXDC2- HSCs in xenograft reconstitution.\",\n      \"method\": \"GFP knock-in reporter mouse (Plxdc2-GFP); transplantation assays; novel anti-human PLXDC2 antibody; xenograft model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic reporter knock-in with functional transplantation readout in two species (mouse and human); single lab but direct functional validation\",\n      \"pmids\": [\"41372396\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLXDC2 is a type I transmembrane receptor that serves as a cell-surface receptor for PEDF (forming dissociable homooligomers) and secreted PTEN (activating JAK2-STAT1 in macrophages), binds cortactin and PTP1B through its extracellular and intracellular domains respectively to regulate invadopodium formation and cancer cell invasion, acts as a cell-non-autonomous mitogen for neural progenitors via its shed extracellular domain, modulates microglial homeostasis through PPARγ-NF-κB signaling, marks hematopoietic stem cells, and is transcriptionally regulated downstream of c-Met/ERK1/2-ELK1 signaling to drive EMT and cancer stem cell plasticity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLXDC2 is a type I transmembrane cell-surface receptor that transduces extracellular ligand cues into intracellular signaling to control cell proliferation, immune phenotype, and cancer cell behavior [#0, #5]. It functions as a receptor for PEDF, forming dissociable homooligomers under basal conditions that are activated when PEDF binding disrupts the oligomer, with intracellular-domain residues being critical for receptor activity [#0]. A second ligand, secreted extracellular PTEN, binds PLXDC2 on macrophages and triggers JAK2-STAT1 signaling that reprograms tumor-associated macrophages from an immunosuppressive to an inflammatory state, enhancing CD8+ T and NK cell activation [#5]. In cancer, PLXDC2 promotes invadopodium formation and invasion by binding PTP1B through its intracellular region and binding cortactin through its extracellular region, sustaining elevated phospho-cortactin by preventing its dephosphorylation [#1, #3]; PLXDC2 is itself induced downstream of c-Met/ERK1/2-ELK1 signaling to drive EMT and cancer stem cell plasticity [#4]. Its shed extracellular domain acts as a cell-non-autonomous mitogen for embryonic neural progenitors [#2], and in microglia PLXDC2 maintains a homeostatic state via PPARγ–NF-κB signaling to limit neuroinflammation [#7]. PLXDC2 also marks hematopoietic stem cells with long-term multilineage reconstitution capacity [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying the first physical partner of PLXDC2 established that its extracellular region engages the actin-regulatory protein cortactin, hinting at a role in cytoskeletal/invasive processes.\",\n      \"evidence\": \"Affinity pulldown and binding-domain mapping for TEM7R (PLXDC2)\",\n      \"pmids\": [\"15574754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the cortactin interaction not tested here\", \"Single lab, no reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed PLXDC2 acts cell-non-autonomously as a mitogen, localizing the proliferative activity to a cleaved/shed extracellular domain rather than full-length receptor signaling.\",\n      \"evidence\": \"In ovo electroporation in chick neural tube plus mouse neuroepithelial cultures with extracellular-domain constructs\",\n      \"pmids\": [\"21283688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/partner mediating the mitogenic effect on progenitors unidentified\", \"Protease responsible for ectodomain shedding unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined PLXDC2 as a bona fide PEDF receptor with a regulatory mechanism—homooligomers dissociated by ligand binding—answering how the receptor is activated.\",\n      \"evidence\": \"Reciprocal loss/gain-of-function across cellular models, oligomerization assays, intracellular-domain mutagenesis\",\n      \"pmids\": [\"25535841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of PEDF–PLXDC2 signaling not delineated\", \"Structural basis of oligomer dissociation not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"First link of PLXDC2 to coagulation-factor gene expression, suggesting a transcriptional/regulatory role beyond surface receptor function.\",\n      \"evidence\": \"siRNA knockdown in a hepatocellular carcinoma cell line with F5/F2/F10 mRNA readout\",\n      \"pmids\": [\"31271701\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single siRNA, single cell line, not independently confirmed\", \"No mechanistic pathway connecting PLXDC2 to coagulation factor transcription\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a mechanism for PLXDC2-driven cancer invasion by showing it sequesters PTP1B to protect phospho-cortactin, connecting the earlier cortactin interaction to invadopodia.\",\n      \"evidence\": \"Co-IP with PTP1B, knockdown/overexpression invasion assays, phospho-cortactin measurement in gastric cancer cells\",\n      \"pmids\": [\"35661947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP not reciprocally validated structurally\", \"Whether PEDF/PTEN ligand engagement modulates the PTP1B interaction untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed PLXDC2 downstream of c-Met/ERK1/2-ELK1 signaling and showed it drives EMT and cancer stem cell plasticity, explaining a route to radioresistance.\",\n      \"evidence\": \"Phospho-antibody arrays, knockdown, c-Met inhibition (SU11274), EMT/CSC assays, orthotopic HNSCC model\",\n      \"pmids\": [\"37089864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ELK1 occupancy of the PLXDC2 promoter not shown\", \"Effectors mediating PLXDC2-induced EMT undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified secreted PTEN as a second PLXDC2 ligand and mapped a JAK2-STAT1 axis that reprograms tumor-associated macrophages, establishing an immunomodulatory receptor function.\",\n      \"evidence\": \"Binding assays, intratumoral PTEN injection in mice, JAK2-STAT1 analysis, macrophage/T/NK co-cultures, anti-PD-1 combination\",\n      \"pmids\": [\"39197453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a normally intracellular phosphatase becomes a secreted ligand not fully resolved\", \"Relationship between PTEN and PEDF binding sites on PLXDC2 unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated PLXDC2 maintains microglial homeostasis via PPARγ–NF-κB signaling, defining a neuroprotective role in ischemic injury, while a complementary study linked it to Aβ phagocytosis and cytokine control.\",\n      \"evidence\": \"In vivo AAV overexpression/lentivirus knockdown in microglia with PPARγ/NF-κB readouts (stroke); BV2 overexpression with Aβ phagocytosis and cytokine assays (Alzheimer model)\",\n      \"pmids\": [\"40345569\", \"41126775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand driving microglial PLXDC2 signaling not identified\", \"BV2 phagocytosis study is single overexpression in one cell line\", \"Mechanism connecting PLXDC2 to PPARγ activation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established PLXDC2 as a surface marker of long-term reconstituting hematopoietic stem cells in both mouse and human, extending its biology to stem cell identity.\",\n      \"evidence\": \"Plxdc2-GFP knock-in reporter, transplantation assays, anti-human PLXDC2 antibody, xenograft reconstitution\",\n      \"pmids\": [\"41372396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional requirement of PLXDC2 for HSC maintenance vs. correlation as a marker not separated\", \"Ligand/signaling in HSCs undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single receptor reconciles distinct ligands (PEDF, secreted PTEN), an ectodomain-shedding mitogen activity, and tissue-specific signaling outputs (JAK2-STAT1, PPARγ-NF-κB, PTP1B/cortactin) into a unified mechanism remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of PLXDC2 with any ligand\", \"Intracellular signaling effectors of the full-length receptor incompletely mapped\", \"Whether the same domain mediates PEDF vs PTEN binding unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PEDF\", \"PTEN\", \"PTP1B\", \"CTTN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}