{"gene":"CD248","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2007,"finding":"CD248/endosialin binds extracellular matrix proteins fibronectin and collagen types I and IV as specific ligands; cells expressing CD248 show enhanced adhesion to fibronectin and enhanced migration through matrigel, both of which are blocked by a humanized anti-CD248 antibody.","method":"Binding assays, cell adhesion assays, transwell migration assay, antibody blocking","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct binding and functional cell-based assays in a single lab, two orthogonal methods (binding + functional readouts)","pmids":["17986615"],"is_preprint":false},{"year":2005,"finding":"Endosialin (TEM1/CD248) is a cell surface glycoprotein predominantly expressed by fibroblasts and a subset of pericytes associated with tumor vessels, not by tumor endothelium, as established by monoclonal antibody characterization and cellular localization studies.","method":"Monoclonal antibody generation, immunofluorescence, flow cytometry, subcellular localization","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — replicated across multiple labs using antibody-based approaches, consistent with multiple subsequent studies","pmids":["15862292"],"is_preprint":false},{"year":2010,"finding":"CD248/endosialin mediates proliferation of primary human pericytes through PDGF receptor signaling: TEM-1 knockdown abrogates PDGF-BB-induced proliferation, ERK-1/2 phosphorylation, and c-Fos expression.","method":"siRNA knockdown, western blot (phospho-ERK), c-Fos expression assay, cell proliferation assay","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA KD with multiple downstream pathway readouts in a single lab","pmids":["20484976"],"is_preprint":false},{"year":2015,"finding":"CD248 deletion in hepatic stellate cells (HSCs) reduces susceptibility to liver fibrosis via PDGF signaling: CD248-/- HSCs do not proliferate in response to PDGF-BB, and c-fos expression is significantly reduced in CD248-/- HSCs after stimulation.","method":"CD248 knockout mouse model, CCl4-induced fibrosis, HSC isolation, PDGF-BB stimulation, c-fos expression assay","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with defined cellular phenotype plus in vitro mechanistic follow-up with multiple readouts, independent replication of PDGF-signaling mechanism","pmids":["26078290"],"is_preprint":false},{"year":2010,"finding":"CD248's cytoplasmic domain is required for inflammatory arthritis responses: CD248 cytoplasmic domain-deficient (CD248CyD/CyD) mice show reduced arthritis severity, with impaired TNFα-induced monocyte adhesion to fibroblasts and reduced HIF1α, PIGF, VEGF, and MMP-9 activity in response to TGF-β.","method":"Transgenic mice lacking the cytoplasmic domain (CD248CyD/CyD), CAIA model, ELISA, immunohistochemistry, in vitro fibroblast assays","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with defined cytoplasmic domain requirement, multiple orthogonal functional readouts in single study","pmids":["20722022"],"is_preprint":false},{"year":2011,"finding":"The cytoplasmic domain of CD248 facilitates tumor growth via fibroblast-mediated mechanisms: CD248CyD/CyD mice show reduced fibrosarcoma and lung carcinoma growth; CD248CyD/CyD fibroblasts have impaired PDGF-BB-induced migration, reduced MMP-9 activation, and increased expression of tumor suppressor factors (transgelin/SM22α, Hes, Hey1).","method":"CD248 cytoplasmic domain-knockout mouse tumor models, conditioned media experiments, fibroblast migration assay, RT-PCR, MMP activity assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with mechanistic in vitro follow-up, single lab","pmids":["21549007"],"is_preprint":false},{"year":2008,"finding":"Endosialin (Tem1) is specifically expressed by tumor-associated myofibroblasts and mural cells (not endothelial cells); siRNA silencing of endosialin in fibroblasts strongly inhibits migration and proliferation.","method":"Expression profiling, immunostaining, siRNA knockdown, migration and proliferation assays","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with defined proliferation/migration phenotype, consistent with multiple other studies on cellular identity","pmids":["18187565"],"is_preprint":false},{"year":2008,"finding":"Endosialin (Tem1) binds Mac-2 BP/90K via a C-terminal fragment of Mac-2 BP/90K containing collagen and galectin-3 binding sites; this interaction is repulsive in loss-of-function adhesion experiments, with Mac-2 BP/90K-expressing tumor cells repelled from endosialin-expressing fibroblasts.","method":"Co-immunoprecipitation, biochemical binding assays, adhesion/loss-of-function experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct binding characterization with functional adhesion readout, single lab with multiple methods","pmids":["18490383"],"is_preprint":false},{"year":2017,"finding":"CD248 directly binds to multimerin-2 (MMRN2) via its C-type lectin domain; the binding of CD248 to MMRN2 occurs on a region distinct from (non-competing with) the CLEC14A/CD93 binding region. Mutation within the C-type lectin domain long-loop region abolishes MMRN2 binding. CLEC14A and CD248 can simultaneously bind MMRN2 at the endothelial-pericyte interface in human pancreatic cancer.","method":"Direct binding assays, mutagenesis of C-type lectin domain, simultaneous binding assay, immunofluorescence in tumor tissue","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding demonstrated with mutagenesis validation and in vivo co-localization in single rigorous study","pmids":["28671670"],"is_preprint":false},{"year":2012,"finding":"CD248 negatively regulates bone formation: CD248-/- mice have higher bone mass and superior mechanical properties. Primary osteoblasts from CD248-/- mice show increased mineralization in vitro and increased bone formation in vivo, associated with defective PDGF-BB/PDGFR signal transduction.","method":"CD248 knockout mouse, micro-CT, 3-point bending test, primary osteoblast culture, mineralization assay, calcein labeling (mineral apposition rate), PDGF-BB stimulation assay","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic knockout with multiple orthogonal bone phenotype measurements and in vitro signaling mechanistic data","pmids":["22674221"],"is_preprint":false},{"year":2022,"finding":"CD248 derepresses Wnt/β-catenin signaling in pericytes by interacting with Wnt pathway repressors IGFBP4 and LGALS3BP, leading to upregulation of angiogenic factors OPN and SERPINE1 and enhanced angiogenesis and lung tumor growth.","method":"Cd248 knockout mouse orthotopic lung cancer model, co-immunoprecipitation (CD248 with IGFBP4 and LGALS3BP), β-catenin reporter assays, OPN/SERPINE1 rescue experiments, β-catenin inhibitor treatment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of binding partners, in vivo KO model, rescue experiments with multiple orthogonal approaches in a single rigorous study","pmids":["35950912"],"is_preprint":false},{"year":2019,"finding":"TEM1/CD248 interacts with PDGF receptor α (PDGFRα) by co-immunoprecipitation; TEM1 knockdown suppresses PDGF-BB-induced downstream signaling, migration, adhesion, and proliferation in fibroblasts, and TEM1-deleted mice show attenuated wound healing with reduced fibroblast activation and collagen deposition.","method":"Co-immunoprecipitation, shRNA knockdown, in vitro migration/adhesion/proliferation assays, in vivo wound healing model with TEM1-knockout mice, immunofluorescence","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus in vivo KO with in vitro mechanistic follow-up, multiple orthogonal methods in single study","pmids":["30986375"],"is_preprint":false},{"year":2014,"finding":"CD248 is required for PDGFR-β-dependent capillary sprouting (but not splitting) angiogenesis in skeletal muscle: CD248-/- mice have a specific defect in capillary sprouting that can be mimicked by blocking PDGFRβ signaling with imatinib in wild-type mice.","method":"CD248 knockout mouse, skeletal muscle functional overload and vasodilator angiogenesis models, imatinib treatment, gene expression assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with pharmacological mimicry and defined pathway placement, single lab","pmids":["25243742"],"is_preprint":false},{"year":2011,"finding":"CD248 expressed on human naive CD8+ T cells (but not mouse CD8+ T cells) suppresses their proliferation: transfection of CD248-negative MOLT-4 cells with CD248 cDNA reduces proliferation, and knockdown of CD248 on naive CD8+ T cells increases proliferation, demonstrating a cell-type-specific quiescence-maintaining function.","method":"CD248 cDNA transfection, siRNA knockdown, flow cytometry, proliferation assay","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain-of-function and loss-of-function experiments with defined proliferation phenotype, single lab with orthogonal approaches","pmids":["21466550"],"is_preprint":false},{"year":2020,"finding":"CD248 on fibroblasts interacts specifically with galectin-3 on macrophages; this interaction induces CCL17 and CCL22 expression in macrophages, which activates collagen production in myofibroblasts, promoting tissue fibrosis. Cd248-/- mice show attenuated renal and peritoneal fibrosis with decreased macrophage-expressed CCL17/CCL22.","method":"Cd248 knockout mouse UUO/peritoneal fibrosis models, parabiosis with GFP reporter mice, CD248-galectin-3 interaction assay, macrophage chemokine expression (Ccl17, Ccl22) in isolated macrophages, galectin-3-deficient macrophages","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model combined with direct protein interaction assay and mechanistic pathway dissection using multiple genetic tools","pmids":["33033277"],"is_preprint":false},{"year":2019,"finding":"Adipocyte-specific and inducible CD248 knockout in mice results in increased microvascular density and attenuated hypoxia, inflammation, and fibrosis in white adipose tissue, with improvements in insulin sensitivity and glucose tolerance, indicating CD248 acts as a microenvironmental sensor mediating adipose hypoxia response.","method":"Adipocyte-specific inducible Cd248 knockout mice (before and after diet-induced obesity), metabolic phenotyping, histology, omics analyses, gene knockdown in human adipocytes","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific inducible KO with multiple physiological readouts, single lab","pmids":["31221584"],"is_preprint":false},{"year":2008,"finding":"Anti-endosialin antibodies inhibit endothelial precursor cell (EPC) migration and tube formation in vitro, and inhibit circulating murine EPC in vivo, indicating a functional role for CD248/TEM1 in EPC-mediated tumor angiogenesis.","method":"Anti-endosialin antibody blocking, EPC migration assay, matrigel tube formation assay, flow cytometry, in vivo EPC inhibition assay","journal":"Molecular cancer therapeutics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — antibody blocking functional assays, single lab, mechanism not fully elucidated","pmids":["18723498"],"is_preprint":false},{"year":2008,"finding":"Anti-endosialin antibodies prevent pericyte tube formation on matrigel and inhibit pericyte migration in culture, demonstrating a direct functional role for CD248 in pericyte behavior.","method":"Anti-endosialin antibody blocking, pericyte tube formation assay, migration assay","journal":"Microvascular research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — antibody blocking functional assays, single lab, limited mechanistic depth","pmids":["18761022"],"is_preprint":false},{"year":2015,"finding":"CD248 targeting by antibody-mediated internalization (MORAb-004) reduces CD248 levels on pericyte surfaces, impairs pericyte maturation (reduced α-SMA expression, pericyte depolarization), and causes dysfunctional tumor microvessels, suppressing tumor growth and metastasis.","method":"Human CD248 knock-in mouse model, MORAb-004 antibody treatment, syngeneic tumor models, immunofluorescence, vessel morphology analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vivo model with mechanistic cellular readouts (pericyte maturation markers), single lab with multiple phenotypic endpoints","pmids":["26327620"],"is_preprint":false},{"year":2022,"finding":"CD248 expressed on cancer-associated fibroblasts (CAFs) promotes CXCL12 secretion; CD248 knockdown on CAFs reduces CXCL12 secretion and M2 macrophage polarization/chemotaxis (blocked by CXCR4 antagonist), thereby impairing NSCLC progression.","method":"CAF isolation from NSCLC patients, CD248 siRNA knockdown, CXCL12 ELISA, macrophage co-culture polarization assay, CXCR4 blocking, in vitro and in vivo tumor progression assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function in primary human cells with multiple downstream pathway readouts, single lab","pmids":["35985448"],"is_preprint":false},{"year":2018,"finding":"CD248 silencing in systemic sclerosis mesenchymal stem cells (SSc-MSCs) inhibits both TGF-β and PDGF-BB signaling pathways, blocking myofibroblast differentiation and proliferation, demonstrating that CD248 modulates both TGFβ and PDGF downstream signaling in stromal cells.","method":"CD248 siRNA silencing in SSc-MSCs, TGF-β and PDGF-BB stimulation, Western blotting, qRT-PCR, immunofluorescence","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with two growth factor signaling pathway readouts, single lab","pmids":["30285896"],"is_preprint":false},{"year":2019,"finding":"CD248 expression in colorectal cancer cells is transcriptionally regulated via Sp1 downstream of TLR2/6 and TLR5 activation through NF-κB; miR-125b-5p suppresses Sp1 and CD248 expression, and CD248 upregulation promotes drug resistance and epithelial-mesenchymal transition.","method":"TLR ligand stimulation, NF-κB inhibition, miR-125b-5p mimic transfection, Sp1/CD248 gene silencing, RT-PCR, drug resistance assays, invasion assays","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple genetic perturbations defining regulatory pathway for CD248 expression, single lab","pmids":["31746054"],"is_preprint":false},{"year":2012,"finding":"CD248 expression on thymic mesenchymal stromal cells is required for postnatal thymus development and regeneration following Salmonella infection: CD248-/- mice have a hypocellular thymus with loss of all thymocyte populations and impaired regeneration.","method":"CD248 knockout mouse model, thymus cellularity analysis, flow cytometry of thymocyte populations, Salmonella infection model","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with defined cellular phenotype and defined stromal cell requirement, single lab","pmids":["23650598"],"is_preprint":false},{"year":2010,"finding":"CD248 expression on stromal cells is required for efficient lymph node expansion following immunization; in vitro, CD248 expression in stromal cells confers a pro-proliferative and pro-migratory phenotype.","method":"CD248 knockout mouse immunization model, LN cellularity analysis, in vitro CD248 transfection with proliferation/migration assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with in vitro gain-of-function validation, single lab","pmids":["20432232"],"is_preprint":false}],"current_model":"CD248 (endosialin/TEM1) is a type I transmembrane C-type lectin-like glycoprotein expressed on the surface of activated mesenchymal cells (fibroblasts, pericytes, myofibroblasts) that functions as a co-receptor/scaffold facilitating PDGF receptor signaling (PDGFRα and PDGFRβ) to promote cell proliferation, migration, and collagen deposition; it directly binds extracellular matrix proteins (fibronectin, collagen I/IV), the endothelial matrix protein MMRN2 via its C-type lectin domain, galectin-3 on macrophages to induce CCL17-mediated fibrosis, Mac-2 BP/90K in a repulsive adhesion interaction, and Wnt pathway repressors IGFBP4/LGALS3BP to derepress Wnt/β-catenin signaling and upregulate angiogenic factors; its conserved cytoplasmic domain is required for multiple downstream functions including MMP-9 activation, HIF1α/VEGF expression, and inflammatory cytokine responses, while on human naive CD8+ T cells CD248 paradoxically maintains quiescence."},"narrative":{"mechanistic_narrative":"CD248 (endosialin/TEM1) is a cell-surface glycoprotein of activated mesenchymal cells—tumor-associated fibroblasts, myofibroblasts, and a subset of pericytes—that acts as a stromal co-receptor and matrix-engagement scaffold driving proliferation, migration, and tissue remodeling [PMID:15862292, PMID:18187565]. Its central mechanistic role is to potentiate platelet-derived growth factor receptor signaling: CD248 co-immunoprecipitates with PDGFRα, and its loss abrogates PDGF-BB-induced proliferation, ERK1/2 phosphorylation, c-Fos induction, migration, and collagen deposition across pericytes, hepatic stellate cells, fibroblasts, and osteoblasts [PMID:20484976, PMID:26078290, PMID:22674221, PMID:30986375]. This PDGFR-dependent axis places CD248 at the center of capillary sprouting angiogenesis, wound healing, and fibrogenesis [PMID:30986375, PMID:25243742]. CD248 engages the extracellular matrix and matrix-associated proteins directly, binding fibronectin and collagens I/IV to mediate adhesion and migration [PMID:17986615], the endothelial matrix protein MMRN2 through its C-type lectin domain [PMID:28671670], and Mac-2 BP/90K in a repulsive adhesion interaction [PMID:18490383]. The conserved cytoplasmic domain is required for downstream effector functions including MMP-9 activation and HIF1α/VEGF expression, as cytoplasmic-domain-deleted mice show attenuated inflammatory arthritis and tumor growth [PMID:20722022, PMID:21549007]. CD248 also derepresses Wnt/β-catenin signaling by sequestering the repressors IGFBP4 and LGALS3BP to upregulate angiogenic factors [PMID:35950912], and mediates cell-cell crosstalk with macrophages—binding galectin-3 to induce CCL17/CCL22-driven fibrosis [PMID:33033277] and promoting CXCL12-dependent M2 polarization in cancer-associated fibroblasts [PMID:35985448]. Beyond its mesenchymal roles, CD248 on human naive CD8+ T cells paradoxically maintains quiescence by suppressing proliferation [PMID:21466550].","teleology":[{"year":2005,"claim":"Establishing which cell type expresses endosialin resolved whether it marks tumor endothelium or stroma, redirecting the field toward a perivascular/fibroblast role.","evidence":"Monoclonal antibody characterization with immunofluorescence and flow cytometry localizing endosialin to tumor-associated fibroblasts and pericytes","pmids":["15862292"],"confidence":"Medium","gaps":["Did not define a ligand or signaling function","Cellular identity assigned by antibody localization, not lineage tracing"]},{"year":2007,"claim":"Identifying fibronectin and collagens I/IV as direct ligands gave CD248 a concrete matrix-engagement function underlying adhesion and migration.","evidence":"Binding assays, cell adhesion and transwell migration assays with antibody blocking","pmids":["17986615"],"confidence":"Medium","gaps":["Binding domain not mapped","Did not connect matrix binding to an intracellular signaling pathway"]},{"year":2008,"claim":"Loss-of-function and direct binding studies extended CD248's role to additional partners and functional outputs in stromal and vascular cells.","evidence":"siRNA knockdown of migration/proliferation in fibroblasts; co-IP and adhesion assays defining a repulsive Mac-2 BP/90K interaction; antibody-blocking of EPC and pericyte tube formation","pmids":["18187565","18490383","18723498","18761022"],"confidence":"Medium","gaps":["Mechanism linking ligand binding to migration phenotype unresolved","Antibody-blocking EPC/pericyte assays were Low confidence and not mechanistically dissected"]},{"year":2010,"claim":"Genetic and knockdown studies established the PDGFR signaling axis and the requirement of the cytoplasmic domain, defining CD248 as a signaling co-receptor rather than a passive adhesion molecule.","evidence":"siRNA knockdown abolishing PDGF-BB-induced proliferation/ERK/c-Fos in pericytes; CD248 cytoplasmic-domain-deleted mice with reduced arthritis, impaired monocyte adhesion, and reduced HIF1α/VEGF/MMP-9; stromal KO impairing lymph node expansion","pmids":["20484976","20722022","20432232"],"confidence":"High","gaps":["Cytoplasmic domain interactors mediating downstream signaling not identified","Direct physical PDGFR interaction not yet shown"]},{"year":2011,"claim":"In vivo tumor models and the discovery of a T-cell-specific quiescence role broadened CD248 function beyond stromal proliferation.","evidence":"CD248 cytoplasmic-domain-knockout tumor models with impaired fibroblast migration and MMP-9; CD248 cDNA transfection and knockdown in human naive CD8+ T cells altering proliferation","pmids":["21549007","21466550"],"confidence":"Medium","gaps":["Mechanism of T-cell quiescence not defined","Why function is human-CD8-specific and not mouse unexplained"]},{"year":2012,"claim":"Knockout phenotypes in bone and thymus showed CD248 governs PDGFR-dependent mesenchymal function across diverse tissues.","evidence":"CD248-/- mice with increased bone mass and defective osteoblast PDGF signaling; CD248-/- mice with hypocellular thymus and impaired regeneration","pmids":["22674221","23650598"],"confidence":"Medium","gaps":["Tissue-specific contribution of stromal vs other cell types not separated in bone","Molecular basis of thymic stromal requirement unresolved"]},{"year":2015,"claim":"Fibrosis and antibody-targeting models confirmed CD248 as a therapeutically tractable driver of PDGF-dependent fibrogenesis and pericyte maturation.","evidence":"CD248-/- mice protected from CCl4 liver fibrosis with PDGF-unresponsive hepatic stellate cells; MORAb-004 antibody internalization impairing pericyte maturation and tumor vessels in CD248 knock-in mice","pmids":["26078290","26327620"],"confidence":"High","gaps":["Antibody mechanism of CD248 downregulation not fully defined","Pericyte vs fibroblast contribution to fibrosis not dissected"]},{"year":2017,"claim":"Domain-resolved binding to MMRN2 defined a C-type lectin-mediated interaction at the endothelial-pericyte interface, distinct from CLEC14A.","evidence":"Direct binding assays, C-type lectin domain mutagenesis abolishing MMRN2 binding, simultaneous binding with CLEC14A, and co-localization in human pancreatic cancer","pmids":["28671670"],"confidence":"High","gaps":["Functional consequence of MMRN2 binding for signaling not established","Whether MMRN2 binding modulates PDGFR axis unknown"]},{"year":2019,"claim":"Reciprocal co-IP with PDGFRα and metabolic/regulatory studies cemented the receptor partnership and revealed transcriptional control and microenvironmental sensing roles.","evidence":"Co-IP of TEM1 with PDGFRα plus knockdown and KO wound-healing phenotypes; adipocyte-specific inducible KO improving metabolism and reducing hypoxia/fibrosis; Sp1/TLR/NF-κB and miR-125b-5p regulation of CD248 in colorectal cancer","pmids":["30986375","31221584","31746054"],"confidence":"High","gaps":["Stoichiometry and structural basis of the PDGFRα interaction not resolved","How CD248 senses hypoxia mechanistically unclear"]},{"year":2022,"claim":"Wnt derepression and macrophage crosstalk mechanisms explained how CD248 amplifies angiogenesis and fibrosis through partner sequestration and paracrine chemokine induction.","evidence":"Co-IP of CD248 with IGFBP4/LGALS3BP and β-catenin reporter/rescue assays in KO lung cancer models; CD248-galectin-3 interaction inducing macrophage CCL17/CCL22; CAF CD248-CXCL12 axis driving M2 polarization via CXCR4","pmids":["35950912","33033277","35985448"],"confidence":"High","gaps":["How a single surface protein coordinates PDGFR, Wnt, and chemokine outputs not integrated","Direct vs indirect nature of some interactions not all reciprocally validated"]},{"year":null,"claim":"The structural and biochemical basis by which the cytoplasmic domain transduces signals from PDGFR and matrix engagement remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of CD248 or its cytoplasmic-domain interactome","Mechanism distinguishing co-receptor vs adhesion vs sequestration functions unresolved","Basis of cell-type-specific quiescence on CD8+ T cells unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,3,11]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,8,18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,11]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,19,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,9]}],"complexes":[],"partners":["PDGFRA","MMRN2","LGALS3BP","IGFBP4","LGALS3","FN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HCU0","full_name":"Endosialin","aliases":["Tumor endothelial marker 1"],"length_aa":757,"mass_kda":80.9,"function":"Cell surface glycoprotein involved in various biological processes including angiogenesis, immune response modulation, and tissue remodeling and repair. Participates in pericyte proliferation through positive modulation of the PDGF receptor signaling pathway (PubMed:20484976). Acts as a scaffold for factor X, triggering allosteric changes and the spatial re-alignment of factor X with the TF-factor VIIa complex, thereby enhancing coagulation activation. Modulates the insulin signaling pathway by interacting with insulin receptor/INSR and by diminishing its capacity to be autophosphorylated in response to insulin. Also regulates LPS-induced inflammatory response in macrophages by favoring the production of proinflammatory cytokines. In human, negatively regulates T-cell proliferation compared with stromal cells where it increases proliferation (PubMed:21466550)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9HCU0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD248","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD248","total_profiled":1310},"omim":[{"mim_id":"606064","title":"CD248 ANTIGEN; CD248","url":"https://www.omim.org/entry/606064"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":219.6},{"tissue":"breast","ntpm":146.3}],"url":"https://www.proteinatlas.org/search/CD248"},"hgnc":{"alias_symbol":["TEM1"],"prev_symbol":["CD164L1"]},"alphafold":{"accession":"Q9HCU0","domains":[{"cath_id":"3.10.100.10","chopping":"23-160","consensus_level":"medium","plddt":91.3522,"start":23,"end":160},{"cath_id":"-","chopping":"162-231","consensus_level":"medium","plddt":87.2357,"start":162,"end":231},{"cath_id":"2.10.25.10","chopping":"239-273","consensus_level":"medium","plddt":84.2177,"start":239,"end":273},{"cath_id":"2.10.25.10","chopping":"298-352","consensus_level":"medium","plddt":93.1125,"start":298,"end":352}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCU0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCU0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCU0-F1-predicted_aligned_error_v6.png","plddt_mean":63.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD248","jax_strain_url":"https://www.jax.org/strain/search?query=CD248"},"sequence":{"accession":"Q9HCU0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HCU0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HCU0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCU0"}},"corpus_meta":[{"pmid":"10219244","id":"PMC_10219244","title":"Exit from mitosis is triggered by Tem1-dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex.","date":"1999","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/10219244","citation_count":631,"is_preprint":false},{"pmid":"8356032","id":"PMC_8356032","title":"Crystal structure of Escherichia coli TEM1 beta-lactamase at 1.8 A resolution.","date":"1993","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/8356032","citation_count":343,"is_preprint":false},{"pmid":"15292151","id":"PMC_15292151","title":"Identification of the secretion and translocation domain of the enteropathogenic and enterohemorrhagic Escherichia coli effector Cif, using TEM-1 beta-lactamase as a new fluorescence-based reporter.","date":"2004","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/15292151","citation_count":265,"is_preprint":false},{"pmid":"25723163","id":"PMC_25723163","title":"Evolvability as a function of purifying selection in TEM-1 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Investigating the potential role of specific residues on the activity of Pseudomonas-specific enzymes.","date":"1993","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8223651","citation_count":23,"is_preprint":false},{"pmid":"27956635","id":"PMC_27956635","title":"Low-stringency selection of TEM1 for BLIP shows interface plasticity and selection for faster binders.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27956635","citation_count":22,"is_preprint":false},{"pmid":"24716914","id":"PMC_24716914","title":"Increased expression of P2RY2, CD248 and EphB1 in gastric cancers from Chilean patients.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24716914","citation_count":22,"is_preprint":false},{"pmid":"26683319","id":"PMC_26683319","title":"Contribution of PBP3 Substitutions and TEM-1, TEM-15, and ROB-1 Beta-Lactamases to Cefotaxime Resistance in Haemophilus influenzae and Haemophilus parainfluenzae.","date":"2015","source":"Microbial drug resistance (Larchmont, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26683319","citation_count":22,"is_preprint":false},{"pmid":"26507466","id":"PMC_26507466","title":"Coupling spindle position with mitotic exit in budding yeast: The multifaceted role of the small GTPase Tem1.","date":"2015","source":"Small GTPases","url":"https://pubmed.ncbi.nlm.nih.gov/26507466","citation_count":21,"is_preprint":false},{"pmid":"23650598","id":"PMC_23650598","title":"CD248 expression on mesenchymal stromal cells is required for post-natal and infection-dependent thymus remodelling and regeneration.","date":"2012","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/23650598","citation_count":21,"is_preprint":false},{"pmid":"18840610","id":"PMC_18840610","title":"Structural insight into the kinetics and DeltaCp of interactions between TEM-1 beta-lactamase and beta-lactamase inhibitory protein (BLIP).","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18840610","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49755,"output_tokens":5709,"usd":0.11745,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14376,"output_tokens":3964,"usd":0.08549,"stage2_stop_reason":"end_turn"},"total_usd":0.20294,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"CD248/endosialin binds extracellular matrix proteins fibronectin and collagen types I and IV as specific ligands; cells expressing CD248 show enhanced adhesion to fibronectin and enhanced migration through matrigel, both of which are blocked by a humanized anti-CD248 antibody.\",\n      \"method\": \"Binding assays, cell adhesion assays, transwell migration assay, antibody blocking\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct binding and functional cell-based assays in a single lab, two orthogonal methods (binding + functional readouts)\",\n      \"pmids\": [\"17986615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Endosialin (TEM1/CD248) is a cell surface glycoprotein predominantly expressed by fibroblasts and a subset of pericytes associated with tumor vessels, not by tumor endothelium, as established by monoclonal antibody characterization and cellular localization studies.\",\n      \"method\": \"Monoclonal antibody generation, immunofluorescence, flow cytometry, subcellular localization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — replicated across multiple labs using antibody-based approaches, consistent with multiple subsequent studies\",\n      \"pmids\": [\"15862292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD248/endosialin mediates proliferation of primary human pericytes through PDGF receptor signaling: TEM-1 knockdown abrogates PDGF-BB-induced proliferation, ERK-1/2 phosphorylation, and c-Fos expression.\",\n      \"method\": \"siRNA knockdown, western blot (phospho-ERK), c-Fos expression assay, cell proliferation assay\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA KD with multiple downstream pathway readouts in a single lab\",\n      \"pmids\": [\"20484976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD248 deletion in hepatic stellate cells (HSCs) reduces susceptibility to liver fibrosis via PDGF signaling: CD248-/- HSCs do not proliferate in response to PDGF-BB, and c-fos expression is significantly reduced in CD248-/- HSCs after stimulation.\",\n      \"method\": \"CD248 knockout mouse model, CCl4-induced fibrosis, HSC isolation, PDGF-BB stimulation, c-fos expression assay\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with defined cellular phenotype plus in vitro mechanistic follow-up with multiple readouts, independent replication of PDGF-signaling mechanism\",\n      \"pmids\": [\"26078290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD248's cytoplasmic domain is required for inflammatory arthritis responses: CD248 cytoplasmic domain-deficient (CD248CyD/CyD) mice show reduced arthritis severity, with impaired TNFα-induced monocyte adhesion to fibroblasts and reduced HIF1α, PIGF, VEGF, and MMP-9 activity in response to TGF-β.\",\n      \"method\": \"Transgenic mice lacking the cytoplasmic domain (CD248CyD/CyD), CAIA model, ELISA, immunohistochemistry, in vitro fibroblast assays\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with defined cytoplasmic domain requirement, multiple orthogonal functional readouts in single study\",\n      \"pmids\": [\"20722022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The cytoplasmic domain of CD248 facilitates tumor growth via fibroblast-mediated mechanisms: CD248CyD/CyD mice show reduced fibrosarcoma and lung carcinoma growth; CD248CyD/CyD fibroblasts have impaired PDGF-BB-induced migration, reduced MMP-9 activation, and increased expression of tumor suppressor factors (transgelin/SM22α, Hes, Hey1).\",\n      \"method\": \"CD248 cytoplasmic domain-knockout mouse tumor models, conditioned media experiments, fibroblast migration assay, RT-PCR, MMP activity assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with mechanistic in vitro follow-up, single lab\",\n      \"pmids\": [\"21549007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Endosialin (Tem1) is specifically expressed by tumor-associated myofibroblasts and mural cells (not endothelial cells); siRNA silencing of endosialin in fibroblasts strongly inhibits migration and proliferation.\",\n      \"method\": \"Expression profiling, immunostaining, siRNA knockdown, migration and proliferation assays\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with defined proliferation/migration phenotype, consistent with multiple other studies on cellular identity\",\n      \"pmids\": [\"18187565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Endosialin (Tem1) binds Mac-2 BP/90K via a C-terminal fragment of Mac-2 BP/90K containing collagen and galectin-3 binding sites; this interaction is repulsive in loss-of-function adhesion experiments, with Mac-2 BP/90K-expressing tumor cells repelled from endosialin-expressing fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation, biochemical binding assays, adhesion/loss-of-function experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct binding characterization with functional adhesion readout, single lab with multiple methods\",\n      \"pmids\": [\"18490383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD248 directly binds to multimerin-2 (MMRN2) via its C-type lectin domain; the binding of CD248 to MMRN2 occurs on a region distinct from (non-competing with) the CLEC14A/CD93 binding region. Mutation within the C-type lectin domain long-loop region abolishes MMRN2 binding. CLEC14A and CD248 can simultaneously bind MMRN2 at the endothelial-pericyte interface in human pancreatic cancer.\",\n      \"method\": \"Direct binding assays, mutagenesis of C-type lectin domain, simultaneous binding assay, immunofluorescence in tumor tissue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding demonstrated with mutagenesis validation and in vivo co-localization in single rigorous study\",\n      \"pmids\": [\"28671670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD248 negatively regulates bone formation: CD248-/- mice have higher bone mass and superior mechanical properties. Primary osteoblasts from CD248-/- mice show increased mineralization in vitro and increased bone formation in vivo, associated with defective PDGF-BB/PDGFR signal transduction.\",\n      \"method\": \"CD248 knockout mouse, micro-CT, 3-point bending test, primary osteoblast culture, mineralization assay, calcein labeling (mineral apposition rate), PDGF-BB stimulation assay\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic knockout with multiple orthogonal bone phenotype measurements and in vitro signaling mechanistic data\",\n      \"pmids\": [\"22674221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD248 derepresses Wnt/β-catenin signaling in pericytes by interacting with Wnt pathway repressors IGFBP4 and LGALS3BP, leading to upregulation of angiogenic factors OPN and SERPINE1 and enhanced angiogenesis and lung tumor growth.\",\n      \"method\": \"Cd248 knockout mouse orthotopic lung cancer model, co-immunoprecipitation (CD248 with IGFBP4 and LGALS3BP), β-catenin reporter assays, OPN/SERPINE1 rescue experiments, β-catenin inhibitor treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of binding partners, in vivo KO model, rescue experiments with multiple orthogonal approaches in a single rigorous study\",\n      \"pmids\": [\"35950912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TEM1/CD248 interacts with PDGF receptor α (PDGFRα) by co-immunoprecipitation; TEM1 knockdown suppresses PDGF-BB-induced downstream signaling, migration, adhesion, and proliferation in fibroblasts, and TEM1-deleted mice show attenuated wound healing with reduced fibroblast activation and collagen deposition.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, in vitro migration/adhesion/proliferation assays, in vivo wound healing model with TEM1-knockout mice, immunofluorescence\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus in vivo KO with in vitro mechanistic follow-up, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30986375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD248 is required for PDGFR-β-dependent capillary sprouting (but not splitting) angiogenesis in skeletal muscle: CD248-/- mice have a specific defect in capillary sprouting that can be mimicked by blocking PDGFRβ signaling with imatinib in wild-type mice.\",\n      \"method\": \"CD248 knockout mouse, skeletal muscle functional overload and vasodilator angiogenesis models, imatinib treatment, gene expression assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with pharmacological mimicry and defined pathway placement, single lab\",\n      \"pmids\": [\"25243742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD248 expressed on human naive CD8+ T cells (but not mouse CD8+ T cells) suppresses their proliferation: transfection of CD248-negative MOLT-4 cells with CD248 cDNA reduces proliferation, and knockdown of CD248 on naive CD8+ T cells increases proliferation, demonstrating a cell-type-specific quiescence-maintaining function.\",\n      \"method\": \"CD248 cDNA transfection, siRNA knockdown, flow cytometry, proliferation assay\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain-of-function and loss-of-function experiments with defined proliferation phenotype, single lab with orthogonal approaches\",\n      \"pmids\": [\"21466550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD248 on fibroblasts interacts specifically with galectin-3 on macrophages; this interaction induces CCL17 and CCL22 expression in macrophages, which activates collagen production in myofibroblasts, promoting tissue fibrosis. Cd248-/- mice show attenuated renal and peritoneal fibrosis with decreased macrophage-expressed CCL17/CCL22.\",\n      \"method\": \"Cd248 knockout mouse UUO/peritoneal fibrosis models, parabiosis with GFP reporter mice, CD248-galectin-3 interaction assay, macrophage chemokine expression (Ccl17, Ccl22) in isolated macrophages, galectin-3-deficient macrophages\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model combined with direct protein interaction assay and mechanistic pathway dissection using multiple genetic tools\",\n      \"pmids\": [\"33033277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Adipocyte-specific and inducible CD248 knockout in mice results in increased microvascular density and attenuated hypoxia, inflammation, and fibrosis in white adipose tissue, with improvements in insulin sensitivity and glucose tolerance, indicating CD248 acts as a microenvironmental sensor mediating adipose hypoxia response.\",\n      \"method\": \"Adipocyte-specific inducible Cd248 knockout mice (before and after diet-induced obesity), metabolic phenotyping, histology, omics analyses, gene knockdown in human adipocytes\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific inducible KO with multiple physiological readouts, single lab\",\n      \"pmids\": [\"31221584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Anti-endosialin antibodies inhibit endothelial precursor cell (EPC) migration and tube formation in vitro, and inhibit circulating murine EPC in vivo, indicating a functional role for CD248/TEM1 in EPC-mediated tumor angiogenesis.\",\n      \"method\": \"Anti-endosialin antibody blocking, EPC migration assay, matrigel tube formation assay, flow cytometry, in vivo EPC inhibition assay\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — antibody blocking functional assays, single lab, mechanism not fully elucidated\",\n      \"pmids\": [\"18723498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Anti-endosialin antibodies prevent pericyte tube formation on matrigel and inhibit pericyte migration in culture, demonstrating a direct functional role for CD248 in pericyte behavior.\",\n      \"method\": \"Anti-endosialin antibody blocking, pericyte tube formation assay, migration assay\",\n      \"journal\": \"Microvascular research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — antibody blocking functional assays, single lab, limited mechanistic depth\",\n      \"pmids\": [\"18761022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD248 targeting by antibody-mediated internalization (MORAb-004) reduces CD248 levels on pericyte surfaces, impairs pericyte maturation (reduced α-SMA expression, pericyte depolarization), and causes dysfunctional tumor microvessels, suppressing tumor growth and metastasis.\",\n      \"method\": \"Human CD248 knock-in mouse model, MORAb-004 antibody treatment, syngeneic tumor models, immunofluorescence, vessel morphology analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo model with mechanistic cellular readouts (pericyte maturation markers), single lab with multiple phenotypic endpoints\",\n      \"pmids\": [\"26327620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD248 expressed on cancer-associated fibroblasts (CAFs) promotes CXCL12 secretion; CD248 knockdown on CAFs reduces CXCL12 secretion and M2 macrophage polarization/chemotaxis (blocked by CXCR4 antagonist), thereby impairing NSCLC progression.\",\n      \"method\": \"CAF isolation from NSCLC patients, CD248 siRNA knockdown, CXCL12 ELISA, macrophage co-culture polarization assay, CXCR4 blocking, in vitro and in vivo tumor progression assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function in primary human cells with multiple downstream pathway readouts, single lab\",\n      \"pmids\": [\"35985448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD248 silencing in systemic sclerosis mesenchymal stem cells (SSc-MSCs) inhibits both TGF-β and PDGF-BB signaling pathways, blocking myofibroblast differentiation and proliferation, demonstrating that CD248 modulates both TGFβ and PDGF downstream signaling in stromal cells.\",\n      \"method\": \"CD248 siRNA silencing in SSc-MSCs, TGF-β and PDGF-BB stimulation, Western blotting, qRT-PCR, immunofluorescence\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with two growth factor signaling pathway readouts, single lab\",\n      \"pmids\": [\"30285896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD248 expression in colorectal cancer cells is transcriptionally regulated via Sp1 downstream of TLR2/6 and TLR5 activation through NF-κB; miR-125b-5p suppresses Sp1 and CD248 expression, and CD248 upregulation promotes drug resistance and epithelial-mesenchymal transition.\",\n      \"method\": \"TLR ligand stimulation, NF-κB inhibition, miR-125b-5p mimic transfection, Sp1/CD248 gene silencing, RT-PCR, drug resistance assays, invasion assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple genetic perturbations defining regulatory pathway for CD248 expression, single lab\",\n      \"pmids\": [\"31746054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD248 expression on thymic mesenchymal stromal cells is required for postnatal thymus development and regeneration following Salmonella infection: CD248-/- mice have a hypocellular thymus with loss of all thymocyte populations and impaired regeneration.\",\n      \"method\": \"CD248 knockout mouse model, thymus cellularity analysis, flow cytometry of thymocyte populations, Salmonella infection model\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with defined cellular phenotype and defined stromal cell requirement, single lab\",\n      \"pmids\": [\"23650598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD248 expression on stromal cells is required for efficient lymph node expansion following immunization; in vitro, CD248 expression in stromal cells confers a pro-proliferative and pro-migratory phenotype.\",\n      \"method\": \"CD248 knockout mouse immunization model, LN cellularity analysis, in vitro CD248 transfection with proliferation/migration assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with in vitro gain-of-function validation, single lab\",\n      \"pmids\": [\"20432232\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD248 (endosialin/TEM1) is a type I transmembrane C-type lectin-like glycoprotein expressed on the surface of activated mesenchymal cells (fibroblasts, pericytes, myofibroblasts) that functions as a co-receptor/scaffold facilitating PDGF receptor signaling (PDGFRα and PDGFRβ) to promote cell proliferation, migration, and collagen deposition; it directly binds extracellular matrix proteins (fibronectin, collagen I/IV), the endothelial matrix protein MMRN2 via its C-type lectin domain, galectin-3 on macrophages to induce CCL17-mediated fibrosis, Mac-2 BP/90K in a repulsive adhesion interaction, and Wnt pathway repressors IGFBP4/LGALS3BP to derepress Wnt/β-catenin signaling and upregulate angiogenic factors; its conserved cytoplasmic domain is required for multiple downstream functions including MMP-9 activation, HIF1α/VEGF expression, and inflammatory cytokine responses, while on human naive CD8+ T cells CD248 paradoxically maintains quiescence.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD248 (endosialin/TEM1) is a cell-surface glycoprotein of activated mesenchymal cells—tumor-associated fibroblasts, myofibroblasts, and a subset of pericytes—that acts as a stromal co-receptor and matrix-engagement scaffold driving proliferation, migration, and tissue remodeling [#1, #6]. Its central mechanistic role is to potentiate platelet-derived growth factor receptor signaling: CD248 co-immunoprecipitates with PDGFRα, and its loss abrogates PDGF-BB-induced proliferation, ERK1/2 phosphorylation, c-Fos induction, migration, and collagen deposition across pericytes, hepatic stellate cells, fibroblasts, and osteoblasts [#2, #3, #9, #11]. This PDGFR-dependent axis places CD248 at the center of capillary sprouting angiogenesis, wound healing, and fibrogenesis [#11, #12]. CD248 engages the extracellular matrix and matrix-associated proteins directly, binding fibronectin and collagens I/IV to mediate adhesion and migration [#0], the endothelial matrix protein MMRN2 through its C-type lectin domain [#8], and Mac-2 BP/90K in a repulsive adhesion interaction [#7]. The conserved cytoplasmic domain is required for downstream effector functions including MMP-9 activation and HIF1α/VEGF expression, as cytoplasmic-domain-deleted mice show attenuated inflammatory arthritis and tumor growth [#4, #5]. CD248 also derepresses Wnt/β-catenin signaling by sequestering the repressors IGFBP4 and LGALS3BP to upregulate angiogenic factors [#10], and mediates cell-cell crosstalk with macrophages—binding galectin-3 to induce CCL17/CCL22-driven fibrosis [#14] and promoting CXCL12-dependent M2 polarization in cancer-associated fibroblasts [#19]. Beyond its mesenchymal roles, CD248 on human naive CD8+ T cells paradoxically maintains quiescence by suppressing proliferation [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing which cell type expresses endosialin resolved whether it marks tumor endothelium or stroma, redirecting the field toward a perivascular/fibroblast role.\",\n      \"evidence\": \"Monoclonal antibody characterization with immunofluorescence and flow cytometry localizing endosialin to tumor-associated fibroblasts and pericytes\",\n      \"pmids\": [\"15862292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define a ligand or signaling function\", \"Cellular identity assigned by antibody localization, not lineage tracing\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying fibronectin and collagens I/IV as direct ligands gave CD248 a concrete matrix-engagement function underlying adhesion and migration.\",\n      \"evidence\": \"Binding assays, cell adhesion and transwell migration assays with antibody blocking\",\n      \"pmids\": [\"17986615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding domain not mapped\", \"Did not connect matrix binding to an intracellular signaling pathway\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Loss-of-function and direct binding studies extended CD248's role to additional partners and functional outputs in stromal and vascular cells.\",\n      \"evidence\": \"siRNA knockdown of migration/proliferation in fibroblasts; co-IP and adhesion assays defining a repulsive Mac-2 BP/90K interaction; antibody-blocking of EPC and pericyte tube formation\",\n      \"pmids\": [\"18187565\", \"18490383\", \"18723498\", \"18761022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ligand binding to migration phenotype unresolved\", \"Antibody-blocking EPC/pericyte assays were Low confidence and not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic and knockdown studies established the PDGFR signaling axis and the requirement of the cytoplasmic domain, defining CD248 as a signaling co-receptor rather than a passive adhesion molecule.\",\n      \"evidence\": \"siRNA knockdown abolishing PDGF-BB-induced proliferation/ERK/c-Fos in pericytes; CD248 cytoplasmic-domain-deleted mice with reduced arthritis, impaired monocyte adhesion, and reduced HIF1α/VEGF/MMP-9; stromal KO impairing lymph node expansion\",\n      \"pmids\": [\"20484976\", \"20722022\", \"20432232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic domain interactors mediating downstream signaling not identified\", \"Direct physical PDGFR interaction not yet shown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"In vivo tumor models and the discovery of a T-cell-specific quiescence role broadened CD248 function beyond stromal proliferation.\",\n      \"evidence\": \"CD248 cytoplasmic-domain-knockout tumor models with impaired fibroblast migration and MMP-9; CD248 cDNA transfection and knockdown in human naive CD8+ T cells altering proliferation\",\n      \"pmids\": [\"21549007\", \"21466550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of T-cell quiescence not defined\", \"Why function is human-CD8-specific and not mouse unexplained\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Knockout phenotypes in bone and thymus showed CD248 governs PDGFR-dependent mesenchymal function across diverse tissues.\",\n      \"evidence\": \"CD248-/- mice with increased bone mass and defective osteoblast PDGF signaling; CD248-/- mice with hypocellular thymus and impaired regeneration\",\n      \"pmids\": [\"22674221\", \"23650598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific contribution of stromal vs other cell types not separated in bone\", \"Molecular basis of thymic stromal requirement unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Fibrosis and antibody-targeting models confirmed CD248 as a therapeutically tractable driver of PDGF-dependent fibrogenesis and pericyte maturation.\",\n      \"evidence\": \"CD248-/- mice protected from CCl4 liver fibrosis with PDGF-unresponsive hepatic stellate cells; MORAb-004 antibody internalization impairing pericyte maturation and tumor vessels in CD248 knock-in mice\",\n      \"pmids\": [\"26078290\", \"26327620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Antibody mechanism of CD248 downregulation not fully defined\", \"Pericyte vs fibroblast contribution to fibrosis not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Domain-resolved binding to MMRN2 defined a C-type lectin-mediated interaction at the endothelial-pericyte interface, distinct from CLEC14A.\",\n      \"evidence\": \"Direct binding assays, C-type lectin domain mutagenesis abolishing MMRN2 binding, simultaneous binding with CLEC14A, and co-localization in human pancreatic cancer\",\n      \"pmids\": [\"28671670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MMRN2 binding for signaling not established\", \"Whether MMRN2 binding modulates PDGFR axis unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reciprocal co-IP with PDGFRα and metabolic/regulatory studies cemented the receptor partnership and revealed transcriptional control and microenvironmental sensing roles.\",\n      \"evidence\": \"Co-IP of TEM1 with PDGFRα plus knockdown and KO wound-healing phenotypes; adipocyte-specific inducible KO improving metabolism and reducing hypoxia/fibrosis; Sp1/TLR/NF-κB and miR-125b-5p regulation of CD248 in colorectal cancer\",\n      \"pmids\": [\"30986375\", \"31221584\", \"31746054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the PDGFRα interaction not resolved\", \"How CD248 senses hypoxia mechanistically unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Wnt derepression and macrophage crosstalk mechanisms explained how CD248 amplifies angiogenesis and fibrosis through partner sequestration and paracrine chemokine induction.\",\n      \"evidence\": \"Co-IP of CD248 with IGFBP4/LGALS3BP and β-catenin reporter/rescue assays in KO lung cancer models; CD248-galectin-3 interaction inducing macrophage CCL17/CCL22; CAF CD248-CXCL12 axis driving M2 polarization via CXCR4\",\n      \"pmids\": [\"35950912\", \"33033277\", \"35985448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single surface protein coordinates PDGFR, Wnt, and chemokine outputs not integrated\", \"Direct vs indirect nature of some interactions not all reciprocally validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural and biochemical basis by which the cytoplasmic domain transduces signals from PDGFR and matrix engagement remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of CD248 or its cytoplasmic-domain interactome\", \"Mechanism distinguishing co-receptor vs adhesion vs sequestration functions unresolved\", \"Basis of cell-type-specific quiescence on CD8+ T cells unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 3, 11]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 8, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 19, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PDGFRA\", \"MMRN2\", \"LGALS3BP\", \"IGFBP4\", \"LGALS3\", \"FN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}