{"gene":"CD248","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"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 demonstrated by monoclonal antibody characterization and cell localization studies.","method":"Monoclonal antibody characterization, immunohistochemistry, cell fractionation/surface expression analysis","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 — direct surface expression determination with multiple antibodies, replicated in subsequent studies","pmids":["15862292"],"is_preprint":false},{"year":2007,"finding":"CD248/endosialin directly binds fibronectin and collagen types I and IV as extracellular matrix ligands, and cells expressing CD248 exhibit enhanced adhesion to fibronectin and enhanced migration through Matrigel; these effects are blocked by a humanized anti-CD248 antibody.","method":"Binding assays (pulldown/co-precipitation), cell adhesion assays, Matrigel migration assay, antibody blocking","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (binding, adhesion, migration) in a single study with functional blockade","pmids":["17986615"],"is_preprint":false},{"year":2008,"finding":"Endosialin (Tem1) is expressed by tumor-associated myofibroblasts and mural cells (not endothelial cells); siRNA knockdown of endosialin in fibroblasts strongly inhibited migration and proliferation.","method":"Extensive expression profiling, siRNA knockdown, migration and proliferation assays","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, clean knockdown with defined cellular phenotypes","pmids":["18187565"],"is_preprint":false},{"year":2008,"finding":"Tumor stroma marker endosialin (Tem1) binds specifically to Mac-2 BP/90K via a C-terminal fragment of Mac-2 BP/90K that contains binding sites for galectin-3 and collagens; this interaction results in a repulsive outcome when Mac-2 BP/90K-expressing tumor cells contact endosialin-expressing fibroblasts.","method":"Biochemical binding analysis, Co-IP, loss-of-function adhesion experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical identification of binding partner with functional consequence (repulsive adhesion), single lab","pmids":["18490383"],"is_preprint":false},{"year":2008,"finding":"Anti-endosialin antibodies inhibit pericyte tube formation in culture and pericyte migration, demonstrating a functional role for CD248 in pericyte behavior during angiogenesis.","method":"Antibody blocking, in vitro tube formation assay, migration assay","journal":"Microvascular research","confidence":"Medium","confidence_rationale":"Tier 3 — antibody blocking with functional readout, single lab","pmids":["18761022"],"is_preprint":false},{"year":2010,"finding":"CD248 mediates proliferation of primary human pericytes through a PDGF receptor signaling pathway: TEM-1 knockdown impairs PDGF-BB-induced proliferation, ERK-1/2 phosphorylation, and c-Fos expression.","method":"siRNA knockdown, Western blotting for phospho-ERK and c-Fos, proliferation assays with PDGF-BB stimulation","journal":"Cancer biology & therapy","confidence":"High","confidence_rationale":"Tier 2 — clean knockdown with multiple downstream signaling readouts, mechanistic pathway placement","pmids":["20484976"],"is_preprint":false},{"year":2010,"finding":"The cytoplasmic domain of CD248 is required for its role in arthritis: CD248-deficient or cytoplasmic domain-deleted mice show reduced synovial hyperplasia, reduced leukocyte accumulation, and impaired TNF-α-induced monocyte adhesion to fibroblasts; cytoplasmic domain-deleted fibroblasts show reduced HIF-1α, placental growth factor, VEGF expression, and MMP-9 activity in response to TGF-β.","method":"Transgenic mouse models (CD248-KO and cytoplasmic domain deletion), collagen antibody-induced arthritis, ELISA, immunohistochemistry, in vitro fibroblast assays","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic models with multiple orthogonal mechanistic readouts","pmids":["20722022"],"is_preprint":false},{"year":2011,"finding":"The cytoplasmic domain of CD248 is required for tumor growth support: CD248 cytoplasmic domain-deleted mice show significantly reduced fibrosarcoma and Lewis lung carcinoma growth; CD248-CyD fibroblasts produce conditioned media less effective at supporting tumor cell survival, show reduced MMP-9 activity, impaired PDGF-BB-induced migration, and express higher levels of tumor suppressor factors (transgelin/SM22α, Hes, Hey1).","method":"Transgenic mouse tumor models, conditioned media assay, MMP-9 activity, migration assay, gene expression analysis","journal":"BMC cancer","confidence":"High","confidence_rationale":"Tier 2 — genetic model with multiple mechanistic readouts, consistent with companion arthritis study","pmids":["21549007"],"is_preprint":false},{"year":2011,"finding":"CD248 is expressed on naive CD8+ human (but not mouse) T cells and maintains them in a quiescent state: transfection of CD248 into CD248-negative T cells reduces proliferation, while CD248 knockdown on naive CD8+ T cells increases proliferation.","method":"Flow cytometry, cDNA transfection, siRNA knockdown, proliferation assays","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with proliferation readout, single lab","pmids":["21466550"],"is_preprint":false},{"year":2012,"finding":"Genetic deletion of CD248 results in higher bone mass and increased osteoblast-mediated bone formation; CD248-knockout osteoblasts show increased mineralization in vitro and do not proliferate in response to PDGF-BB, attributable to a defect in PDGF signal transduction.","method":"CD248-KO mouse model, micro-CT, 3-point bending, in vitro mineralization, PDGF-BB stimulation assays","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple orthogonal functional readouts, mechanistic link to PDGF signaling","pmids":["22674221"],"is_preprint":false},{"year":2015,"finding":"CD248 deletion reduces susceptibility to liver fibrosis via impaired PDGF signaling: CD248-/- hepatic stellate cells (HSCs) fail to proliferate in response to PDGF-BB, with significantly reduced c-Fos expression, while PDGFR-α and PDGFR-β expression levels are unchanged.","method":"CD248-/- mouse model, CCl4-induced fibrosis, isolated primary HSC proliferation assays, PDGF-BB stimulation, c-Fos gene expression","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with mechanistic in vitro dissection of PDGF signaling pathway, replicated across cell types","pmids":["26078290"],"is_preprint":false},{"year":2014,"finding":"CD248 is required specifically for PDGFRβ-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.","method":"CD248-/- mouse model, mechanical angiogenesis induction models (shear stress vs. functional overload), Imatinib treatment, gene expression analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with pharmacological validation, two distinct angiogenesis paradigms separating mechanisms","pmids":["25243742"],"is_preprint":false},{"year":2017,"finding":"CD248 (endosialin) directly binds multimerin-2 (MMRN2) via its C-type lectin domain, with binding dependent on a long-loop region and abrogated by mutations within the domain; the binding site on MMRN2 is distinct from (non-competing with) the sites bound by CLEC14A and CD93, and CLEC14A and CD248 can simultaneously bind MMRN2 at the endothelial-pericyte interface.","method":"Direct binding assays, mutagenesis of C-type lectin domain, co-localization in human pancreatic cancer sections","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding with mutagenesis validation and functional consequence, orthogonal in vivo localization","pmids":["28671670"],"is_preprint":false},{"year":2019,"finding":"TEM1/CD248 physically associates with PDGF receptor α (co-localization in subcellular organelles and co-immunoprecipitation), and TEM1 knockdown impairs PDGF-BB-induced downstream signaling as well as migration, adhesion, and proliferation of fibroblasts; wound healing is retarded in TEM1-deleted mice with attenuated fibroblast activation and collagen deposition.","method":"Co-immunoprecipitation, subcellular co-localization, shRNA knockdown, migration/adhesion/proliferation assays, TEM1-knockout mouse wound healing model","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP identifies physical interaction with PDGFRα, validated by KO mouse phenotype and multiple in vitro functional assays","pmids":["30986375"],"is_preprint":false},{"year":2019,"finding":"CD248 acts as a microenvironmental sensor mediating part of the adipose tissue response to hypoxia; adipocyte-specific CD248 knockout increases microvascular density and attenuates hypoxia, inflammation, and fibrosis, leading to improved insulin sensitivity and glucose tolerance.","method":"Adipocyte-specific and inducible CD248 knockout mice, diet-induced obesity model, omics analysis, in vitro gene knockdown in human adipocytes","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with multiple metabolic phenotypes and mechanistic omics support","pmids":["31221584"],"is_preprint":false},{"year":2022,"finding":"CD248 derepresses Wnt/β-catenin signaling in pericytes by interacting with Wnt pathway repressors IGFBP4 and LGALS3BP (galectin-3BP/SERPINE1), leading to upregulation of OPN and SERPINE1, enhanced angiogenesis, and lung cancer growth.","method":"CD248-knockout mouse orthotopic lung cancer models, co-immunoprecipitation of CD248 with IGFBP4 and LGALS3BP, Wnt/β-catenin pathway analysis, β-catenin inhibitor treatment, recombinant factor rescue experiments","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — Co-IP identifies binding partners, genetic KO + pharmacological inhibition + rescue experiments provide strong mechanistic support","pmids":["35950912"],"is_preprint":false},{"year":2022,"finding":"CD248 expression on cancer-associated fibroblasts (CAFs) promotes CXCL12 secretion, which mediates M2 macrophage polarization and NSCLC progression; CD248 knockdown in CAFs reduces CXCL12 secretion, and CXCR4 blockade reduces M2 macrophage chemotaxis.","method":"CD248 siRNA knockdown in primary patient-derived CAFs, CXCL12 ELISA, macrophage polarization assays, CXCR4 blocking, in vivo tumor models","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic knockdown with defined cytokine and immune cell phenotype, single lab","pmids":["35985448"],"is_preprint":false},{"year":2020,"finding":"CD248 on fibroblast/myofibroblasts interacts specifically with galectin-3 on macrophages; this interaction induces CCL17 expression in macrophages, which then activates collagen production in myofibroblasts; Cd248 knockout reduces macrophage infiltration and attenuates renal and peritoneal fibrosis.","method":"Cd248-/- mouse models, parabiosis with GFP reporter mice, galectin-3-deficient macrophage experiments, co-interaction studies, in vivo DNA vaccination","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with parabiosis to track cell source, galectin-3 KO validation, defines CD248-galectin-3 interaction as mechanistic step","pmids":["33033277"],"is_preprint":false},{"year":2015,"finding":"CD248 deletion protects against renal fibrosis and microvascular rarefaction following unilateral ureteral obstruction; CD248-/- pericytes show less migration and differentiation toward myofibroblast phenotype, and CD248-/- fibroblasts proliferate less and deposit less collagen in vitro.","method":"UUO mouse model, CD248-/- genetic deletion, pericyte migration assay, collagen deposition assay","journal":"Nephron","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with mechanistic in vitro cellular readouts, single lab","pmids":["26633297"],"is_preprint":false},{"year":2015,"finding":"Targeting endosialin/CD248 via antibody-mediated internalization (MORAb-004) reduces CD248 levels on pericyte surfaces, impairs pericyte maturation (reduced α-SMA expression, pericyte depolarization), results in dysfunctional tumor microvessels, and suppresses tumor growth and metastasis.","method":"Human CD248 knock-in mouse syngeneic tumor models, anti-CD248 antibody treatment, immunofluorescent staining for vessel markers, α-SMA","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo functional study with mechanistic imaging of pericyte maturation markers, single lab","pmids":["26327620"],"is_preprint":false},{"year":2019,"finding":"In TLR2/6- and TLR5-modified chemoresistant colon cancer cells, TLR activation reduces miR-125b-5p levels, leading to Sp1-mediated CD248 upregulation via NF-κB; elevated CD248 promotes invasiveness and drug resistance, which are reversed by miR-125b-5p mimic transfection or CD248 gene silencing.","method":"TLR2/6 and TLR5 ligand stimulation, miR-125b-5p mimic transfection, Sp1 and CD248 siRNA knockdown, invasion and drug resistance assays","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — pathway placement via multiple gain/loss-of-function experiments with mechanistic signaling readouts, single lab","pmids":["31746054"],"is_preprint":false},{"year":2018,"finding":"CD248 silencing in systemic sclerosis mesenchymal stem cells inhibits both TGF-β-induced myofibroblast differentiation and PDGF-BB-induced proliferation, demonstrating CD248 is required upstream of both TGF-β and PDGF-BB signaling pathways in fibrotic perivascular stromal cells.","method":"siRNA knockdown of CD248 in SSc-MSCs, TGF-β and PDGF-BB stimulation, Western blot for α-SMA and Ki-67","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic knockdown dissecting two signaling pathways, single lab","pmids":["30285896"],"is_preprint":false}],"current_model":"CD248 (endosialin/TEM1) is a type I transmembrane C-type lectin-like glycoprotein expressed on the surface of fibroblasts, pericytes, and myofibroblasts that functions as a co-regulator of PDGF receptor signaling (physically interacting with PDGFRα and PDGFRβ) to drive proliferation and migration of stromal cells; it also binds extracellular matrix ligands (fibronectin, collagens I/IV), MMRN2 via its C-type lectin domain, Mac-2 BP/90K, and galectin-3 on macrophages, and its cytoplasmic domain transduces signals regulating HIF-1α, VEGF, MMP-9, Wnt/β-catenin (through sequestration of IGFBP4 and LGALS3BP), and NF-κB pathways, collectively supporting tumor stroma permissiveness, angiogenesis, and fibrosis."},"narrative":{"teleology":[{"year":2005,"claim":"Resolving the cellular identity of CD248-expressing cells in tumors established that endosialin marks fibroblasts and pericytes rather than endothelial cells, redefining the stromal context for all subsequent functional studies.","evidence":"Monoclonal antibody characterization and immunohistochemistry on tumor sections","pmids":["15862292"],"confidence":"High","gaps":["No signaling function or binding partner identified at this stage","Expression in non-tumor tissues not systematically profiled"]},{"year":2007,"claim":"Identification of fibronectin and collagens I/IV as direct ECM ligands for CD248, and demonstration that this binding promotes cell adhesion and migration, established CD248 as a functional adhesion/migration receptor on stromal cells.","evidence":"Pulldown/binding assays, cell adhesion assays, Matrigel migration with anti-CD248 antibody blocking","pmids":["17986615"],"confidence":"High","gaps":["ECM-binding domain not mapped","Signaling events downstream of ECM engagement not defined"]},{"year":2008,"claim":"siRNA knockdown demonstrating that CD248 is required for fibroblast proliferation and migration, together with identification of Mac-2 BP/90K as a binding partner, broadened the receptor's functional repertoire beyond ECM adhesion to include cell-cell interactions and proliferative signaling.","evidence":"siRNA knockdown proliferation/migration assays; biochemical binding analysis and co-IP for Mac-2 BP/90K interaction","pmids":["18187565","18490383"],"confidence":"High","gaps":["Signaling pathway downstream of Mac-2 BP/90K engagement unknown","Relationship between ECM binding and proliferative roles unclear"]},{"year":2010,"claim":"Mechanistic dissection showed CD248 is required for PDGF-BB–induced ERK1/2 phosphorylation and c-Fos expression in pericytes, while cytoplasmic domain deletion in mice revealed that this domain controls HIF-1α, VEGF, MMP-9, and monocyte adhesion in inflammatory arthritis, establishing CD248 as a signaling co-receptor upstream of PDGFR.","evidence":"siRNA knockdown with phospho-ERK/c-Fos Western blots; CD248-KO and cytoplasmic domain-deleted transgenic mice in collagen antibody–induced arthritis with ELISA and fibroblast stimulation","pmids":["20484976","20722022"],"confidence":"High","gaps":["Direct physical interaction with PDGFRs not yet demonstrated","How the cytoplasmic domain couples to HIF-1α and MMP-9 transcription not defined"]},{"year":2011,"claim":"Cytoplasmic domain deletion reduced tumor growth in vivo and derepressed tumor suppressors (transgelin/SM22α, Hes, Hey1) in fibroblasts, while CD248 expression on naive CD8+ T cells maintained quiescence, revealing functions beyond stromal cells.","evidence":"Transgenic mouse tumor models with conditioned media and gene expression analysis; flow cytometry with gain/loss-of-function in human T cells","pmids":["21549007","21466550"],"confidence":"High","gaps":["Mechanism of tumor suppressor derepression upon cytoplasmic domain loss unknown","T cell quiescence role not replicated in mouse and species difference unexplained"]},{"year":2012,"claim":"CD248 knockout increased bone mass and osteoblast mineralization due to defective PDGF signal transduction, extending the PDGFR co-receptor function to bone homeostasis.","evidence":"CD248-KO mice with micro-CT, three-point bending, in vitro mineralization, and PDGF-BB stimulation","pmids":["22674221"],"confidence":"High","gaps":["Whether CD248 interacts with PDGFRα or PDGFRβ in osteoblasts not determined","Structural basis of PDGFR co-receptor function unknown"]},{"year":2015,"claim":"CD248 loss protected against liver and renal fibrosis—hepatic stellate cells and pericytes showed impaired PDGF-BB proliferation and migration, and anti-CD248 antibody internalization disrupted pericyte maturation and tumor vasculature—consolidating CD248 as a master regulator of PDGF-dependent fibrotic and angiogenic remodeling.","evidence":"CD248-KO mice in CCl4 liver fibrosis and UUO renal fibrosis models; anti-CD248 antibody treatment in human CD248 knock-in syngeneic tumor models","pmids":["26078290","26633297","25243742","26327620"],"confidence":"High","gaps":["How CD248 modulates PDGFR signaling without altering receptor expression remains mechanistically undefined","Whether CD248 affects PDGFR internalization or clustering not tested"]},{"year":2017,"claim":"Mapping the MMRN2-binding site to the C-type lectin domain of CD248 via mutagenesis, and showing simultaneous CLEC14A/CD248 engagement of MMRN2, defined a molecular bridge at the endothelial–pericyte interface.","evidence":"Direct binding assays with C-type lectin domain mutants; co-localization in human pancreatic cancer sections","pmids":["28671670"],"confidence":"High","gaps":["Functional consequence of MMRN2 binding for angiogenesis not shown in loss-of-function models","Crystal structure of CD248 C-type lectin domain not available"]},{"year":2019,"claim":"Co-immunoprecipitation demonstrated physical association of CD248 with PDGFRα, and KO mouse wound healing showed CD248 is required for fibroblast activation and collagen deposition, confirming CD248 as a direct PDGFR-associated co-receptor.","evidence":"Co-IP and subcellular co-localization; TEM1-KO mouse wound healing model with shRNA validation in vitro","pmids":["30986375"],"confidence":"High","gaps":["Whether CD248 also physically interacts with PDGFRβ via co-IP not shown","Stoichiometry and domain requirements for the CD248–PDGFRα complex unknown"]},{"year":2019,"claim":"Adipocyte-specific CD248 knockout revealed a role as a microenvironmental hypoxia sensor in adipose tissue, improving insulin sensitivity and reducing fibrosis, extending CD248 function to metabolic regulation.","evidence":"Conditional adipocyte-specific CD248-KO mice on high-fat diet with metabolic phenotyping and omics analysis","pmids":["31221584"],"confidence":"High","gaps":["Molecular mechanism of hypoxia sensing by CD248 not defined","Relationship to HIF-1α regulation in adipocytes not directly tested"]},{"year":2020,"claim":"Identification of galectin-3 on macrophages as a CD248 binding partner driving a CCL17-dependent macrophage–myofibroblast profibrotic loop established a direct intercellular signaling mechanism for CD248 in organ fibrosis.","evidence":"CD248-KO and galectin-3-KO mice, parabiosis with GFP reporter, co-interaction studies in renal and peritoneal fibrosis","pmids":["33033277"],"confidence":"High","gaps":["Whether the CD248–galectin-3 interaction uses the C-type lectin domain not mapped","Downstream signaling in macrophages leading to CCL17 induction not characterized"]},{"year":2022,"claim":"CD248 was shown to derepress Wnt/β-catenin signaling by sequestering IGFBP4 and LGALS3BP, and separately to drive CXCL12 secretion from cancer-associated fibroblasts to polarize macrophages toward M2, revealing two new effector mechanisms in the tumor microenvironment.","evidence":"Co-IP of CD248 with IGFBP4 and LGALS3BP, β-catenin inhibitor rescue, KO orthotopic lung cancer models; CD248 siRNA in patient-derived CAFs with CXCL12 ELISA and macrophage polarization assays","pmids":["35950912","35985448"],"confidence":"High","gaps":["Whether Wnt derepression and CXCL12 secretion are linked or independent pathways not resolved","Structural basis for IGFBP4/LGALS3BP sequestration unknown"]},{"year":null,"claim":"The structural basis for CD248's co-receptor function with PDGFRs, the identity of the intracellular adaptors coupling the cytoplasmic domain to HIF-1α/MMP-9/Wnt pathways, and whether CD248's multiple extracellular ligand interactions are coordinated or context-specific remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of CD248 or its complexes","Cytoplasmic domain interactome not defined by unbiased proteomics","Relative contributions of ECM binding vs. PDGFR co-receptor function to each disease phenotype not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,3,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,10,13,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,9,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4,12,13]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,3,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,9,10,11,13,15,21]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1,6,7,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,16,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16,17]}],"complexes":[],"partners":["PDGFRA","MMRN2","LGALS3","LGALS3BP","IGFBP4","FN1"],"other_free_text":[]},"mechanistic_narrative":"CD248 (endosialin/TEM1) is a type I transmembrane C-type lectin-like glycoprotein expressed on fibroblasts, pericytes, and myofibroblasts that functions as an essential co-regulator of PDGF receptor signaling and extracellular matrix engagement, thereby controlling stromal cell proliferation, migration, and differentiation across diverse tissue contexts including tumor stroma, fibrosis, bone homeostasis, and wound healing [PMID:15862292, PMID:20484976, PMID:22674221, PMID:30986375]. CD248 physically associates with PDGFRα and is required for PDGF-BB–induced ERK1/2 phosphorylation, c-Fos expression, and downstream proliferative responses in pericytes, hepatic stellate cells, and fibroblasts, while its C-type lectin domain directly binds extracellular matrix ligands (fibronectin, collagens I/IV) and multimerin-2 at the endothelial–pericyte interface [PMID:17986615, PMID:28671670, PMID:26078290]. The cytoplasmic domain transduces signals that regulate HIF-1α, VEGF, MMP-9 activity, and Wnt/β-catenin pathway activation—the latter through sequestration of the Wnt repressors IGFBP4 and LGALS3BP—collectively supporting angiogenesis, tumor growth, and organ fibrosis [PMID:20722022, PMID:21549007, PMID:35950912]. CD248 on fibroblasts also engages galectin-3 on macrophages to induce CCL17 and promote a profibrotic macrophage–myofibroblast feedback loop, and on cancer-associated fibroblasts it drives CXCL12 secretion that polarizes macrophages toward an M2 phenotype [PMID:33033277, PMID:35985448]."},"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":630,"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":341,"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":264,"is_preprint":false},{"pmid":"26446903","id":"PMC_26446903","title":"Coevolutionary Landscape Inference and the Context-Dependence of Mutations in 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APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24716914","citation_count":22,"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":"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":"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},{"pmid":"3032386","id":"PMC_3032386","title":"Oligonucleotide probes for the detection of TEM-1 and TEM-2 beta-lactamase genes and their transposons.","date":"1987","source":"Canadian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/3032386","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":"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":20,"is_preprint":false},{"pmid":"7840555","id":"PMC_7840555","title":"Effect of threonine-to-methionine substitution at position 265 on structure and function of TEM-1 beta-lactamase.","date":"1994","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/7840555","citation_count":20,"is_preprint":false},{"pmid":"3145862","id":"PMC_3145862","title":"Synergistic effect of dosage and bacterial inoculum in TEM-1 mediated antibiotic resistance.","date":"1988","source":"European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/3145862","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48552,"output_tokens":5072,"usd":0.110868},"stage2":{"model":"claude-opus-4-6","input_tokens":8700,"output_tokens":3467,"usd":0.195263},"total_usd":0.306131,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\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 demonstrated by monoclonal antibody characterization and cell localization studies.\",\n      \"method\": \"Monoclonal antibody characterization, immunohistochemistry, cell fractionation/surface expression analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct surface expression determination with multiple antibodies, replicated in subsequent studies\",\n      \"pmids\": [\"15862292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD248/endosialin directly binds fibronectin and collagen types I and IV as extracellular matrix ligands, and cells expressing CD248 exhibit enhanced adhesion to fibronectin and enhanced migration through Matrigel; these effects are blocked by a humanized anti-CD248 antibody.\",\n      \"method\": \"Binding assays (pulldown/co-precipitation), cell adhesion assays, Matrigel migration assay, antibody blocking\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (binding, adhesion, migration) in a single study with functional blockade\",\n      \"pmids\": [\"17986615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Endosialin (Tem1) is expressed by tumor-associated myofibroblasts and mural cells (not endothelial cells); siRNA knockdown of endosialin in fibroblasts strongly inhibited migration and proliferation.\",\n      \"method\": \"Extensive expression profiling, siRNA knockdown, migration and proliferation assays\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, clean knockdown with defined cellular phenotypes\",\n      \"pmids\": [\"18187565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tumor stroma marker endosialin (Tem1) binds specifically to Mac-2 BP/90K via a C-terminal fragment of Mac-2 BP/90K that contains binding sites for galectin-3 and collagens; this interaction results in a repulsive outcome when Mac-2 BP/90K-expressing tumor cells contact endosialin-expressing fibroblasts.\",\n      \"method\": \"Biochemical binding analysis, Co-IP, loss-of-function adhesion experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical identification of binding partner with functional consequence (repulsive adhesion), single lab\",\n      \"pmids\": [\"18490383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Anti-endosialin antibodies inhibit pericyte tube formation in culture and pericyte migration, demonstrating a functional role for CD248 in pericyte behavior during angiogenesis.\",\n      \"method\": \"Antibody blocking, in vitro tube formation assay, migration assay\",\n      \"journal\": \"Microvascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — antibody blocking with functional readout, single lab\",\n      \"pmids\": [\"18761022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD248 mediates proliferation of primary human pericytes through a PDGF receptor signaling pathway: TEM-1 knockdown impairs PDGF-BB-induced proliferation, ERK-1/2 phosphorylation, and c-Fos expression.\",\n      \"method\": \"siRNA knockdown, Western blotting for phospho-ERK and c-Fos, proliferation assays with PDGF-BB stimulation\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean knockdown with multiple downstream signaling readouts, mechanistic pathway placement\",\n      \"pmids\": [\"20484976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The cytoplasmic domain of CD248 is required for its role in arthritis: CD248-deficient or cytoplasmic domain-deleted mice show reduced synovial hyperplasia, reduced leukocyte accumulation, and impaired TNF-α-induced monocyte adhesion to fibroblasts; cytoplasmic domain-deleted fibroblasts show reduced HIF-1α, placental growth factor, VEGF expression, and MMP-9 activity in response to TGF-β.\",\n      \"method\": \"Transgenic mouse models (CD248-KO and cytoplasmic domain deletion), collagen antibody-induced arthritis, ELISA, immunohistochemistry, in vitro fibroblast assays\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic models with multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"20722022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The cytoplasmic domain of CD248 is required for tumor growth support: CD248 cytoplasmic domain-deleted mice show significantly reduced fibrosarcoma and Lewis lung carcinoma growth; CD248-CyD fibroblasts produce conditioned media less effective at supporting tumor cell survival, show reduced MMP-9 activity, impaired PDGF-BB-induced migration, and express higher levels of tumor suppressor factors (transgelin/SM22α, Hes, Hey1).\",\n      \"method\": \"Transgenic mouse tumor models, conditioned media assay, MMP-9 activity, migration assay, gene expression analysis\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic model with multiple mechanistic readouts, consistent with companion arthritis study\",\n      \"pmids\": [\"21549007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD248 is expressed on naive CD8+ human (but not mouse) T cells and maintains them in a quiescent state: transfection of CD248 into CD248-negative T cells reduces proliferation, while CD248 knockdown on naive CD8+ T cells increases proliferation.\",\n      \"method\": \"Flow cytometry, cDNA transfection, siRNA knockdown, proliferation assays\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with proliferation readout, single lab\",\n      \"pmids\": [\"21466550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Genetic deletion of CD248 results in higher bone mass and increased osteoblast-mediated bone formation; CD248-knockout osteoblasts show increased mineralization in vitro and do not proliferate in response to PDGF-BB, attributable to a defect in PDGF signal transduction.\",\n      \"method\": \"CD248-KO mouse model, micro-CT, 3-point bending, in vitro mineralization, PDGF-BB stimulation assays\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple orthogonal functional readouts, mechanistic link to PDGF signaling\",\n      \"pmids\": [\"22674221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD248 deletion reduces susceptibility to liver fibrosis via impaired PDGF signaling: CD248-/- hepatic stellate cells (HSCs) fail to proliferate in response to PDGF-BB, with significantly reduced c-Fos expression, while PDGFR-α and PDGFR-β expression levels are unchanged.\",\n      \"method\": \"CD248-/- mouse model, CCl4-induced fibrosis, isolated primary HSC proliferation assays, PDGF-BB stimulation, c-Fos gene expression\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanistic in vitro dissection of PDGF signaling pathway, replicated across cell types\",\n      \"pmids\": [\"26078290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD248 is required specifically for PDGFRβ-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.\",\n      \"method\": \"CD248-/- mouse model, mechanical angiogenesis induction models (shear stress vs. functional overload), Imatinib treatment, gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with pharmacological validation, two distinct angiogenesis paradigms separating mechanisms\",\n      \"pmids\": [\"25243742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD248 (endosialin) directly binds multimerin-2 (MMRN2) via its C-type lectin domain, with binding dependent on a long-loop region and abrogated by mutations within the domain; the binding site on MMRN2 is distinct from (non-competing with) the sites bound by CLEC14A and CD93, and CLEC14A and CD248 can simultaneously bind MMRN2 at the endothelial-pericyte interface.\",\n      \"method\": \"Direct binding assays, mutagenesis of C-type lectin domain, co-localization in human pancreatic cancer sections\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding with mutagenesis validation and functional consequence, orthogonal in vivo localization\",\n      \"pmids\": [\"28671670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TEM1/CD248 physically associates with PDGF receptor α (co-localization in subcellular organelles and co-immunoprecipitation), and TEM1 knockdown impairs PDGF-BB-induced downstream signaling as well as migration, adhesion, and proliferation of fibroblasts; wound healing is retarded in TEM1-deleted mice with attenuated fibroblast activation and collagen deposition.\",\n      \"method\": \"Co-immunoprecipitation, subcellular co-localization, shRNA knockdown, migration/adhesion/proliferation assays, TEM1-knockout mouse wound healing model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP identifies physical interaction with PDGFRα, validated by KO mouse phenotype and multiple in vitro functional assays\",\n      \"pmids\": [\"30986375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD248 acts as a microenvironmental sensor mediating part of the adipose tissue response to hypoxia; adipocyte-specific CD248 knockout increases microvascular density and attenuates hypoxia, inflammation, and fibrosis, leading to improved insulin sensitivity and glucose tolerance.\",\n      \"method\": \"Adipocyte-specific and inducible CD248 knockout mice, diet-induced obesity model, omics analysis, in vitro gene knockdown in human adipocytes\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple metabolic phenotypes and mechanistic omics support\",\n      \"pmids\": [\"31221584\"],\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 (galectin-3BP/SERPINE1), leading to upregulation of OPN and SERPINE1, enhanced angiogenesis, and lung cancer growth.\",\n      \"method\": \"CD248-knockout mouse orthotopic lung cancer models, co-immunoprecipitation of CD248 with IGFBP4 and LGALS3BP, Wnt/β-catenin pathway analysis, β-catenin inhibitor treatment, recombinant factor rescue experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifies binding partners, genetic KO + pharmacological inhibition + rescue experiments provide strong mechanistic support\",\n      \"pmids\": [\"35950912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD248 expression on cancer-associated fibroblasts (CAFs) promotes CXCL12 secretion, which mediates M2 macrophage polarization and NSCLC progression; CD248 knockdown in CAFs reduces CXCL12 secretion, and CXCR4 blockade reduces M2 macrophage chemotaxis.\",\n      \"method\": \"CD248 siRNA knockdown in primary patient-derived CAFs, CXCL12 ELISA, macrophage polarization assays, CXCR4 blocking, in vivo tumor models\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic knockdown with defined cytokine and immune cell phenotype, single lab\",\n      \"pmids\": [\"35985448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD248 on fibroblast/myofibroblasts interacts specifically with galectin-3 on macrophages; this interaction induces CCL17 expression in macrophages, which then activates collagen production in myofibroblasts; Cd248 knockout reduces macrophage infiltration and attenuates renal and peritoneal fibrosis.\",\n      \"method\": \"Cd248-/- mouse models, parabiosis with GFP reporter mice, galectin-3-deficient macrophage experiments, co-interaction studies, in vivo DNA vaccination\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with parabiosis to track cell source, galectin-3 KO validation, defines CD248-galectin-3 interaction as mechanistic step\",\n      \"pmids\": [\"33033277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD248 deletion protects against renal fibrosis and microvascular rarefaction following unilateral ureteral obstruction; CD248-/- pericytes show less migration and differentiation toward myofibroblast phenotype, and CD248-/- fibroblasts proliferate less and deposit less collagen in vitro.\",\n      \"method\": \"UUO mouse model, CD248-/- genetic deletion, pericyte migration assay, collagen deposition assay\",\n      \"journal\": \"Nephron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanistic in vitro cellular readouts, single lab\",\n      \"pmids\": [\"26633297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Targeting endosialin/CD248 via antibody-mediated internalization (MORAb-004) reduces CD248 levels on pericyte surfaces, impairs pericyte maturation (reduced α-SMA expression, pericyte depolarization), results in dysfunctional tumor microvessels, and suppresses tumor growth and metastasis.\",\n      \"method\": \"Human CD248 knock-in mouse syngeneic tumor models, anti-CD248 antibody treatment, immunofluorescent staining for vessel markers, α-SMA\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo functional study with mechanistic imaging of pericyte maturation markers, single lab\",\n      \"pmids\": [\"26327620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In TLR2/6- and TLR5-modified chemoresistant colon cancer cells, TLR activation reduces miR-125b-5p levels, leading to Sp1-mediated CD248 upregulation via NF-κB; elevated CD248 promotes invasiveness and drug resistance, which are reversed by miR-125b-5p mimic transfection or CD248 gene silencing.\",\n      \"method\": \"TLR2/6 and TLR5 ligand stimulation, miR-125b-5p mimic transfection, Sp1 and CD248 siRNA knockdown, invasion and drug resistance assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement via multiple gain/loss-of-function experiments with mechanistic signaling readouts, single lab\",\n      \"pmids\": [\"31746054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD248 silencing in systemic sclerosis mesenchymal stem cells inhibits both TGF-β-induced myofibroblast differentiation and PDGF-BB-induced proliferation, demonstrating CD248 is required upstream of both TGF-β and PDGF-BB signaling pathways in fibrotic perivascular stromal cells.\",\n      \"method\": \"siRNA knockdown of CD248 in SSc-MSCs, TGF-β and PDGF-BB stimulation, Western blot for α-SMA and Ki-67\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic knockdown dissecting two signaling pathways, single lab\",\n      \"pmids\": [\"30285896\"],\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 fibroblasts, pericytes, and myofibroblasts that functions as a co-regulator of PDGF receptor signaling (physically interacting with PDGFRα and PDGFRβ) to drive proliferation and migration of stromal cells; it also binds extracellular matrix ligands (fibronectin, collagens I/IV), MMRN2 via its C-type lectin domain, Mac-2 BP/90K, and galectin-3 on macrophages, and its cytoplasmic domain transduces signals regulating HIF-1α, VEGF, MMP-9, Wnt/β-catenin (through sequestration of IGFBP4 and LGALS3BP), and NF-κB pathways, collectively supporting tumor stroma permissiveness, angiogenesis, and fibrosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD248 (endosialin/TEM1) is a type I transmembrane C-type lectin-like glycoprotein expressed on fibroblasts, pericytes, and myofibroblasts that functions as an essential co-regulator of PDGF receptor signaling and extracellular matrix engagement, thereby controlling stromal cell proliferation, migration, and differentiation across diverse tissue contexts including tumor stroma, fibrosis, bone homeostasis, and wound healing [PMID:15862292, PMID:20484976, PMID:22674221, PMID:30986375]. CD248 physically associates with PDGFRα and is required for PDGF-BB–induced ERK1/2 phosphorylation, c-Fos expression, and downstream proliferative responses in pericytes, hepatic stellate cells, and fibroblasts, while its C-type lectin domain directly binds extracellular matrix ligands (fibronectin, collagens I/IV) and multimerin-2 at the endothelial–pericyte interface [PMID:17986615, PMID:28671670, PMID:26078290]. The cytoplasmic domain transduces signals that regulate HIF-1α, VEGF, MMP-9 activity, and Wnt/β-catenin pathway activation—the latter through sequestration of the Wnt repressors IGFBP4 and LGALS3BP—collectively supporting angiogenesis, tumor growth, and organ fibrosis [PMID:20722022, PMID:21549007, PMID:35950912]. CD248 on fibroblasts also engages galectin-3 on macrophages to induce CCL17 and promote a profibrotic macrophage–myofibroblast feedback loop, and on cancer-associated fibroblasts it drives CXCL12 secretion that polarizes macrophages toward an M2 phenotype [PMID:33033277, PMID:35985448].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolving the cellular identity of CD248-expressing cells in tumors established that endosialin marks fibroblasts and pericytes rather than endothelial cells, redefining the stromal context for all subsequent functional studies.\",\n      \"evidence\": \"Monoclonal antibody characterization and immunohistochemistry on tumor sections\",\n      \"pmids\": [\"15862292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No signaling function or binding partner identified at this stage\", \"Expression in non-tumor tissues not systematically profiled\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of fibronectin and collagens I/IV as direct ECM ligands for CD248, and demonstration that this binding promotes cell adhesion and migration, established CD248 as a functional adhesion/migration receptor on stromal cells.\",\n      \"evidence\": \"Pulldown/binding assays, cell adhesion assays, Matrigel migration with anti-CD248 antibody blocking\",\n      \"pmids\": [\"17986615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ECM-binding domain not mapped\", \"Signaling events downstream of ECM engagement not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"siRNA knockdown demonstrating that CD248 is required for fibroblast proliferation and migration, together with identification of Mac-2 BP/90K as a binding partner, broadened the receptor's functional repertoire beyond ECM adhesion to include cell-cell interactions and proliferative signaling.\",\n      \"evidence\": \"siRNA knockdown proliferation/migration assays; biochemical binding analysis and co-IP for Mac-2 BP/90K interaction\",\n      \"pmids\": [\"18187565\", \"18490383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway downstream of Mac-2 BP/90K engagement unknown\", \"Relationship between ECM binding and proliferative roles unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mechanistic dissection showed CD248 is required for PDGF-BB–induced ERK1/2 phosphorylation and c-Fos expression in pericytes, while cytoplasmic domain deletion in mice revealed that this domain controls HIF-1α, VEGF, MMP-9, and monocyte adhesion in inflammatory arthritis, establishing CD248 as a signaling co-receptor upstream of PDGFR.\",\n      \"evidence\": \"siRNA knockdown with phospho-ERK/c-Fos Western blots; CD248-KO and cytoplasmic domain-deleted transgenic mice in collagen antibody–induced arthritis with ELISA and fibroblast stimulation\",\n      \"pmids\": [\"20484976\", \"20722022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction with PDGFRs not yet demonstrated\", \"How the cytoplasmic domain couples to HIF-1α and MMP-9 transcription not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Cytoplasmic domain deletion reduced tumor growth in vivo and derepressed tumor suppressors (transgelin/SM22α, Hes, Hey1) in fibroblasts, while CD248 expression on naive CD8+ T cells maintained quiescence, revealing functions beyond stromal cells.\",\n      \"evidence\": \"Transgenic mouse tumor models with conditioned media and gene expression analysis; flow cytometry with gain/loss-of-function in human T cells\",\n      \"pmids\": [\"21549007\", \"21466550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of tumor suppressor derepression upon cytoplasmic domain loss unknown\", \"T cell quiescence role not replicated in mouse and species difference unexplained\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"CD248 knockout increased bone mass and osteoblast mineralization due to defective PDGF signal transduction, extending the PDGFR co-receptor function to bone homeostasis.\",\n      \"evidence\": \"CD248-KO mice with micro-CT, three-point bending, in vitro mineralization, and PDGF-BB stimulation\",\n      \"pmids\": [\"22674221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD248 interacts with PDGFRα or PDGFRβ in osteoblasts not determined\", \"Structural basis of PDGFR co-receptor function unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"CD248 loss protected against liver and renal fibrosis—hepatic stellate cells and pericytes showed impaired PDGF-BB proliferation and migration, and anti-CD248 antibody internalization disrupted pericyte maturation and tumor vasculature—consolidating CD248 as a master regulator of PDGF-dependent fibrotic and angiogenic remodeling.\",\n      \"evidence\": \"CD248-KO mice in CCl4 liver fibrosis and UUO renal fibrosis models; anti-CD248 antibody treatment in human CD248 knock-in syngeneic tumor models\",\n      \"pmids\": [\"26078290\", \"26633297\", \"25243742\", \"26327620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD248 modulates PDGFR signaling without altering receptor expression remains mechanistically undefined\", \"Whether CD248 affects PDGFR internalization or clustering not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping the MMRN2-binding site to the C-type lectin domain of CD248 via mutagenesis, and showing simultaneous CLEC14A/CD248 engagement of MMRN2, defined a molecular bridge at the endothelial–pericyte interface.\",\n      \"evidence\": \"Direct binding assays with C-type lectin domain mutants; co-localization in human pancreatic cancer sections\",\n      \"pmids\": [\"28671670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MMRN2 binding for angiogenesis not shown in loss-of-function models\", \"Crystal structure of CD248 C-type lectin domain not available\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Co-immunoprecipitation demonstrated physical association of CD248 with PDGFRα, and KO mouse wound healing showed CD248 is required for fibroblast activation and collagen deposition, confirming CD248 as a direct PDGFR-associated co-receptor.\",\n      \"evidence\": \"Co-IP and subcellular co-localization; TEM1-KO mouse wound healing model with shRNA validation in vitro\",\n      \"pmids\": [\"30986375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD248 also physically interacts with PDGFRβ via co-IP not shown\", \"Stoichiometry and domain requirements for the CD248–PDGFRα complex unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Adipocyte-specific CD248 knockout revealed a role as a microenvironmental hypoxia sensor in adipose tissue, improving insulin sensitivity and reducing fibrosis, extending CD248 function to metabolic regulation.\",\n      \"evidence\": \"Conditional adipocyte-specific CD248-KO mice on high-fat diet with metabolic phenotyping and omics analysis\",\n      \"pmids\": [\"31221584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of hypoxia sensing by CD248 not defined\", \"Relationship to HIF-1α regulation in adipocytes not directly tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of galectin-3 on macrophages as a CD248 binding partner driving a CCL17-dependent macrophage–myofibroblast profibrotic loop established a direct intercellular signaling mechanism for CD248 in organ fibrosis.\",\n      \"evidence\": \"CD248-KO and galectin-3-KO mice, parabiosis with GFP reporter, co-interaction studies in renal and peritoneal fibrosis\",\n      \"pmids\": [\"33033277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the CD248–galectin-3 interaction uses the C-type lectin domain not mapped\", \"Downstream signaling in macrophages leading to CCL17 induction not characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CD248 was shown to derepress Wnt/β-catenin signaling by sequestering IGFBP4 and LGALS3BP, and separately to drive CXCL12 secretion from cancer-associated fibroblasts to polarize macrophages toward M2, revealing two new effector mechanisms in the tumor microenvironment.\",\n      \"evidence\": \"Co-IP of CD248 with IGFBP4 and LGALS3BP, β-catenin inhibitor rescue, KO orthotopic lung cancer models; CD248 siRNA in patient-derived CAFs with CXCL12 ELISA and macrophage polarization assays\",\n      \"pmids\": [\"35950912\", \"35985448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Wnt derepression and CXCL12 secretion are linked or independent pathways not resolved\", \"Structural basis for IGFBP4/LGALS3BP sequestration unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for CD248's co-receptor function with PDGFRs, the identity of the intracellular adaptors coupling the cytoplasmic domain to HIF-1α/MMP-9/Wnt pathways, and whether CD248's multiple extracellular ligand interactions are coordinated or context-specific remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of CD248 or its complexes\", \"Cytoplasmic domain interactome not defined by unbiased proteomics\", \"Relative contributions of ECM binding vs. PDGFR co-receptor function to each disease phenotype not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 3, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 10, 13, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 9, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4, 12, 13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 3, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 9, 10, 11, 13, 15, 21]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1, 6, 7, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 16, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PDGFRA\",\n      \"MMRN2\",\n      \"LGALS3\",\n      \"LGALS3BP\",\n      \"IGFBP4\",\n      \"FN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}