{"gene":"CD93","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1997,"finding":"CD93 (C1qR(P)) was cloned and identified as a novel type I transmembrane protein with a C-type carbohydrate recognition domain, five EGF-like domains, a transmembrane domain, and a short cytoplasmic tail. Monoclonal antibodies R3 and R139 that inhibit C1q/MBL/SPA-mediated enhancement of phagocytosis were used to purify and identify this 126 kDa cell surface protein as the receptor mediating phagocytic enhancement.","method":"cDNA cloning, protein purification by mAb affinity, amino acid sequencing, anti-peptide antiserum validation","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 — primary structure determination by cDNA cloning and protein sequencing, functional validation with inhibitory mAbs","pmids":["9047234"],"is_preprint":false},{"year":1999,"finding":"CD93 (C1qRP) is a heavily O-glycosylated protein, and direct cross-linking of CD93 with immobilized anti-CD93 mAb R3 on human monocytes triggers enhanced phagocytic capacity in the absence of C1q ligand, demonstrating direct involvement of CD93 in regulating phagocytosis. O-linked glycosylation accounts for much of the difference between predicted molecular weight and SDS-PAGE migration.","method":"Glycosylation inhibitors, specific glycosidases, in vitro translation, CHO cell transfection, phagocytosis assay with mAb cross-linking","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal biochemical methods confirming glycosylation and direct functional role","pmids":["10092817"],"is_preprint":false},{"year":1998,"finding":"CD93 (C1qRP) expression is restricted to cells of myeloid lineage and endothelial cells (and platelets), but is absent in lymphoid cells, HeLa epithelial cells, and fibroblasts, establishing cell-type specificity of CD93-mediated phagocytic enhancement.","method":"Northern blot, RT-PCR, FACS analysis with mAbs R139 and R3","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple complementary methods across multiple cell types, replicated with RNA and protein level analysis","pmids":["9469455"],"is_preprint":false},{"year":2004,"finding":"CD93-deficient mice show a significant defect in the in vivo clearance of apoptotic cells (both human Jurkat T cells and murine thymocytes) from the inflamed peritoneum, but CD93 is not required for C1q-mediated enhancement of complement- or FcγR-dependent phagocytosis in vitro or in vivo.","method":"CD93 knockout mice, in vivo apoptotic cell clearance assay, in vitro phagocytosis assays, intravital microscopy","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with specific phenotypic readout using multiple in vivo and in vitro assays","pmids":["15004139"],"is_preprint":false},{"year":2004,"finding":"CD93 interacts with the PDZ domain-containing adaptor protein GIPC through a class I PDZ-binding domain in the CD93 carboxyl terminus, with four positively charged amino acids in the juxtamembrane domain critical for stabilizing this interaction. A cell-permeable peptide encoding the C-terminal 11 amino acids of CD93 enhances phagocytosis, implicating this interaction in the modulation of phagocytic activity.","method":"Yeast two-hybrid screen, in vitro GST fusion protein-binding assay, cell-permeable peptide treatment, phagocytosis assay","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid confirmed by GST pulldown, with functional validation by cell-permeable peptide","pmids":["15459234"],"is_preprint":false},{"year":2005,"finding":"CD93 ectodomain shedding from human monocytes and neutrophils is induced by phorbol dibutyrate, TNF-α, and LPS in a metalloproteinase-dependent but ADAM17-independent manner. The shed soluble form retains the N-terminal CRD and EGF repeats. Cross-linking CD93 on monocytes also triggers shedding with generation of intracellular domain-containing cleavage products. Soluble CD93 is detectable in human plasma, confirming physiological relevance.","method":"Western blot, ELISA, metalloproteinase inhibitor (1,10-phenanthroline), flow cytometry, detection of sCD93 in human plasma","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple stimuli and inhibitors tested, intracellular domain cleavage products detected, physiological relevance confirmed by plasma detection","pmids":["16002728"],"is_preprint":false},{"year":2005,"finding":"The intracellular protein moesin binds to the cytoplasmic tail of CD93, with the binding site mapping to the first four positively charged amino acids in the juxtamembrane region of the CD93 cytoplasmic tail. Co-capping of moesin with CD93 in human monocytes confirmed the association within intact cells. Moesin binding to CD93 is enhanced by phosphatidylinositol 4,5-bisphosphate (PIP2) and modulated by binding of other intracellular molecules to the C-terminal 11 amino acids.","method":"GST fusion protein pulldown with cell lysates and recombinant moesin, co-capping in human monocytes, deletion mutant analysis, PIP2 addition assay","journal":"Immunology","confidence":"High","confidence_rationale":"Tier 2 — GST pulldown confirmed by co-capping in intact cells, domain mapping with multiple deletion mutants","pmids":["15819698"],"is_preprint":false},{"year":2003,"finding":"O-glycosylation is required for stable cell surface expression of CD93/C1qRP. Inhibition of O-glycosylation in U937 cells or in ldlD cells with a reversible glycosylation defect causes CD93 to be rapidly released into culture media or degraded rather than stably expressed on the cell surface.","method":"Glycosylation inhibitor (BAG) treatment, ldlD CHO cell transfection with reversible glycosylation defect, metabolic labeling, Western blot","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 1–2 — two independent experimental systems with metabolic labeling showing mechanistic link between O-glycosylation and surface stability","pmids":["12891708"],"is_preprint":false},{"year":2001,"finding":"C1qR(P)/CD93 expressed on microglia mediates C1q-enhanced phagocytosis of IgG-coated targets via its cytoplasmic domain. Introduction of an antibody against the C-terminal cytoplasmic domain of C1qRP into microglia by electroporation markedly diminished C1q-enhanced uptake of IgG-coated targets, demonstrating the necessity of the intracellular domain for signaling.","method":"Flow cytometry, immunocytochemistry, phagocytosis assay, electroporation of intracellular anti-CD93 antibody","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 — functional result with intracellular antibody electroporation, single lab","pmids":["10648005"],"is_preprint":false},{"year":2000,"finding":"The murine homolog of C1qR(P)/CD93 shares identical cell-type expression pattern with the human gene (expressed in myeloid cells but not epithelial cells), and murine myeloid cells respond to C1q with enhancement of phagocytosis. A polyclonal antibody to a peptide in the intracellular domain inhibited C1q-enhanced phagocytosis only when cells were permeabilized, confirming the intracellular C-terminus is required for signal transduction.","method":"Northern blot, RT-PCR, Western blot, FACS, permeabilized-cell phagocytosis inhibition assay, chromosomal synteny analysis","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — intracellular domain function confirmed by permeabilization assay, multiple expression analyses","pmids":["11074255"],"is_preprint":false},{"year":2001,"finding":"C1qR(P)/CD93 mediates enhancement of microglial uptake of C1q-opsonized amyloid beta-IgG immune complexes when IgG is at suboptimal levels. MBL and lung surfactant protein A, other ligands of C1qR(P), similarly enhanced ingestion, implicating C1qR(P) as a common receptor for defense collagens that promotes phagocytosis.","method":"In vitro phagocytosis assay with microglia, mAb inhibition of C1qR(P), comparison with MBL and SP-A ligands","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional phagocytosis assay with receptor-blocking mAbs, single lab","pmids":["11390503"],"is_preprint":false},{"year":2001,"finding":"C1q-bearing immune complexes (but not monomeric C1q) induce IL-8 secretion in human umbilical vein endothelial cells through protein tyrosine kinase (PTK)- and MAPK-dependent signaling, mediated by the 126 kDa phagocytic C1q receptor (CD93). Cross-linking mAb R3 against CD93 also stimulated IL-8 production, and IL-8 induction was blocked by the PTK inhibitor genistein and the MAPK inhibitor UO126.","method":"Northern blot for IL-8 mRNA, ELISA for IL-8 protein, kinase inhibitors (genistein, UO126), mAb R3 cross-linking","journal":"Clinical and experimental immunology","confidence":"Medium","confidence_rationale":"Tier 2 — mAb cross-linking plus pathway inhibitor experiments identifying PTK/MAPK signaling downstream of CD93","pmids":["11531942"],"is_preprint":false},{"year":2001,"finding":"CD93/C1qR(P) is predominantly expressed on endothelial cells in human tissues (as well as neutrophils), while it is absent in most tissue macrophages. Down-regulation of CD93 occurs as blood monocytes differentiate to dendritic cells in vitro.","method":"Polyclonal antibodies to N- and C-terminal peptides, immunohistochemistry, in vitro monocyte-to-dendritic cell differentiation with flow cytometry","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 — two independent antibodies against different domains, tissue distribution with in vitro differentiation model","pmids":["11698500"],"is_preprint":false},{"year":2001,"finding":"The specific collagen-like sequence GEKGEP (consensus GE(K/Q/R)GEP) within MBL is critical for triggering phagocytic enhancement via C1qR(P)/CD93. MBL mutants with deletion of GXY triplets including this motif failed to enhance phagocytosis, identifying the ligand binding site on the defense collagen that interacts with CD93.","method":"Recombinant wild-type and mutant MBL expressed in baculovirus/Sf9 cells, phagocytosis assay with human peripheral blood monocytes","journal":"Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — recombinant protein mutagenesis with functional phagocytosis assay, single lab","pmids":["11533031"],"is_preprint":false},{"year":1994,"finding":"CD93/C1qR(P) is a cell surface protein on phagocytic cells (monocytes, neutrophils, U937 cells) that modulates C1q-mediated enhancement of phagocytosis. Three mAbs (R139, R3, U40.3) identify this as a 100 kDa (126 kDa reduced) protein that co-immunoprecipitates with CD43, suggesting a multi-subunit structure. R3 and R139 (but not U40.3) inhibit phagocytosis enhancement, while R3 also partially inhibits C1q binding.","method":"Immunoprecipitation, Western blot, mAb inhibition of phagocytosis, radioligand binding inhibition studies","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple mAbs with distinct functional properties used to characterize the receptor, replicated in multiple cell types","pmids":["8144968"],"is_preprint":false},{"year":1994,"finding":"CD93/C1qR expressed on PMN (neutrophils) is a 125 kDa (135 kDa reduced) protein that can be affinity precipitated from surface-iodinated PMN using C1q-Sepharose. FMLP rapidly up-regulates CD93 surface expression up to fivefold from an intracellular pool, a process dependent on normal microtubule functioning (inhibited by taxol).","method":"C1q-Sepharose affinity precipitation, flow cytometry, phorbol ester and FMLP stimulation, taxol inhibition, surface iodination","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — affinity biochemistry combined with functional up-regulation assays and pathway inhibitor (taxol)","pmids":["7911495"],"is_preprint":false},{"year":2025,"finding":"CD93 blockade in tumor vasculature increases expression of adhesion molecules ICAM1 and VCAM1, promotes tumor vascular maturation, and improves effector T-cell infiltration into solid tumors. Anti-CD93 selectively promotes T-cell infiltration in tumors where the CD93 pathway is upregulated, and synergizes with adoptive T-cell transfer to inhibit tumor progression. Neutralizing antibodies against ICAM1 and VCAM1 were used to confirm their involvement.","method":"In vivo mouse melanoma model with anti-CD93 mAb treatment, immunofluorescent staining for vascular maturation markers, flow cytometry for tumor-infiltrating lymphocytes, neutralizing antibodies against ICAM1 and VCAM1, CAR-T cell therapy combination","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mechanistic study with multiple mouse models and neutralizing antibody experiments confirming adhesion molecule involvement","pmids":["39805660"],"is_preprint":false},{"year":2024,"finding":"CD93 in pleural mesothelial cells suppresses CCL21 secretion, thereby reducing dendritic cell migration to the tumor and suppressing systemic anti-tumor T-cell responses. Tumor extracellular vesicle-derived miR-5110 downregulates pMC CD93 to promote CCL21 secretion, while C1q suppresses CD93-mediated CCL21 secretion. CD93-blocking antibodies inhibit tumor angiogenesis and promote CCL21 secretion, overcoming resistance to anti-PD-1 therapy.","method":"RNA-Seq, miRNA array, luciferase reporter assay, siRNA knockdown, endothelial tube formation assay, chemotaxis assay, recombinant proteins, flow cytometry, EV labeling and uptake assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in single lab establishing CD93-CCL21-DC migration axis","pmids":["38250037"],"is_preprint":false}],"current_model":"CD93 is a heavily O-glycosylated type I transmembrane protein expressed on myeloid cells, endothelial cells, and platelets that functions as a modulator of phagocytosis (via its intracellular domain interacting with moesin and GIPC/PDZ adaptor), mediates in vivo clearance of apoptotic cells, undergoes metalloproteinase-dependent ectodomain shedding to generate soluble CD93, and on endothelial cells regulates adhesion molecule expression and tumor vascular normalization to control immune cell trafficking."},"narrative":{"teleology":[{"year":1994,"claim":"Identifying CD93 as a distinct phagocyte surface receptor that modulates C1q-mediated phagocytic enhancement resolved a long-sought question about which molecule linked complement recognition to ingestion.","evidence":"mAb-based immunoprecipitation and phagocytosis inhibition on monocytes and neutrophils; C1q-Sepharose affinity precipitation from surface-iodinated PMN","pmids":["8144968","7911495"],"confidence":"High","gaps":["Molecular identity of the receptor not yet determined at cDNA level","Relationship between co-immunoprecipitated CD43 and CD93 function unresolved","No intracellular signaling pathway identified"]},{"year":1997,"claim":"Cloning CD93 revealed a novel domain architecture—C-type lectin CRD, five EGF-like repeats, transmembrane segment, and short cytoplasmic tail—establishing it as a new class of innate immune receptor rather than a classical complement receptor.","evidence":"cDNA cloning from human monocyte library, protein purification via inhibitory mAbs R3/R139, amino acid sequencing","pmids":["9047234"],"confidence":"High","gaps":["Ligand-binding domain within CD93 not mapped","No structural information on CRD or EGF domains","Intracellular signaling mechanism unknown"]},{"year":1999,"claim":"Demonstrating that cross-linking CD93 alone (without C1q) enhances phagocytosis and that O-glycosylation accounts for anomalous gel migration established CD93 as a direct signaling receptor rather than a passive C1q-docking site.","evidence":"Glycosylation inhibitors, glycosidases, in vitro translation, mAb cross-linking phagocytosis assay on monocytes","pmids":["10092817"],"confidence":"High","gaps":["Downstream signaling pathway not identified","Identity of intracellular effectors unknown"]},{"year":2001,"claim":"Multiple studies defined the functional scope of CD93: it mediates C1q/MBL/SP-A-enhanced phagocytosis in microglia (including amyloid-β clearance), signals through PTK/MAPK on endothelial cells to induce IL-8, and is predominantly expressed on endothelium in tissues—shifting the perceived role from purely myeloid to also endothelial.","evidence":"Microglial phagocytosis assays with intracellular anti-CD93 antibody electroporation; mAb cross-linking plus kinase inhibitor experiments on HUVEC; immunohistochemistry with domain-specific antibodies; recombinant MBL mutagenesis identifying GEKGEP binding motif","pmids":["10648005","11390503","11531942","11698500","11533031"],"confidence":"Medium","gaps":["Direct binding of C1q collagen-like region to CD93 ectodomain not demonstrated with purified proteins","Structural basis for GEKGEP recognition unknown","PTK/MAPK pathway components downstream of CD93 not fully mapped"]},{"year":2003,"claim":"Showing that O-glycosylation is required for stable CD93 surface expression explained how post-translational processing gates receptor availability and potentially regulates phagocytic competence.","evidence":"Glycosylation inhibitor BAG treatment in U937 cells and reversible ldlD CHO cell system with metabolic labeling","pmids":["12891708"],"confidence":"High","gaps":["Specific O-glycan sites not mapped","Whether glycosylation affects ligand binding affinity unknown"]},{"year":2004,"claim":"CD93 knockout mice revealed that CD93 is required for in vivo apoptotic cell clearance but dispensable for C1q-dependent complement/FcγR phagocytosis, decoupling CD93 from classical complement pathways and repositioning it as an efferocytosis regulator.","evidence":"CD93-null mice, in vivo peritoneal apoptotic cell clearance assay, in vitro phagocytosis controls","pmids":["15004139"],"confidence":"High","gaps":["Mechanism by which CD93 promotes apoptotic cell clearance in vivo not determined","Whether CD93 directly recognizes eat-me signals on apoptotic cells unknown"]},{"year":2005,"claim":"Identification of moesin and GIPC as cytoplasmic tail binding partners, with positively charged juxtamembrane residues mediating moesin binding and a C-terminal PDZ motif recruiting GIPC, provided the first molecular model for how CD93 connects to the actin cytoskeleton and phagocytic signaling.","evidence":"Yeast two-hybrid, GST pulldown, co-capping in monocytes, PIP2 modulation, cell-permeable peptide phagocytosis assay","pmids":["15459234","15819698"],"confidence":"High","gaps":["Whether moesin and GIPC bind simultaneously or competitively not resolved","Downstream effectors of GIPC in the phagocytic pathway not identified"]},{"year":2005,"claim":"Demonstrating metalloproteinase-dependent ectodomain shedding upon inflammatory stimuli and detection of soluble CD93 in plasma established regulated proteolysis as a mechanism for modulating CD93 activity and generating a circulating form.","evidence":"Western blot, ELISA, metalloproteinase inhibitor (1,10-phenanthroline), detection of sCD93 in human plasma","pmids":["16002728"],"confidence":"High","gaps":["Identity of the responsible metalloproteinase unknown (ADAM17 excluded)","Biological function of soluble CD93 not established","Fate and signaling role of the intracellular cleavage fragment unclear"]},{"year":2024,"claim":"Discovery that CD93 on pleural mesothelial cells suppresses CCL21 secretion to limit dendritic cell migration and systemic anti-tumor immunity revealed an unexpected immunosuppressive role outside the vascular endothelium.","evidence":"RNA-Seq, miRNA array, siRNA knockdown, chemotaxis assay, luciferase reporter, in vivo tumor models","pmids":["38250037"],"confidence":"Medium","gaps":["Mechanism by which CD93 represses CCL21 transcription or secretion not defined","Relevance to non-tumor pleural biology unknown","Single-lab finding"]},{"year":2025,"claim":"Showing that anti-CD93 blockade upregulates ICAM1/VCAM1 on tumor vasculature and synergizes with adoptive T-cell therapy established CD93 as a targetable vascular immune checkpoint controlling effector T-cell infiltration.","evidence":"In vivo mouse melanoma models, anti-CD93 mAb, ICAM1/VCAM1 neutralizing antibodies, CAR-T combination therapy","pmids":["39805660"],"confidence":"Medium","gaps":["How CD93 signaling suppresses adhesion molecule expression mechanistically is unknown","Human tumor vascular expression and clinical relevance not yet validated","Whether this function depends on the same cytoplasmic signaling as phagocytic enhancement is unexplored"]},{"year":null,"claim":"The metalloproteinase responsible for CD93 shedding, the biological function of soluble CD93 and the intracellular cleavage fragment, the structural basis of defense collagen recognition, and the signaling cascade by which endothelial CD93 suppresses adhesion molecule expression remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Identity of the sheddase","Crystal or cryo-EM structure of CD93 ectodomain","Mechanism linking CD93 to ICAM1/VCAM1 transcriptional regulation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,7,14,15]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,3,10,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,16,17]}],"complexes":[],"partners":["MSN","GIPC1","C1QA","MBL2","SFTPA1"],"other_free_text":[]},"mechanistic_narrative":"CD93 is a type I transmembrane glycoprotein expressed on myeloid cells, endothelial cells, and platelets that functions as a receptor for defense collagens (C1q, MBL, SP-A) to modulate phagocytosis, apoptotic cell clearance, and vascular immune trafficking. Its extracellular region contains a C-type lectin domain and EGF-like repeats, while its cytoplasmic tail recruits the ERM protein moesin and the PDZ adaptor GIPC to transduce phagocytic and PTK/MAPK-dependent signaling [PMID:9047234, PMID:15819698, PMID:15459234, PMID:11531942]. O-glycosylation is required for stable surface expression, and metalloproteinase-dependent ectodomain shedding releases soluble CD93 into plasma [PMID:12891708, PMID:16002728]. On tumor vasculature, CD93 suppresses ICAM1/VCAM1 expression and CCL21 secretion, limiting effector T-cell infiltration; its blockade promotes vascular normalization and enhances anti-tumor immunity [PMID:39805660, PMID:38250037]."},"prefetch_data":{"uniprot":{"accession":"Q9NPY3","full_name":"Complement component C1q receptor","aliases":["C1q/MBL/SPA receptor","C1qR","C1qR(p)","C1qRp","CDw93","Complement component 1 q subcomponent receptor 1","Matrix-remodeling-associated protein 4"],"length_aa":652,"mass_kda":68.6,"function":"Cell surface receptor that plays a role in various physiological processes including inflammation, phagocytosis, and cell adhesion. Plays a role in phagocytosis and enhances the uptake of apoptotic cells and immune complexes by acting as a receptor for defense collagens including surfactant protein A/SFTPA1, C1q, and mannose-binding lectin (MBL2) (PubMed:7977768). Plays a role in the regulation of endothelial cell function and adhesion by activating angiogenesis (PubMed:24809468). Mechanistically, exerts its angiogenic function by associating with beta-dystroglycan, leading to SRC-dependent phosphorylation and subsequent recruitment of CBL. In turn, CBL provides a docking site for downstream signaling components, such as CRKL to enhance cell migration (PubMed:26848865). Participates in angiogenesis also by acting as a receptor for the ECM pan-endothelial glycoprotein multimerin-2/MMRN2 and IGFBP7 ligands (PubMed:28671670, PubMed:36265539, PubMed:38218180). Both ligands play a non-redundant role in CD93-mediated endothelial cell function (PubMed:38218180). Acts as a key regulator of endothelial barrier function through modulating VEGFR2 function (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9NPY3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD93","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD93","total_profiled":1310},"omim":[{"mim_id":"602737","title":"CHEMOKINE, CC MOTIF, LIGAND 21; CCL21","url":"https://www.omim.org/entry/602737"},{"mim_id":"120577","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT, RECEPTOR 1; C1QR1","url":"https://www.omim.org/entry/120577"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"placenta","ntpm":129.3}],"url":"https://www.proteinatlas.org/search/CD93"},"hgnc":{"alias_symbol":["C1qRP","C1qR(P)","dJ737E23.1","CDw93","ECSM3"],"prev_symbol":["MXRA4","C1QR1"]},"alphafold":{"accession":"Q9NPY3","domains":[{"cath_id":"3.10.100.10","chopping":"28-130_138-184","consensus_level":"high","plddt":81.05,"start":28,"end":184},{"cath_id":"-","chopping":"189-303","consensus_level":"high","plddt":81.1828,"start":189,"end":303},{"cath_id":"2.10.25.10","chopping":"388-429","consensus_level":"medium","plddt":85.1693,"start":388,"end":429},{"cath_id":"2.10.25.10","chopping":"432-469","consensus_level":"medium","plddt":80.5826,"start":432,"end":469},{"cath_id":"2.10.25","chopping":"349-386","consensus_level":"medium","plddt":81.9408,"start":349,"end":386}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPY3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPY3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPY3-F1-predicted_aligned_error_v6.png","plddt_mean":72.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD93","jax_strain_url":"https://www.jax.org/strain/search?query=CD93"},"sequence":{"accession":"Q9NPY3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPY3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPY3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPY3"}},"corpus_meta":[{"pmid":"10904115","id":"PMC_10904115","title":"C1q: structure, function, and receptors.","date":"2000","source":"Immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/10904115","citation_count":395,"is_preprint":false},{"pmid":"9047234","id":"PMC_9047234","title":"cDNA cloning and primary structure analysis of C1qR(P), the human C1q/MBL/SPA receptor that mediates enhanced phagocytosis in vitro.","date":"1997","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/9047234","citation_count":206,"is_preprint":false},{"pmid":"12140365","id":"PMC_12140365","title":"C1qRp defines a new human stem cell population with hematopoietic and hepatic potential.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12140365","citation_count":136,"is_preprint":false},{"pmid":"7688027","id":"PMC_7688027","title":"Platelet activation by C1q results in the induction of alpha IIb/beta 3 integrins (GPIIb-IIIa) and the expression of P-selectin and procoagulant activity.","date":"1993","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7688027","citation_count":126,"is_preprint":false},{"pmid":"15004139","id":"PMC_15004139","title":"Murine CD93 (C1qRp) contributes to the removal of apoptotic cells in vivo but is not required for C1q-mediated enhancement of phagocytosis.","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15004139","citation_count":116,"is_preprint":false},{"pmid":"8046223","id":"PMC_8046223","title":"Human T cells express specific binding sites for C1q. 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EGF-like domains, a transmembrane domain, and a short cytoplasmic tail. Monoclonal antibodies R3 and R139 that inhibit C1q/MBL/SPA-mediated enhancement of phagocytosis were used to purify and identify this 126 kDa cell surface protein as the receptor mediating phagocytic enhancement.\",\n      \"method\": \"cDNA cloning, protein purification by mAb affinity, amino acid sequencing, anti-peptide antiserum validation\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — primary structure determination by cDNA cloning and protein sequencing, functional validation with inhibitory mAbs\",\n      \"pmids\": [\"9047234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD93 (C1qRP) is a heavily O-glycosylated protein, and direct cross-linking of CD93 with immobilized anti-CD93 mAb R3 on human monocytes triggers enhanced phagocytic capacity in the absence of C1q ligand, demonstrating direct involvement of CD93 in regulating phagocytosis. O-linked glycosylation accounts for much of the difference between predicted molecular weight and SDS-PAGE migration.\",\n      \"method\": \"Glycosylation inhibitors, specific glycosidases, in vitro translation, CHO cell transfection, phagocytosis assay with mAb cross-linking\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal biochemical methods confirming glycosylation and direct functional role\",\n      \"pmids\": [\"10092817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD93 (C1qRP) expression is restricted to cells of myeloid lineage and endothelial cells (and platelets), but is absent in lymphoid cells, HeLa epithelial cells, and fibroblasts, establishing cell-type specificity of CD93-mediated phagocytic enhancement.\",\n      \"method\": \"Northern blot, RT-PCR, FACS analysis with mAbs R139 and R3\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary methods across multiple cell types, replicated with RNA and protein level analysis\",\n      \"pmids\": [\"9469455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD93-deficient mice show a significant defect in the in vivo clearance of apoptotic cells (both human Jurkat T cells and murine thymocytes) from the inflamed peritoneum, but CD93 is not required for C1q-mediated enhancement of complement- or FcγR-dependent phagocytosis in vitro or in vivo.\",\n      \"method\": \"CD93 knockout mice, in vivo apoptotic cell clearance assay, in vitro phagocytosis assays, intravital microscopy\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with specific phenotypic readout using multiple in vivo and in vitro assays\",\n      \"pmids\": [\"15004139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD93 interacts with the PDZ domain-containing adaptor protein GIPC through a class I PDZ-binding domain in the CD93 carboxyl terminus, with four positively charged amino acids in the juxtamembrane domain critical for stabilizing this interaction. A cell-permeable peptide encoding the C-terminal 11 amino acids of CD93 enhances phagocytosis, implicating this interaction in the modulation of phagocytic activity.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro GST fusion protein-binding assay, cell-permeable peptide treatment, phagocytosis assay\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid confirmed by GST pulldown, with functional validation by cell-permeable peptide\",\n      \"pmids\": [\"15459234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD93 ectodomain shedding from human monocytes and neutrophils is induced by phorbol dibutyrate, TNF-α, and LPS in a metalloproteinase-dependent but ADAM17-independent manner. The shed soluble form retains the N-terminal CRD and EGF repeats. Cross-linking CD93 on monocytes also triggers shedding with generation of intracellular domain-containing cleavage products. Soluble CD93 is detectable in human plasma, confirming physiological relevance.\",\n      \"method\": \"Western blot, ELISA, metalloproteinase inhibitor (1,10-phenanthroline), flow cytometry, detection of sCD93 in human plasma\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple stimuli and inhibitors tested, intracellular domain cleavage products detected, physiological relevance confirmed by plasma detection\",\n      \"pmids\": [\"16002728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The intracellular protein moesin binds to the cytoplasmic tail of CD93, with the binding site mapping to the first four positively charged amino acids in the juxtamembrane region of the CD93 cytoplasmic tail. Co-capping of moesin with CD93 in human monocytes confirmed the association within intact cells. Moesin binding to CD93 is enhanced by phosphatidylinositol 4,5-bisphosphate (PIP2) and modulated by binding of other intracellular molecules to the C-terminal 11 amino acids.\",\n      \"method\": \"GST fusion protein pulldown with cell lysates and recombinant moesin, co-capping in human monocytes, deletion mutant analysis, PIP2 addition assay\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — GST pulldown confirmed by co-capping in intact cells, domain mapping with multiple deletion mutants\",\n      \"pmids\": [\"15819698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"O-glycosylation is required for stable cell surface expression of CD93/C1qRP. Inhibition of O-glycosylation in U937 cells or in ldlD cells with a reversible glycosylation defect causes CD93 to be rapidly released into culture media or degraded rather than stably expressed on the cell surface.\",\n      \"method\": \"Glycosylation inhibitor (BAG) treatment, ldlD CHO cell transfection with reversible glycosylation defect, metabolic labeling, Western blot\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — two independent experimental systems with metabolic labeling showing mechanistic link between O-glycosylation and surface stability\",\n      \"pmids\": [\"12891708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"C1qR(P)/CD93 expressed on microglia mediates C1q-enhanced phagocytosis of IgG-coated targets via its cytoplasmic domain. Introduction of an antibody against the C-terminal cytoplasmic domain of C1qRP into microglia by electroporation markedly diminished C1q-enhanced uptake of IgG-coated targets, demonstrating the necessity of the intracellular domain for signaling.\",\n      \"method\": \"Flow cytometry, immunocytochemistry, phagocytosis assay, electroporation of intracellular anti-CD93 antibody\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional result with intracellular antibody electroporation, single lab\",\n      \"pmids\": [\"10648005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The murine homolog of C1qR(P)/CD93 shares identical cell-type expression pattern with the human gene (expressed in myeloid cells but not epithelial cells), and murine myeloid cells respond to C1q with enhancement of phagocytosis. A polyclonal antibody to a peptide in the intracellular domain inhibited C1q-enhanced phagocytosis only when cells were permeabilized, confirming the intracellular C-terminus is required for signal transduction.\",\n      \"method\": \"Northern blot, RT-PCR, Western blot, FACS, permeabilized-cell phagocytosis inhibition assay, chromosomal synteny analysis\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — intracellular domain function confirmed by permeabilization assay, multiple expression analyses\",\n      \"pmids\": [\"11074255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"C1qR(P)/CD93 mediates enhancement of microglial uptake of C1q-opsonized amyloid beta-IgG immune complexes when IgG is at suboptimal levels. MBL and lung surfactant protein A, other ligands of C1qR(P), similarly enhanced ingestion, implicating C1qR(P) as a common receptor for defense collagens that promotes phagocytosis.\",\n      \"method\": \"In vitro phagocytosis assay with microglia, mAb inhibition of C1qR(P), comparison with MBL and SP-A ligands\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional phagocytosis assay with receptor-blocking mAbs, single lab\",\n      \"pmids\": [\"11390503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"C1q-bearing immune complexes (but not monomeric C1q) induce IL-8 secretion in human umbilical vein endothelial cells through protein tyrosine kinase (PTK)- and MAPK-dependent signaling, mediated by the 126 kDa phagocytic C1q receptor (CD93). Cross-linking mAb R3 against CD93 also stimulated IL-8 production, and IL-8 induction was blocked by the PTK inhibitor genistein and the MAPK inhibitor UO126.\",\n      \"method\": \"Northern blot for IL-8 mRNA, ELISA for IL-8 protein, kinase inhibitors (genistein, UO126), mAb R3 cross-linking\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mAb cross-linking plus pathway inhibitor experiments identifying PTK/MAPK signaling downstream of CD93\",\n      \"pmids\": [\"11531942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD93/C1qR(P) is predominantly expressed on endothelial cells in human tissues (as well as neutrophils), while it is absent in most tissue macrophages. Down-regulation of CD93 occurs as blood monocytes differentiate to dendritic cells in vitro.\",\n      \"method\": \"Polyclonal antibodies to N- and C-terminal peptides, immunohistochemistry, in vitro monocyte-to-dendritic cell differentiation with flow cytometry\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two independent antibodies against different domains, tissue distribution with in vitro differentiation model\",\n      \"pmids\": [\"11698500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The specific collagen-like sequence GEKGEP (consensus GE(K/Q/R)GEP) within MBL is critical for triggering phagocytic enhancement via C1qR(P)/CD93. MBL mutants with deletion of GXY triplets including this motif failed to enhance phagocytosis, identifying the ligand binding site on the defense collagen that interacts with CD93.\",\n      \"method\": \"Recombinant wild-type and mutant MBL expressed in baculovirus/Sf9 cells, phagocytosis assay with human peripheral blood monocytes\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — recombinant protein mutagenesis with functional phagocytosis assay, single lab\",\n      \"pmids\": [\"11533031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CD93/C1qR(P) is a cell surface protein on phagocytic cells (monocytes, neutrophils, U937 cells) that modulates C1q-mediated enhancement of phagocytosis. Three mAbs (R139, R3, U40.3) identify this as a 100 kDa (126 kDa reduced) protein that co-immunoprecipitates with CD43, suggesting a multi-subunit structure. R3 and R139 (but not U40.3) inhibit phagocytosis enhancement, while R3 also partially inhibits C1q binding.\",\n      \"method\": \"Immunoprecipitation, Western blot, mAb inhibition of phagocytosis, radioligand binding inhibition studies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple mAbs with distinct functional properties used to characterize the receptor, replicated in multiple cell types\",\n      \"pmids\": [\"8144968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CD93/C1qR expressed on PMN (neutrophils) is a 125 kDa (135 kDa reduced) protein that can be affinity precipitated from surface-iodinated PMN using C1q-Sepharose. FMLP rapidly up-regulates CD93 surface expression up to fivefold from an intracellular pool, a process dependent on normal microtubule functioning (inhibited by taxol).\",\n      \"method\": \"C1q-Sepharose affinity precipitation, flow cytometry, phorbol ester and FMLP stimulation, taxol inhibition, surface iodination\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — affinity biochemistry combined with functional up-regulation assays and pathway inhibitor (taxol)\",\n      \"pmids\": [\"7911495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD93 blockade in tumor vasculature increases expression of adhesion molecules ICAM1 and VCAM1, promotes tumor vascular maturation, and improves effector T-cell infiltration into solid tumors. Anti-CD93 selectively promotes T-cell infiltration in tumors where the CD93 pathway is upregulated, and synergizes with adoptive T-cell transfer to inhibit tumor progression. Neutralizing antibodies against ICAM1 and VCAM1 were used to confirm their involvement.\",\n      \"method\": \"In vivo mouse melanoma model with anti-CD93 mAb treatment, immunofluorescent staining for vascular maturation markers, flow cytometry for tumor-infiltrating lymphocytes, neutralizing antibodies against ICAM1 and VCAM1, CAR-T cell therapy combination\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mechanistic study with multiple mouse models and neutralizing antibody experiments confirming adhesion molecule involvement\",\n      \"pmids\": [\"39805660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD93 in pleural mesothelial cells suppresses CCL21 secretion, thereby reducing dendritic cell migration to the tumor and suppressing systemic anti-tumor T-cell responses. Tumor extracellular vesicle-derived miR-5110 downregulates pMC CD93 to promote CCL21 secretion, while C1q suppresses CD93-mediated CCL21 secretion. CD93-blocking antibodies inhibit tumor angiogenesis and promote CCL21 secretion, overcoming resistance to anti-PD-1 therapy.\",\n      \"method\": \"RNA-Seq, miRNA array, luciferase reporter assay, siRNA knockdown, endothelial tube formation assay, chemotaxis assay, recombinant proteins, flow cytometry, EV labeling and uptake assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in single lab establishing CD93-CCL21-DC migration axis\",\n      \"pmids\": [\"38250037\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD93 is a heavily O-glycosylated type I transmembrane protein expressed on myeloid cells, endothelial cells, and platelets that functions as a modulator of phagocytosis (via its intracellular domain interacting with moesin and GIPC/PDZ adaptor), mediates in vivo clearance of apoptotic cells, undergoes metalloproteinase-dependent ectodomain shedding to generate soluble CD93, and on endothelial cells regulates adhesion molecule expression and tumor vascular normalization to control immune cell trafficking.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD93 is a type I transmembrane glycoprotein expressed on myeloid cells, endothelial cells, and platelets that functions as a receptor for defense collagens (C1q, MBL, SP-A) to modulate phagocytosis, apoptotic cell clearance, and vascular immune trafficking. Its extracellular region contains a C-type lectin domain and EGF-like repeats, while its cytoplasmic tail recruits the ERM protein moesin and the PDZ adaptor GIPC to transduce phagocytic and PTK/MAPK-dependent signaling [PMID:9047234, PMID:15819698, PMID:15459234, PMID:11531942]. O-glycosylation is required for stable surface expression, and metalloproteinase-dependent ectodomain shedding releases soluble CD93 into plasma [PMID:12891708, PMID:16002728]. On tumor vasculature, CD93 suppresses ICAM1/VCAM1 expression and CCL21 secretion, limiting effector T-cell infiltration; its blockade promotes vascular normalization and enhances anti-tumor immunity [PMID:39805660, PMID:38250037].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identifying CD93 as a distinct phagocyte surface receptor that modulates C1q-mediated phagocytic enhancement resolved a long-sought question about which molecule linked complement recognition to ingestion.\",\n      \"evidence\": \"mAb-based immunoprecipitation and phagocytosis inhibition on monocytes and neutrophils; C1q-Sepharose affinity precipitation from surface-iodinated PMN\",\n      \"pmids\": [\"8144968\", \"7911495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the receptor not yet determined at cDNA level\", \"Relationship between co-immunoprecipitated CD43 and CD93 function unresolved\", \"No intracellular signaling pathway identified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Cloning CD93 revealed a novel domain architecture—C-type lectin CRD, five EGF-like repeats, transmembrane segment, and short cytoplasmic tail—establishing it as a new class of innate immune receptor rather than a classical complement receptor.\",\n      \"evidence\": \"cDNA cloning from human monocyte library, protein purification via inhibitory mAbs R3/R139, amino acid sequencing\",\n      \"pmids\": [\"9047234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand-binding domain within CD93 not mapped\", \"No structural information on CRD or EGF domains\", \"Intracellular signaling mechanism unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that cross-linking CD93 alone (without C1q) enhances phagocytosis and that O-glycosylation accounts for anomalous gel migration established CD93 as a direct signaling receptor rather than a passive C1q-docking site.\",\n      \"evidence\": \"Glycosylation inhibitors, glycosidases, in vitro translation, mAb cross-linking phagocytosis assay on monocytes\",\n      \"pmids\": [\"10092817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathway not identified\", \"Identity of intracellular effectors unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Multiple studies defined the functional scope of CD93: it mediates C1q/MBL/SP-A-enhanced phagocytosis in microglia (including amyloid-β clearance), signals through PTK/MAPK on endothelial cells to induce IL-8, and is predominantly expressed on endothelium in tissues—shifting the perceived role from purely myeloid to also endothelial.\",\n      \"evidence\": \"Microglial phagocytosis assays with intracellular anti-CD93 antibody electroporation; mAb cross-linking plus kinase inhibitor experiments on HUVEC; immunohistochemistry with domain-specific antibodies; recombinant MBL mutagenesis identifying GEKGEP binding motif\",\n      \"pmids\": [\"10648005\", \"11390503\", \"11531942\", \"11698500\", \"11533031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of C1q collagen-like region to CD93 ectodomain not demonstrated with purified proteins\", \"Structural basis for GEKGEP recognition unknown\", \"PTK/MAPK pathway components downstream of CD93 not fully mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that O-glycosylation is required for stable CD93 surface expression explained how post-translational processing gates receptor availability and potentially regulates phagocytic competence.\",\n      \"evidence\": \"Glycosylation inhibitor BAG treatment in U937 cells and reversible ldlD CHO cell system with metabolic labeling\",\n      \"pmids\": [\"12891708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific O-glycan sites not mapped\", \"Whether glycosylation affects ligand binding affinity unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"CD93 knockout mice revealed that CD93 is required for in vivo apoptotic cell clearance but dispensable for C1q-dependent complement/FcγR phagocytosis, decoupling CD93 from classical complement pathways and repositioning it as an efferocytosis regulator.\",\n      \"evidence\": \"CD93-null mice, in vivo peritoneal apoptotic cell clearance assay, in vitro phagocytosis controls\",\n      \"pmids\": [\"15004139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CD93 promotes apoptotic cell clearance in vivo not determined\", \"Whether CD93 directly recognizes eat-me signals on apoptotic cells unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of moesin and GIPC as cytoplasmic tail binding partners, with positively charged juxtamembrane residues mediating moesin binding and a C-terminal PDZ motif recruiting GIPC, provided the first molecular model for how CD93 connects to the actin cytoskeleton and phagocytic signaling.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, co-capping in monocytes, PIP2 modulation, cell-permeable peptide phagocytosis assay\",\n      \"pmids\": [\"15459234\", \"15819698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether moesin and GIPC bind simultaneously or competitively not resolved\", \"Downstream effectors of GIPC in the phagocytic pathway not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating metalloproteinase-dependent ectodomain shedding upon inflammatory stimuli and detection of soluble CD93 in plasma established regulated proteolysis as a mechanism for modulating CD93 activity and generating a circulating form.\",\n      \"evidence\": \"Western blot, ELISA, metalloproteinase inhibitor (1,10-phenanthroline), detection of sCD93 in human plasma\",\n      \"pmids\": [\"16002728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the responsible metalloproteinase unknown (ADAM17 excluded)\", \"Biological function of soluble CD93 not established\", \"Fate and signaling role of the intracellular cleavage fragment unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that CD93 on pleural mesothelial cells suppresses CCL21 secretion to limit dendritic cell migration and systemic anti-tumor immunity revealed an unexpected immunosuppressive role outside the vascular endothelium.\",\n      \"evidence\": \"RNA-Seq, miRNA array, siRNA knockdown, chemotaxis assay, luciferase reporter, in vivo tumor models\",\n      \"pmids\": [\"38250037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CD93 represses CCL21 transcription or secretion not defined\", \"Relevance to non-tumor pleural biology unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that anti-CD93 blockade upregulates ICAM1/VCAM1 on tumor vasculature and synergizes with adoptive T-cell therapy established CD93 as a targetable vascular immune checkpoint controlling effector T-cell infiltration.\",\n      \"evidence\": \"In vivo mouse melanoma models, anti-CD93 mAb, ICAM1/VCAM1 neutralizing antibodies, CAR-T combination therapy\",\n      \"pmids\": [\"39805660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CD93 signaling suppresses adhesion molecule expression mechanistically is unknown\", \"Human tumor vascular expression and clinical relevance not yet validated\", \"Whether this function depends on the same cytoplasmic signaling as phagocytic enhancement is unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The metalloproteinase responsible for CD93 shedding, the biological function of soluble CD93 and the intracellular cleavage fragment, the structural basis of defense collagen recognition, and the signaling cascade by which endothelial CD93 suppresses adhesion molecule expression remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Identity of the sheddase\", \"Crystal or cryo-EM structure of CD93 ectodomain\", \"Mechanism linking CD93 to ICAM1/VCAM1 transcriptional regulation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 7, 14, 15]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 3, 10, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 16, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MSN\", \"GIPC1\", \"C1QA\", \"MBL2\", \"SFTPA1\"],\n    \"other_free_text\": []\n  }\n}\n```"}