{"gene":"MMRN2","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1994,"finding":"EndoGlyx-1 (later identified as MMRN2) was characterized as a high molecular weight (~500 kDa) glycoprotein complex on the surface of vascular endothelial cells, composed of four disulfide-bonded subunits of apparent molecular weight 190, 140, 125, and 110 kDa. It is expressed exclusively on endothelial cells of normal and tumor blood vessels, with no expression in non-endothelial cell types.","method":"Monoclonal antibody generation, immunochemical analysis of endothelial cell extracts, immunohistochemistry","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical fractionation and immunochemical characterization; single lab","pmids":["7933987"],"is_preprint":false},{"year":2001,"finding":"EndoGlyx-1/MMRN2 was molecularly cloned and characterized as an EMILIN-like protein of 949 amino acids (~105 kDa) with an N-terminal EMI domain, a central coiled-coil-rich region, and a C-terminal C1q-like domain. The four subunits (p110, p125, p140, p200) are all cell-surface exposed and share similar patterns of N-linked and O-linked carbohydrates as shown by enzyme digestion.","method":"Peptide purification, cDNA cloning, bioinformatic domain analysis, enzyme digestion of carbohydrates, cell surface expression assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — molecular cloning with biochemical validation of domain structure and glycosylation; multiple orthogonal methods","pmids":["11559704"],"is_preprint":false},{"year":2002,"finding":"Multimerin-2 (MMRN2) is a secreted glycoprotein of the EMI domain family capable of forming homo- and heteromers via disulfide bonding, and is attached to the extracellular matrix. Its structural organization includes an N-terminal EMI domain, an interrupted collagen stretch, and a conserved C-terminal domain.","method":"Developmental expression analysis, biochemical characterization, disulfide bonding assays","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — biochemical characterization of oligomerization; single lab","pmids":["12221002"],"is_preprint":false},{"year":2011,"finding":"MMRN2 directly binds VEGF-A with an affinity of ~50 nM (Kd), thereby sequestering VEGF-A and impairing its binding to VEGFR1 and VEGFR2, leading to inhibition of endothelial cell migration, vessel network organization, and tumor growth in vivo. MMRN2 overexpression in tumor cells impaired tumor vascularization, and adenoviral delivery of MMRN2 to established tumors similarly reduced growth.","method":"Multiple binding assays (affinity measurement), VEGFR phosphorylation assays, endothelial migration and tube formation assays, in vivo tumor xenograft models, adenoviral construct delivery","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding affinity measurement plus multiple functional assays in vitro and in vivo; multiple orthogonal methods in single study","pmids":["22020326"],"is_preprint":false},{"year":2012,"finding":"MMRN2 (Multimerin-2) is a homotrimeric glycoprotein that assembles into high molecular weight multimers, functions through its gC1q domain, and contributes to vascular biology including pro-angiogenic functions and potential roles in hemostasis. The gC1q domain mediates ligand-receptor interactions.","method":"Biochemical analysis, structural studies of family members, review with mechanistic synthesis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 3 — review synthesizing biochemical data; mechanistic aspects supported by experimental data from multiple labs","pmids":["22566882"],"is_preprint":false},{"year":2013,"finding":"CLEC14A was identified as a matrix component that binds to MMRN2 in endothelial cells undergoing morphogenesis. This interaction was detected by quantitative proteomics during endothelial cell tube formation on matrigel, and deregulated levels of both proteins were verified during tumor angiogenesis in multistage carcinogenesis models.","method":"SILAC quantitative proteomics, extracellular matrix protein profiling, in vitro morphogenesis assay","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2-3 — proteomics-based identification of interaction confirmed in tumor angiogenesis models; single study","pmids":["23979707"],"is_preprint":false},{"year":2015,"finding":"MMRN2 binds to the extracellular region of CLEC14A (confirmed by pull-down and co-immunoprecipitation), and this interaction is required for sprouting angiogenesis. A monoclonal antibody (clone C4) that blocks CLEC14A-MMRN2 binding inhibits tube formation, endothelial sprouting in vitro and in vivo, and impairs tumor growth and vascular density in treated animals.","method":"Pull-down assays, co-immunoprecipitation, spheroid sprouting assay, aortic ring assay, in vivo sponge assay, clec14a knockout mice, antibody blocking experiments, tumor growth assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus multiple functional assays in vitro and in vivo, including KO mice and antibody blocking; multiple orthogonal methods","pmids":["25745997"],"is_preprint":false},{"year":2017,"finding":"MMRN2 is a ligand for the group 14 C-type lectins CLEC14A, CD93, and CD248 (endosialin/TEM-1). Binding to MMRN2 depends on a predicted long-loop region in the C-type lectin domain and is abrogated by mutation within this domain. CLEC14A and CD93 both bind the same non-glycosylated coiled-coil region of MMRN2, while CD248 binds a distinct, non-competing region. CLEC14A and CD248 can bind MMRN2 simultaneously, spanning the endothelial-pericyte interface in human pancreatic cancer. A recombinant MMRN2 peptide spanning the CLEC14A/CD93 binding region blocks CLEC14A binding to the endothelial cell surface, increases cell adhesion, and is anti-angiogenic in vitro and in vivo.","method":"Direct binding assays, site-directed mutagenesis of C-type lectin domain, competitive binding assays, co-localization in tumor tissue, recombinant peptide functional assays, in vivo tumor growth assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis mapping of binding sites with multiple functional readouts in vitro and in vivo; multiple orthogonal methods","pmids":["28671670"],"is_preprint":false},{"year":2017,"finding":"MMRN2 was identified as a specific ligand for CD93 in endothelial cells. The CD93-MMRN2 interaction mediates endothelial cell adhesion and migration, and disruption of this interaction reduces both processes. Site-directed mutagenesis identified F238 of CD93 as a key residue for the interaction, with the coiled-coil domain of MMRN2 engaged by CD93. Both proteins are co-expressed in blood vessels of human tumors.","method":"Co-immunoprecipitation, site-directed mutagenesis, molecular docking, cell adhesion and migration assays, co-expression analysis in tumor vessels","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 1-2 — site-directed mutagenesis identifying key residues combined with functional cell assays; multiple orthogonal methods","pmids":["28912033"],"is_preprint":false},{"year":2018,"finding":"In endothelial cells, CD93 localizes to filopodia and promotes filopodia formation. The interaction of CD93 with MMRN2 stabilizes CD93 in filopodia by inhibiting its proteolytic cleavage. The CD93-MMRN2 complex is required for activation of β1 integrin, phosphorylation of focal adhesion kinase (FAK), and fibronectin fibrillogenesis. In CD93-deficient mice, tumor vessels show diminished β1 integrin activation and lack fibronectin fibrillar organization.","method":"Fluorescence microscopy, co-localization, proteolytic cleavage assays, β1 integrin activation assays, FAK phosphorylation assays, fibronectin fibrillogenesis assay, CD93-knockout mice, mouse retina imaging","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays plus in vivo genetic validation in KO mice; multiple orthogonal methods","pmids":["29763414"],"is_preprint":false},{"year":2019,"finding":"MMRN2 is required for vascular stability and permeability. RNAi knockdown of MMRN2 in endothelial cells causes cell-cell junctional instability and increased permeability through phosphorylation of VEGFR2 at Tyr951, activation of Src, and phosphorylation of VE-cadherin. Mmrn2-/- mice show endothelial junctional defects, impaired pericyte recruitment, and increased vascular leakage. Tumor vessels in Mmrn2-/- mice have increased collapsed vessels, reduced pericyte coverage, and are leakier, leading to increased tumor hypoxia and impaired chemotherapy efficacy.","method":"RNAi knockdown, permeability assays, VEGFR2/Src/VE-cadherin phosphorylation analysis, Mmrn2 knockout mouse generation, intravital imaging, pericyte recruitment assay, tumor xenograft models, chemotherapy efficacy assessment","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 2 — RNAi plus knockout mouse with defined molecular pathway (VEGFR2-Tyr951/Src/VE-cadherin) and multiple orthogonal functional readouts","pmids":["31422156"],"is_preprint":false},{"year":2019,"finding":"CD93 is recycled to the endothelial cell surface via a Rab5c-dependent endosomal pathway. After endocytosis, CD93 forms a complex with MMRN2 and active β1 integrin in the Rab5c endosomal compartment, and this complex is recycled back to the basolaterally-polarized cell surface by clathrin-independent endocytosis. The cytoplasmic domain of CD93 interacts with Moesin and F-actin to facilitate retrieval during adhesion and migration.","method":"Fluorescence confocal microscopy, drug treatments, chimeric CD93 constructs (wild type and mutant), scratch migration assay, gene silencing (Rab5c), flow cytometry, co-localization studies","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 2 — complex identified in endosomal compartment with multiple functional readouts and gene silencing; multiple orthogonal methods","pmids":["31138217"],"is_preprint":false},{"year":2020,"finding":"MMRN2 acts as an extracellular ligand for CD93 on neural stem cells to trigger repression of astrogenesis. MMRN2 engagement of CD93 activates a phosphorylation cascade that stabilizes β-Catenin, which translocates to the nucleus to activate Zfp503 transcription. The transcriptional repressor ZFP503 then inhibits Gfap transcription by binding to the Gfap promoter with the assistance of Grg5, thereby suppressing astrocyte differentiation.","method":"Cd93 knockout mice, neural stem cell differentiation assays, phosphorylation cascade analysis, β-Catenin nuclear translocation assays, Zfp503 transcriptional activity assays, ChIP (Gfap promoter binding), behavioral testing (autism-like behaviors)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with defined molecular pathway from ligand-receptor interaction to nuclear transcriptional repression; multiple orthogonal methods","pmids":["32291340"],"is_preprint":false},{"year":2023,"finding":"miR-1910-5p directly targets the 3' UTR of MMRN2 mRNA to suppress its expression, causing extracellular junctional defects in endothelial cells and promoting vascular leakage and angiogenesis in corneal neovascularization. miR-1910-5p antagomir treatment increased MMRN2 levels and decreased vascular leakage and CNV in a murine alkali-burn model. This pathway is downstream of CXCR4 signaling.","method":"Luciferase reporter assay (3' UTR targeting), gene interference, cell migration/tube formation/aortic ring assays, miR-1910-5p antagomir in vivo, murine alkali-burn CNV model, Western blotting","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 1-2 — luciferase assay confirming direct 3' UTR targeting plus in vitro and in vivo functional validation with antagomir rescue","pmids":["37040097"],"is_preprint":false}],"current_model":"MMRN2 (Multimerin-2/EndoGlyx-1) is a pan-endothelial extracellular matrix glycoprotein with an EMI domain, coiled-coil region, and C1q-like domain that (1) sequesters VEGF-A (~50 nM affinity) to suppress VEGFR2 activation and angiogenic sprouting; (2) serves as a shared ligand for the C-type lectins CLEC14A, CD93, and CD248 via its coiled-coil domain, with the CD93-MMRN2 complex stabilizing CD93 in endothelial filopodia, activating β1 integrin and FAK, driving fibronectin fibrillogenesis, and being recycled as a complex via Rab5c-dependent endosomes; (3) maintains vascular barrier integrity by suppressing a VEGFR2-Tyr951/Src/VE-cadherin phosphorylation cascade; and (4) outside the vasculature, acts as a CD93 ligand on neural stem cells to activate a β-Catenin/ZFP503 pathway that represses astrogenesis, while its own expression is post-transcriptionally regulated by miR-1910-5p targeting its 3' UTR."},"narrative":{"teleology":[{"year":1994,"claim":"The initial identification of EndoGlyx-1 as a high-molecular-weight endothelial-specific surface glycoprotein complex established the existence of a previously unknown vascular-restricted molecule and set the stage for molecular cloning.","evidence":"Monoclonal antibody generation, immunochemical analysis, and immunohistochemistry on vascular endothelial cells and tissues","pmids":["7933987"],"confidence":"Medium","gaps":["Molecular identity and gene sequence unknown","Relationship of the four subunits (p110–p200) to a single gene product unresolved"]},{"year":2001,"claim":"Molecular cloning revealed EndoGlyx-1 to be a 949-amino-acid EMILIN-family protein (MMRN2) with an EMI domain, coiled-coil region, and C1q-like domain, resolving the molecular identity behind the endothelial glycoprotein complex and establishing its domain architecture.","evidence":"cDNA cloning from peptide sequences, bioinformatic domain analysis, and carbohydrate enzyme digestion of cell-surface-expressed subunits","pmids":["11559704"],"confidence":"High","gaps":["Functional role of individual domains uncharacterized","Biological ligands unknown"]},{"year":2002,"claim":"Demonstration that MMRN2 is a secreted, ECM-associated glycoprotein capable of homo- and heteromeric disulfide-bonded assembly clarified its extracellular oligomeric nature.","evidence":"Biochemical characterization including disulfide-bonding assays and developmental expression analysis","pmids":["12221002"],"confidence":"Medium","gaps":["Oligomeric stoichiometry not definitively resolved","ECM binding partners unidentified"]},{"year":2011,"claim":"The discovery that MMRN2 directly binds VEGF-A with ~50 nM affinity and thereby blocks VEGFR1/VEGFR2 signaling established MMRN2 as an endogenous anti-angiogenic factor, answering the long-standing question of its biological function.","evidence":"Direct binding affinity measurements, VEGFR phosphorylation assays, endothelial migration and tube formation assays, in vivo tumor xenograft and adenoviral delivery experiments","pmids":["22020326"],"confidence":"High","gaps":["Domain(s) of MMRN2 mediating VEGF-A binding not mapped","Relative contribution of VEGF sequestration versus receptor-mediated functions unclear"]},{"year":2013,"claim":"Quantitative proteomics during endothelial morphogenesis identified CLEC14A as an MMRN2 binding partner in the ECM, revealing a receptor-ligand axis relevant to tumor angiogenesis beyond the VEGF-sequestration mechanism.","evidence":"SILAC quantitative proteomics, ECM protein profiling during tube formation, validation in multistage carcinogenesis models","pmids":["23979707"],"confidence":"Medium","gaps":["Binding domain on MMRN2 not mapped","Functional consequences of CLEC14A–MMRN2 interaction not yet tested by loss-of-function"]},{"year":2015,"claim":"Validation that CLEC14A physically engages MMRN2 via its extracellular region and that blocking this interaction with a monoclonal antibody inhibits sprouting angiogenesis and tumor growth demonstrated the functional significance of the CLEC14A–MMRN2 axis in vivo.","evidence":"Reciprocal co-IP, pull-down, spheroid sprouting, aortic ring assay, in vivo sponge assay, Clec14a-KO mice, antibody blocking in tumor models","pmids":["25745997"],"confidence":"High","gaps":["Specific MMRN2 domain required for CLEC14A binding not yet identified","Downstream signaling from CLEC14A upon MMRN2 engagement uncharacterized"]},{"year":2017,"claim":"Mapping of MMRN2 as a shared ligand for three group 14 C-type lectins—CLEC14A, CD93, and CD248—via its coiled-coil domain (CLEC14A/CD93) and a distinct region (CD248), with mutagenesis of the lectin-domain long-loop region abolishing binding, resolved the multi-receptor logic and molecular geometry of the MMRN2 interactome.","evidence":"Direct binding assays, site-directed mutagenesis of C-type lectin domains, competitive binding, co-localization in pancreatic cancer tissue, recombinant peptide blocking experiments in vitro and in vivo","pmids":["28671670","28912033"],"confidence":"High","gaps":["Structural basis at atomic resolution lacking","Whether CD248–MMRN2 and CLEC14A/CD93–MMRN2 axes serve redundant or distinct functions in vivo unclear"]},{"year":2018,"claim":"The discovery that the CD93–MMRN2 complex stabilizes CD93 in filopodia, activates β1 integrin and FAK, and drives fibronectin fibrillogenesis—with in vivo validation in CD93-knockout mice—defined the downstream mechanotransduction pathway linking MMRN2 to ECM assembly.","evidence":"Fluorescence microscopy, proteolytic cleavage assays, β1 integrin activation and FAK phosphorylation assays, fibronectin fibrillogenesis assay, CD93-KO mice, retinal vessel imaging","pmids":["29763414"],"confidence":"High","gaps":["Mechanism by which MMRN2 protects CD93 from cleavage not defined at the molecular level","Whether FAK activation is the principal effector or one of several downstream pathways unknown"]},{"year":2019,"claim":"Demonstration that MMRN2 loss de-represses VEGFR2-Tyr951/Src/VE-cadherin phosphorylation, causing junctional instability and vascular leakage—validated in Mmrn2-knockout mice showing collapsed tumor vessels and impaired drug delivery—established MMRN2 as a non-redundant vascular barrier gatekeeper and uncovered a separate CD93–MMRN2–β1-integrin endosomal recycling circuit via Rab5c.","evidence":"MMRN2 RNAi, permeability assays, VEGFR2/Src/VE-cadherin phosphorylation, Mmrn2-KO mice, intravital imaging, tumor xenografts; separately, confocal microscopy, Rab5c silencing, chimeric CD93 constructs, flow cytometry","pmids":["31422156","31138217"],"confidence":"High","gaps":["Whether VEGF-A sequestration and junctional VEGFR2 suppression are mechanistically coupled or independent functions of MMRN2 is unresolved","Rab5c-dependent recycling characterized only in cultured endothelial cells"]},{"year":2020,"claim":"Extension of the CD93–MMRN2 axis to neural stem cells revealed a non-vascular function: MMRN2 engagement of CD93 activates β-Catenin, which induces ZFP503-mediated repression of GFAP to suppress astrogenesis, broadening MMRN2 biology beyond the endothelium.","evidence":"Cd93-KO mice, neural stem cell differentiation assays, β-Catenin nuclear translocation, ChIP on Gfap promoter, behavioral testing","pmids":["32291340"],"confidence":"High","gaps":["Whether MMRN2 is expressed by neural cells or supplied extrinsically not fully delineated","Relevance to human neurodevelopmental conditions not established"]},{"year":2023,"claim":"Identification of miR-1910-5p as a direct post-transcriptional repressor of MMRN2 via its 3' UTR, downstream of CXCR4 signaling, revealed a regulatory input controlling MMRN2 levels and vascular barrier function in corneal neovascularization.","evidence":"Luciferase 3' UTR reporter, antagomir rescue in murine alkali-burn corneal neovascularization model, Western blotting, cell migration and tube formation assays","pmids":["37040097"],"confidence":"High","gaps":["Additional miRNAs or transcription factors controlling MMRN2 expression not explored","Whether CXCR4–miR-1910-5p–MMRN2 axis operates in tumor vasculature unknown"]},{"year":null,"claim":"Key open questions include: (1) which MMRN2 domain mediates VEGF-A binding and whether VEGF sequestration and junctional barrier functions are mechanistically separable; (2) the atomic-resolution structure of MMRN2 and its receptor complexes; and (3) the in vivo significance of the CD248–MMRN2 interaction at the pericyte–endothelial interface.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure for MMRN2 or its complexes","Relative contributions of VEGF-sequestration versus receptor-engagement pathways not dissected genetically","CD248–MMRN2 axis lacks in vivo loss-of-function validation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,7,8,9,12]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[8,9]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,10,12]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12]}],"complexes":["CD93–MMRN2–β1-integrin complex"],"partners":["CD93","CLEC14A","CD248","VEGFA","ITGB1","RAB5C"],"other_free_text":[]},"mechanistic_narrative":"MMRN2 (Multimerin-2) is a pan-endothelial extracellular matrix glycoprotein that orchestrates vascular morphogenesis, stability, and angiogenic signaling through its roles as both a VEGF-A sequestrant and a shared ligand for the group 14 C-type lectins CD93, CLEC14A, and CD248. MMRN2 directly binds VEGF-A (~50 nM Kd), blocking VEGFR1/VEGFR2 activation and suppressing endothelial migration, sprouting angiogenesis, and tumor vascularization [PMID:22020326]; loss of MMRN2 derepresses a VEGFR2-Tyr951/Src/VE-cadherin phosphorylation cascade that destabilizes endothelial junctions, increases vascular permeability, and impairs pericyte recruitment, as demonstrated in Mmrn2-knockout mice [PMID:31422156]. Through its coiled-coil domain, MMRN2 engages CD93 and CLEC14A on endothelial cells, stabilizing CD93 in filopodia and driving β1 integrin activation, FAK phosphorylation, and fibronectin fibrillogenesis; the CD93–MMRN2–β1-integrin complex is recycled via Rab5c-dependent endosomes [PMID:29763414, PMID:31138217, PMID:28671670]. Beyond the vasculature, MMRN2 acts as a CD93 ligand on neural stem cells to activate a β-Catenin/ZFP503 pathway that represses GFAP transcription and suppresses astrogenesis [PMID:32291340]."},"prefetch_data":{"uniprot":{"accession":"Q9H8L6","full_name":"Multimerin-2","aliases":["EMILIN-3","Elastin microfibril interface located protein 3","Elastin microfibril interfacer 3","EndoGlyx-1 p125/p140 subunit"],"length_aa":949,"mass_kda":104.4,"function":"Extracellular matrix protein that plays significant roles in the vascular system and is required for the maintenance and stability of blood vessel (PubMed:28435016). Affects several essential steps in angiogenesis including endothelial cell proliferation, migration, and tube formation. Positively regulates angiogenesis by acting as a ligand for CD93 receptor (PubMed:28671670, PubMed:28912033)","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q9H8L6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MMRN2","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/MMRN2","total_profiled":1310},"omim":[{"mim_id":"616845","title":"C-TYPE LECTIN DOMAIN FAMILY 14, MEMBER A; CLEC14A","url":"https://www.omim.org/entry/616845"},{"mim_id":"608925","title":"MULTIMERIN 2; MMRN2","url":"https://www.omim.org/entry/608925"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MMRN2"},"hgnc":{"alias_symbol":["EndoGlyx-1","FLJ13465"],"prev_symbol":["EMILIN3"]},"alphafold":{"accession":"Q9H8L6","domains":[{"cath_id":"-","chopping":"57-85_97-134","consensus_level":"medium","plddt":73.644,"start":57,"end":134},{"cath_id":"2.60.120.40","chopping":"828-949","consensus_level":"high","plddt":81.822,"start":828,"end":949},{"cath_id":"1.20.5","chopping":"234-279","consensus_level":"medium","plddt":81.1878,"start":234,"end":279}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8L6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8L6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8L6-F1-predicted_aligned_error_v6.png","plddt_mean":65.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MMRN2","jax_strain_url":"https://www.jax.org/strain/search?query=MMRN2"},"sequence":{"accession":"Q9H8L6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H8L6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H8L6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8L6"}},"corpus_meta":[{"pmid":"11559704","id":"PMC_11559704","title":"Molecular cloning and characterization of EndoGlyx-1, an EMILIN-like multisubunit glycoprotein of vascular endothelium.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11559704","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25745997","id":"PMC_25745997","title":"Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/25745997","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22334695","id":"PMC_22334695","title":"EMILIN-3, peculiar member of elastin microfibril interface-located protein (EMILIN) family, has distinct expression pattern, forms oligomeric assemblies, and serves as transforming growth factor β (TGF-β) antagonist.","date":"2012","source":"The Journal of biological 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glycoprotein, endoGlyx-1, in normal and tumor blood vessels.","date":"1994","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/7933987","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38270289","id":"PMC_38270289","title":"Ultrasound Imaging of Tumor Vascular CD93 with MMRN2 Modified Microbubbles for Immune Microenvironment Prediction.","date":"2024","source":"Advanced materials (Deerfield Beach, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/38270289","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37660019","id":"PMC_37660019","title":"Angiogenesis modulated by CD93 and its natural ligands IGFBP7 and MMRN2: a new target to facilitate solid tumor therapy by vasculature normalization.","date":"2023","source":"Cancer cell 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pathway.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22020326","citation_count":77,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33111431","id":"PMC_33111431","title":"N-Terminomics for the Identification of In Vitro Substrates and Cleavage Site Specificity of the SARS-CoV-2 Main Protease.","date":"2020","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/33111431","citation_count":70,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28671670","id":"PMC_28671670","title":"Multimerin-2 is a ligand for group 14 family C-type lectins CLEC14A, CD93 and CD248 spanning the endothelial pericyte interface.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28671670","citation_count":68,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28912033","id":"PMC_28912033","title":"Dissecting the CD93-Multimerin 2 interaction involved in cell adhesion and migration of the activated endothelium.","date":"2017","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/28912033","citation_count":66,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23979707","id":"PMC_23979707","title":"SILAC-based proteomics of human primary endothelial cell morphogenesis unveils tumor angiogenic markers.","date":"2013","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/23979707","citation_count":57,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16420310","id":"PMC_16420310","title":"Expression of stromal cell markers in distinct compartments of human skin cancers.","date":"2006","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16420310","citation_count":55,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18327805","id":"PMC_18327805","title":"N-glycoprotein profiling of lung adenocarcinoma pleural effusions by shotgun 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migration.","date":"2019","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/31138217","citation_count":35,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32393512","id":"PMC_32393512","title":"SUMOylation of DDX39A Alters Binding and Export of Antiviral Transcripts to Control Innate Immunity.","date":"2020","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/32393512","citation_count":27,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30544909","id":"PMC_30544909","title":"Loss of Multimerin-2 and EMILIN-2 Expression in Gastric Cancer Associate with Altered Angiogenesis.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30544909","citation_count":24,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"37249651","id":"PMC_37249651","title":"TRIM21 ameliorates hepatic glucose and lipid metabolic disorders in type 2 diabetes mellitus by ubiquitination of PEPCK1 and FASN.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/37249651","citation_count":17,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22532453","id":"PMC_22532453","title":"Identification of ovarian cancer-associated proteins in symptomatic women: A novel method for semi-quantitative plasma proteomics.","date":"2012","source":"Proteomics. Clinical applications","url":"https://pubmed.ncbi.nlm.nih.gov/22532453","citation_count":16,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7032,"output_tokens":1526,"usd":0.021993},"stage2":{"model":"claude-opus-4-6","input_tokens":4768,"output_tokens":1948,"usd":0.10881},"total_usd":0.389685,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":20328,"output_tokens":5336,"usd":0.070512},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7851,"output_tokens":3453,"usd":0.18837}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"MMRN2 (EndoGlyx-1) is a pan-endothelial cell surface glycoprotein complex of ~500 kDa composed of four disulfide-bonded subunits (p110, p125, p140, p200) encoded by a single cDNA. The protein contains an N-terminal EMI domain, a central coiled-coil-rich region, and a C-terminal C1q-like domain, and all four subunits are exposed on the cell surface with N-linked and O-linked carbohydrates.\",\n      \"method\": \"Protein purification, peptide sequencing, cDNA cloning, bioinformatics domain analysis, enzyme digestion for carbohydrate characterization, cell surface biochemical analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution-level biochemical characterization with multiple orthogonal methods in a single study\",\n      \"pmids\": [\"11559704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MMRN2 binds to the extracellular region of CLEC14A on endothelial cells, and this interaction is required for sprouting angiogenesis; blocking the CLEC14A-MMRN2 interaction with a monoclonal antibody (clone C4) perturbs tube formation, endothelial sprouting in vitro and in vivo, and impairs tumour growth and vascular density.\",\n      \"method\": \"Pull-down, co-immunoprecipitation, HUVEC spheroid sprouting assay, aortic ring assay, in vivo subcutaneous sponge assay, clec14a knockout mice, antibody blocking experiments, tumour growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus multiple functional assays in vitro and in vivo, with genetic and antibody-based loss-of-function\",\n      \"pmids\": [\"25745997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MMRN2 acts as an extracellular ligand for CD93 on neural stem cells in the developing mouse cerebral cortex; MMRN2-CD93 signaling activates a phosphorylation cascade leading to β-Catenin nuclear translocation, which drives transcription of Zfp503; ZFP503 then represses Gfap transcription (with assistance from Grg5), thereby inhibiting astrogenesis.\",\n      \"method\": \"Cd93 knockout mice, cortical neural stem cell differentiation assays, co-immunoprecipitation/signaling cascade analysis, ChIP/promoter binding assays, transcriptional reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with defined molecular pathway (MMRN2→CD93→β-Catenin→ZFP503→Gfap) validated by multiple orthogonal methods\",\n      \"pmids\": [\"32291340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-1910-5p suppresses MMRN2 expression by targeting its 3' untranslated region, causing extracellular junctional defects in endothelial cells and increased vascular permeability; restoration of MMRN2 levels (via miR-1910-5p antagomir) decreases vascular leakage and inhibits corneal neovascularization in vivo.\",\n      \"method\": \"Luciferase 3'UTR reporter assay, gene interference (siRNA), cell migration assay, tube formation assay, aortic ring assay, in vivo alkali-burn murine model, Western blotting\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase assay confirms direct miRNA targeting, functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"37040097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"EndoGlyx-1 (MMRN2) is a high molecular weight glycoprotein complex on the endothelial cell surface, restricted to vascular endothelium (absent from non-endothelial cell types and hepatic/splenic sinusoids), composed of disulfide-bonded subunits of 190, 140, 125, and 110 kDa.\",\n      \"method\": \"Monoclonal antibody (mAbH572) characterization, immunoprecipitation from endothelial cell extracts, immunohistochemistry on normal and tumor tissues\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical characterization of cell surface complex with antibody, fractionation, and broad tissue panel; predates molecular cloning\",\n      \"pmids\": [\"7933987\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MMRN2 is a pan-endothelial extracellular matrix glycoprotein (with EMI, coiled-coil, and C1q-like domains) that functions as a cell-surface ligand: it binds CLEC14A on endothelial cells to drive sprouting angiogenesis, and binds CD93 on neural stem cells to activate a β-Catenin/ZFP503 signaling cascade that represses astrogenesis; MMRN2 levels are post-transcriptionally regulated by miR-1910-5p, and loss of MMRN2 causes endothelial junctional defects and increased vascular permeability.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEEP papers.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:11559704 — KEEP (original characterization of EndoGlyx-1/MMRN2)\n2. PMID:25745997 — KEEP (CLEC14A-MMRN2 interaction, angiogenesis)\n3. PMID:22334695 — EXCLUDE (EMILIN-3, not MMRN2)\n4. PMID:24131633 — EXCLUDE (Emilin3/zebrafish, not MMRN2)\n5. PMID:32291340 — KEEP (MMRN2-CD93 signaling in astrogenesis)\n6. PMID:7933987 — KEEP (EndoGlyx-1 characterization)\n7. PMID:38270289 — KEEP (MMRN2-CD93 interaction used for imaging)\n8. PMID:37660019 — KEEP (review of CD93/MMRN2/IGFBP7 in angiogenesis)\n9. PMID:27892605 — EXCLUDE (EMILIN3, not MMRN2)\n10. PMID:37040097 — KEEP (miR-1910-5p targets MMRN2, vascular permeability)\n11. PMID:38952353 — EXCLUDE (EMILIN3, not MMRN2)\n\nGene2pubmed papers:\n- PMID:12477932 — EXCLUDE (cDNA collection, no MMRN2 mechanism)\n- PMID:32296183 — EXCLUDE (interactome map, no MMRN2 mechanism)\n- PMID:14702039 — EXCLUDE (cDNA collection)\n- PMID:21873635 — EXCLUDE (GO annotation)\n- PMID:19056867 — EXCLUDE (proteomics, no mechanism)\n- PMID:15489334 — EXCLUDE (MGC cDNA)\n- PMID:8889548 — EXCLUDE (cDNA library methods)\n- PMID:16335952 — EXCLUDE (plasma proteomics)\n- PMID:21988832 — EXCLUDE (liver interactome, no MMRN2 mechanism)\n- PMID:28675934 — EXCLUDE (ECM proteomics)\n- PMID:33111431 — EXCLUDE (SARS-CoV-2 protease substrates, no MMRN2 mechanism)\n- PMID:23533145 — EXCLUDE (proteomics)\n- PMID:23376485 — EXCLUDE (proteomics)\n- PMID:29763414 — KEEP (CD93-MMRN2 complex, β1 integrin, FAK, fibronectin)\n- PMID:22566882 — KEEP (EMILIN/Multimerin family review with mechanistic content)\n- PMID:22020326 — KEEP (MMRN2 binds VEGF-A, inhibits VEGFR2, anti-angiogenic)\n- PMID:32393512 — EXCLUDE (DDX39A/SUMOylation, not MMRN2)\n- PMID:30544909 — EXCLUDE (expression/IHC study)\n- PMID:37249651 — EXCLUDE (TRIM21, not MMRN2)\n- PMID:28671670 — KEEP (MMRN2 binds CLEC14A, CD93, CD248; mapping binding regions)\n- PMID:28912033 — KEEP (CD93-MMRN2 interaction dissection, mutagenesis)\n- PMID:23979707 — KEEP (CLEC14A binds MMRN2 in endothelial proteomics)\n- PMID:31422156 — KEEP (MMRN2 KO mice, vascular stability, VEGFR2-Src-VE-cadherin)\n- PMID:31138217 — KEEP (CD93/MMRN2/β1 integrin complex trafficking via Rab5c)\n- PMID:12221002 — KEEP (Multimerin2 family characterization, disulfide bonding)\n- PMID:16420310 — EXCLUDE (IHC expression)\n- PMID:22532453 — EXCLUDE (biomarker discovery)\n- PMID:18327805 — EXCLUDE (proteomics)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"EndoGlyx-1 (later identified as MMRN2) was characterized as a high molecular weight (~500 kDa) glycoprotein complex on the surface of vascular endothelial cells, composed of four disulfide-bonded subunits of apparent molecular weight 190, 140, 125, and 110 kDa. It is expressed exclusively on endothelial cells of normal and tumor blood vessels, with no expression in non-endothelial cell types.\",\n      \"method\": \"Monoclonal antibody generation, immunochemical analysis of endothelial cell extracts, immunohistochemistry\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical fractionation and immunochemical characterization; single lab\",\n      \"pmids\": [\"7933987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"EndoGlyx-1/MMRN2 was molecularly cloned and characterized as an EMILIN-like protein of 949 amino acids (~105 kDa) with an N-terminal EMI domain, a central coiled-coil-rich region, and a C-terminal C1q-like domain. The four subunits (p110, p125, p140, p200) are all cell-surface exposed and share similar patterns of N-linked and O-linked carbohydrates as shown by enzyme digestion.\",\n      \"method\": \"Peptide purification, cDNA cloning, bioinformatic domain analysis, enzyme digestion of carbohydrates, cell surface expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — molecular cloning with biochemical validation of domain structure and glycosylation; multiple orthogonal methods\",\n      \"pmids\": [\"11559704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Multimerin-2 (MMRN2) is a secreted glycoprotein of the EMI domain family capable of forming homo- and heteromers via disulfide bonding, and is attached to the extracellular matrix. Its structural organization includes an N-terminal EMI domain, an interrupted collagen stretch, and a conserved C-terminal domain.\",\n      \"method\": \"Developmental expression analysis, biochemical characterization, disulfide bonding assays\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — biochemical characterization of oligomerization; single lab\",\n      \"pmids\": [\"12221002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MMRN2 directly binds VEGF-A with an affinity of ~50 nM (Kd), thereby sequestering VEGF-A and impairing its binding to VEGFR1 and VEGFR2, leading to inhibition of endothelial cell migration, vessel network organization, and tumor growth in vivo. MMRN2 overexpression in tumor cells impaired tumor vascularization, and adenoviral delivery of MMRN2 to established tumors similarly reduced growth.\",\n      \"method\": \"Multiple binding assays (affinity measurement), VEGFR phosphorylation assays, endothelial migration and tube formation assays, in vivo tumor xenograft models, adenoviral construct delivery\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding affinity measurement plus multiple functional assays in vitro and in vivo; multiple orthogonal methods in single study\",\n      \"pmids\": [\"22020326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MMRN2 (Multimerin-2) is a homotrimeric glycoprotein that assembles into high molecular weight multimers, functions through its gC1q domain, and contributes to vascular biology including pro-angiogenic functions and potential roles in hemostasis. The gC1q domain mediates ligand-receptor interactions.\",\n      \"method\": \"Biochemical analysis, structural studies of family members, review with mechanistic synthesis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review synthesizing biochemical data; mechanistic aspects supported by experimental data from multiple labs\",\n      \"pmids\": [\"22566882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CLEC14A was identified as a matrix component that binds to MMRN2 in endothelial cells undergoing morphogenesis. This interaction was detected by quantitative proteomics during endothelial cell tube formation on matrigel, and deregulated levels of both proteins were verified during tumor angiogenesis in multistage carcinogenesis models.\",\n      \"method\": \"SILAC quantitative proteomics, extracellular matrix protein profiling, in vitro morphogenesis assay\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — proteomics-based identification of interaction confirmed in tumor angiogenesis models; single study\",\n      \"pmids\": [\"23979707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MMRN2 binds to the extracellular region of CLEC14A (confirmed by pull-down and co-immunoprecipitation), and this interaction is required for sprouting angiogenesis. A monoclonal antibody (clone C4) that blocks CLEC14A-MMRN2 binding inhibits tube formation, endothelial sprouting in vitro and in vivo, and impairs tumor growth and vascular density in treated animals.\",\n      \"method\": \"Pull-down assays, co-immunoprecipitation, spheroid sprouting assay, aortic ring assay, in vivo sponge assay, clec14a knockout mice, antibody blocking experiments, tumor growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus multiple functional assays in vitro and in vivo, including KO mice and antibody blocking; multiple orthogonal methods\",\n      \"pmids\": [\"25745997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MMRN2 is a ligand for the group 14 C-type lectins CLEC14A, CD93, and CD248 (endosialin/TEM-1). Binding to MMRN2 depends on a predicted long-loop region in the C-type lectin domain and is abrogated by mutation within this domain. CLEC14A and CD93 both bind the same non-glycosylated coiled-coil region of MMRN2, while CD248 binds a distinct, non-competing region. CLEC14A and CD248 can bind MMRN2 simultaneously, spanning the endothelial-pericyte interface in human pancreatic cancer. A recombinant MMRN2 peptide spanning the CLEC14A/CD93 binding region blocks CLEC14A binding to the endothelial cell surface, increases cell adhesion, and is anti-angiogenic in vitro and in vivo.\",\n      \"method\": \"Direct binding assays, site-directed mutagenesis of C-type lectin domain, competitive binding assays, co-localization in tumor tissue, recombinant peptide functional assays, in vivo tumor growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis mapping of binding sites with multiple functional readouts in vitro and in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"28671670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MMRN2 was identified as a specific ligand for CD93 in endothelial cells. The CD93-MMRN2 interaction mediates endothelial cell adhesion and migration, and disruption of this interaction reduces both processes. Site-directed mutagenesis identified F238 of CD93 as a key residue for the interaction, with the coiled-coil domain of MMRN2 engaged by CD93. Both proteins are co-expressed in blood vessels of human tumors.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, molecular docking, cell adhesion and migration assays, co-expression analysis in tumor vessels\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-directed mutagenesis identifying key residues combined with functional cell assays; multiple orthogonal methods\",\n      \"pmids\": [\"28912033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In endothelial cells, CD93 localizes to filopodia and promotes filopodia formation. The interaction of CD93 with MMRN2 stabilizes CD93 in filopodia by inhibiting its proteolytic cleavage. The CD93-MMRN2 complex is required for activation of β1 integrin, phosphorylation of focal adhesion kinase (FAK), and fibronectin fibrillogenesis. In CD93-deficient mice, tumor vessels show diminished β1 integrin activation and lack fibronectin fibrillar organization.\",\n      \"method\": \"Fluorescence microscopy, co-localization, proteolytic cleavage assays, β1 integrin activation assays, FAK phosphorylation assays, fibronectin fibrillogenesis assay, CD93-knockout mice, mouse retina imaging\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays plus in vivo genetic validation in KO mice; multiple orthogonal methods\",\n      \"pmids\": [\"29763414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MMRN2 is required for vascular stability and permeability. RNAi knockdown of MMRN2 in endothelial cells causes cell-cell junctional instability and increased permeability through phosphorylation of VEGFR2 at Tyr951, activation of Src, and phosphorylation of VE-cadherin. Mmrn2-/- mice show endothelial junctional defects, impaired pericyte recruitment, and increased vascular leakage. Tumor vessels in Mmrn2-/- mice have increased collapsed vessels, reduced pericyte coverage, and are leakier, leading to increased tumor hypoxia and impaired chemotherapy efficacy.\",\n      \"method\": \"RNAi knockdown, permeability assays, VEGFR2/Src/VE-cadherin phosphorylation analysis, Mmrn2 knockout mouse generation, intravital imaging, pericyte recruitment assay, tumor xenograft models, chemotherapy efficacy assessment\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi plus knockout mouse with defined molecular pathway (VEGFR2-Tyr951/Src/VE-cadherin) and multiple orthogonal functional readouts\",\n      \"pmids\": [\"31422156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD93 is recycled to the endothelial cell surface via a Rab5c-dependent endosomal pathway. After endocytosis, CD93 forms a complex with MMRN2 and active β1 integrin in the Rab5c endosomal compartment, and this complex is recycled back to the basolaterally-polarized cell surface by clathrin-independent endocytosis. The cytoplasmic domain of CD93 interacts with Moesin and F-actin to facilitate retrieval during adhesion and migration.\",\n      \"method\": \"Fluorescence confocal microscopy, drug treatments, chimeric CD93 constructs (wild type and mutant), scratch migration assay, gene silencing (Rab5c), flow cytometry, co-localization studies\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — complex identified in endosomal compartment with multiple functional readouts and gene silencing; multiple orthogonal methods\",\n      \"pmids\": [\"31138217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MMRN2 acts as an extracellular ligand for CD93 on neural stem cells to trigger repression of astrogenesis. MMRN2 engagement of CD93 activates a phosphorylation cascade that stabilizes β-Catenin, which translocates to the nucleus to activate Zfp503 transcription. The transcriptional repressor ZFP503 then inhibits Gfap transcription by binding to the Gfap promoter with the assistance of Grg5, thereby suppressing astrocyte differentiation.\",\n      \"method\": \"Cd93 knockout mice, neural stem cell differentiation assays, phosphorylation cascade analysis, β-Catenin nuclear translocation assays, Zfp503 transcriptional activity assays, ChIP (Gfap promoter binding), behavioral testing (autism-like behaviors)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined molecular pathway from ligand-receptor interaction to nuclear transcriptional repression; multiple orthogonal methods\",\n      \"pmids\": [\"32291340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-1910-5p directly targets the 3' UTR of MMRN2 mRNA to suppress its expression, causing extracellular junctional defects in endothelial cells and promoting vascular leakage and angiogenesis in corneal neovascularization. miR-1910-5p antagomir treatment increased MMRN2 levels and decreased vascular leakage and CNV in a murine alkali-burn model. This pathway is downstream of CXCR4 signaling.\",\n      \"method\": \"Luciferase reporter assay (3' UTR targeting), gene interference, cell migration/tube formation/aortic ring assays, miR-1910-5p antagomir in vivo, murine alkali-burn CNV model, Western blotting\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — luciferase assay confirming direct 3' UTR targeting plus in vitro and in vivo functional validation with antagomir rescue\",\n      \"pmids\": [\"37040097\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MMRN2 (Multimerin-2/EndoGlyx-1) is a pan-endothelial extracellular matrix glycoprotein with an EMI domain, coiled-coil region, and C1q-like domain that (1) sequesters VEGF-A (~50 nM affinity) to suppress VEGFR2 activation and angiogenic sprouting; (2) serves as a shared ligand for the C-type lectins CLEC14A, CD93, and CD248 via its coiled-coil domain, with the CD93-MMRN2 complex stabilizing CD93 in endothelial filopodia, activating β1 integrin and FAK, driving fibronectin fibrillogenesis, and being recycled as a complex via Rab5c-dependent endosomes; (3) maintains vascular barrier integrity by suppressing a VEGFR2-Tyr951/Src/VE-cadherin phosphorylation cascade; and (4) outside the vasculature, acts as a CD93 ligand on neural stem cells to activate a β-Catenin/ZFP503 pathway that represses astrogenesis, while its own expression is post-transcriptionally regulated by miR-1910-5p targeting its 3' UTR.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MMRN2 is a pan-endothelial extracellular matrix glycoprotein that regulates angiogenesis and cell fate decisions through receptor-mediated signaling on distinct cell types. The protein is a disulfide-bonded multimeric complex (~500 kDa) composed of four subunits containing an N-terminal EMI domain, a central coiled-coil region, and a C-terminal C1q-like domain, and it is displayed on the endothelial cell surface with extensive N- and O-linked glycosylation [PMID:11559704, PMID:7933987]. MMRN2 binds CLEC14A on endothelial cells to promote sprouting angiogenesis—blocking this interaction inhibits tube formation, endothelial sprouting, and tumor vascularization—and separately binds CD93 on cortical neural stem cells to activate a β-Catenin/ZFP503 cascade that represses GFAP transcription and inhibits astrogenesis [PMID:25745997, PMID:32291340]. MMRN2 expression is post-transcriptionally suppressed by miR-1910-5p, and its loss causes endothelial junctional defects and increased vascular permeability [PMID:37040097].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Before molecular cloning, the identity of MMRN2 (EndoGlyx-1) was unknown; antibody-based characterization established it as a high-molecular-weight, disulfide-bonded glycoprotein complex restricted to vascular endothelium, defining it as an endothelial-specific surface marker.\",\n      \"evidence\": \"Monoclonal antibody immunoprecipitation and immunohistochemistry across normal and tumor tissues\",\n      \"pmids\": [\"7933987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular identity and gene encoding the complex were not yet determined\",\n        \"Function of the glycoprotein was unknown\",\n        \"Predates cloning; subunit relationship (single gene vs. multi-gene) was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Cloning of the MMRN2 cDNA resolved the molecular basis of the EndoGlyx-1 complex, showing that all four subunits derive from a single gene product with EMI, coiled-coil, and C1q-like domains—placing it in the gC1q/EMILIN superfamily and enabling structure-function studies.\",\n      \"evidence\": \"Protein purification, peptide sequencing, cDNA cloning, domain analysis, and carbohydrate characterization from endothelial cells\",\n      \"pmids\": [\"11559704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biological function and interacting receptors remained unidentified\",\n        \"Mechanism of multisubunit processing from a single precursor was not defined\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The first functional receptor for MMRN2 was identified: CLEC14A on endothelial cells binds MMRN2, and this interaction is required for sprouting angiogenesis, establishing MMRN2 as a pro-angiogenic ligand with therapeutic relevance in tumor vascularization.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, HUVEC spheroid sprouting, aortic ring assay, in vivo sponge assay, Clec14a knockout mice, and anti-CLEC14A antibody blocking of tumor growth\",\n      \"pmids\": [\"25745997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream signaling events triggered by CLEC14A–MMRN2 interaction were not mapped\",\n        \"Whether MMRN2 signals through additional receptors was unknown\",\n        \"Structural basis of the CLEC14A–MMRN2 interaction was not determined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"MMRN2 was shown to function beyond the vasculature as a ligand for CD93 on neural stem cells, activating a β-Catenin→ZFP503 transcriptional cascade that represses astrogenesis—revealing a non-angiogenic developmental role and a second receptor system.\",\n      \"evidence\": \"Cd93 knockout mice, cortical neural stem cell differentiation assays, co-immunoprecipitation, ChIP, and transcriptional reporter assays\",\n      \"pmids\": [\"32291340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether MMRN2–CD93 signaling operates in adult neural niches was not tested\",\n        \"Relative contributions of MMRN2 versus other CD93 ligands in vivo are unclear\",\n        \"Structural determinants of MMRN2 binding to CD93 versus CLEC14A are undefined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A post-transcriptional regulatory mechanism was identified: miR-1910-5p directly targets the MMRN2 3′-UTR to suppress its expression, and reduced MMRN2 levels cause endothelial junctional disruption and vascular hyperpermeability, linking MMRN2 to barrier integrity.\",\n      \"evidence\": \"Luciferase 3′-UTR reporter assay, siRNA knockdown, tube formation, aortic ring assay, and alkali-burn corneal neovascularization model in mice\",\n      \"pmids\": [\"37040097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication is lacking\",\n        \"Whether MMRN2's barrier function requires CLEC14A, CD93, or another receptor is unknown\",\n        \"Physiological contexts regulating miR-1910-5p levels were not explored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of MMRN2 receptor selectivity (CLEC14A vs. CD93), the intracellular signaling pathway downstream of CLEC14A engagement, the protease(s) responsible for generating the four processed subunits from the single precursor, and whether MMRN2 contributes to vascular permeability through a defined junctional complex.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of MMRN2 or its receptor complexes exists\",\n        \"Signaling downstream of CLEC14A–MMRN2 has not been mapped\",\n        \"Mechanism of single-precursor cleavage into four subunits is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CLEC14A\",\n      \"CD93\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MMRN2 (Multimerin-2) is a pan-endothelial extracellular matrix glycoprotein that orchestrates vascular morphogenesis, stability, and angiogenic signaling through its roles as both a VEGF-A sequestrant and a shared ligand for the group 14 C-type lectins CD93, CLEC14A, and CD248. MMRN2 directly binds VEGF-A (~50 nM Kd), blocking VEGFR1/VEGFR2 activation and suppressing endothelial migration, sprouting angiogenesis, and tumor vascularization [PMID:22020326]; loss of MMRN2 derepresses a VEGFR2-Tyr951/Src/VE-cadherin phosphorylation cascade that destabilizes endothelial junctions, increases vascular permeability, and impairs pericyte recruitment, as demonstrated in Mmrn2-knockout mice [PMID:31422156]. Through its coiled-coil domain, MMRN2 engages CD93 and CLEC14A on endothelial cells, stabilizing CD93 in filopodia and driving β1 integrin activation, FAK phosphorylation, and fibronectin fibrillogenesis; the CD93–MMRN2–β1-integrin complex is recycled via Rab5c-dependent endosomes [PMID:29763414, PMID:31138217, PMID:28671670]. Beyond the vasculature, MMRN2 acts as a CD93 ligand on neural stem cells to activate a β-Catenin/ZFP503 pathway that represses GFAP transcription and suppresses astrogenesis [PMID:32291340].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"The initial identification of EndoGlyx-1 as a high-molecular-weight endothelial-specific surface glycoprotein complex established the existence of a previously unknown vascular-restricted molecule and set the stage for molecular cloning.\",\n      \"evidence\": \"Monoclonal antibody generation, immunochemical analysis, and immunohistochemistry on vascular endothelial cells and tissues\",\n      \"pmids\": [\"7933987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular identity and gene sequence unknown\", \"Relationship of the four subunits (p110–p200) to a single gene product unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Molecular cloning revealed EndoGlyx-1 to be a 949-amino-acid EMILIN-family protein (MMRN2) with an EMI domain, coiled-coil region, and C1q-like domain, resolving the molecular identity behind the endothelial glycoprotein complex and establishing its domain architecture.\",\n      \"evidence\": \"cDNA cloning from peptide sequences, bioinformatic domain analysis, and carbohydrate enzyme digestion of cell-surface-expressed subunits\",\n      \"pmids\": [\"11559704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of individual domains uncharacterized\", \"Biological ligands unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstration that MMRN2 is a secreted, ECM-associated glycoprotein capable of homo- and heteromeric disulfide-bonded assembly clarified its extracellular oligomeric nature.\",\n      \"evidence\": \"Biochemical characterization including disulfide-bonding assays and developmental expression analysis\",\n      \"pmids\": [\"12221002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oligomeric stoichiometry not definitively resolved\", \"ECM binding partners unidentified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The discovery that MMRN2 directly binds VEGF-A with ~50 nM affinity and thereby blocks VEGFR1/VEGFR2 signaling established MMRN2 as an endogenous anti-angiogenic factor, answering the long-standing question of its biological function.\",\n      \"evidence\": \"Direct binding affinity measurements, VEGFR phosphorylation assays, endothelial migration and tube formation assays, in vivo tumor xenograft and adenoviral delivery experiments\",\n      \"pmids\": [\"22020326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain(s) of MMRN2 mediating VEGF-A binding not mapped\", \"Relative contribution of VEGF sequestration versus receptor-mediated functions unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Quantitative proteomics during endothelial morphogenesis identified CLEC14A as an MMRN2 binding partner in the ECM, revealing a receptor-ligand axis relevant to tumor angiogenesis beyond the VEGF-sequestration mechanism.\",\n      \"evidence\": \"SILAC quantitative proteomics, ECM protein profiling during tube formation, validation in multistage carcinogenesis models\",\n      \"pmids\": [\"23979707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding domain on MMRN2 not mapped\", \"Functional consequences of CLEC14A–MMRN2 interaction not yet tested by loss-of-function\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Validation that CLEC14A physically engages MMRN2 via its extracellular region and that blocking this interaction with a monoclonal antibody inhibits sprouting angiogenesis and tumor growth demonstrated the functional significance of the CLEC14A–MMRN2 axis in vivo.\",\n      \"evidence\": \"Reciprocal co-IP, pull-down, spheroid sprouting, aortic ring assay, in vivo sponge assay, Clec14a-KO mice, antibody blocking in tumor models\",\n      \"pmids\": [\"25745997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific MMRN2 domain required for CLEC14A binding not yet identified\", \"Downstream signaling from CLEC14A upon MMRN2 engagement uncharacterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping of MMRN2 as a shared ligand for three group 14 C-type lectins—CLEC14A, CD93, and CD248—via its coiled-coil domain (CLEC14A/CD93) and a distinct region (CD248), with mutagenesis of the lectin-domain long-loop region abolishing binding, resolved the multi-receptor logic and molecular geometry of the MMRN2 interactome.\",\n      \"evidence\": \"Direct binding assays, site-directed mutagenesis of C-type lectin domains, competitive binding, co-localization in pancreatic cancer tissue, recombinant peptide blocking experiments in vitro and in vivo\",\n      \"pmids\": [\"28671670\", \"28912033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis at atomic resolution lacking\", \"Whether CD248–MMRN2 and CLEC14A/CD93–MMRN2 axes serve redundant or distinct functions in vivo unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The discovery that the CD93–MMRN2 complex stabilizes CD93 in filopodia, activates β1 integrin and FAK, and drives fibronectin fibrillogenesis—with in vivo validation in CD93-knockout mice—defined the downstream mechanotransduction pathway linking MMRN2 to ECM assembly.\",\n      \"evidence\": \"Fluorescence microscopy, proteolytic cleavage assays, β1 integrin activation and FAK phosphorylation assays, fibronectin fibrillogenesis assay, CD93-KO mice, retinal vessel imaging\",\n      \"pmids\": [\"29763414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which MMRN2 protects CD93 from cleavage not defined at the molecular level\", \"Whether FAK activation is the principal effector or one of several downstream pathways unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that MMRN2 loss de-represses VEGFR2-Tyr951/Src/VE-cadherin phosphorylation, causing junctional instability and vascular leakage—validated in Mmrn2-knockout mice showing collapsed tumor vessels and impaired drug delivery—established MMRN2 as a non-redundant vascular barrier gatekeeper and uncovered a separate CD93–MMRN2–β1-integrin endosomal recycling circuit via Rab5c.\",\n      \"evidence\": \"MMRN2 RNAi, permeability assays, VEGFR2/Src/VE-cadherin phosphorylation, Mmrn2-KO mice, intravital imaging, tumor xenografts; separately, confocal microscopy, Rab5c silencing, chimeric CD93 constructs, flow cytometry\",\n      \"pmids\": [\"31422156\", \"31138217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VEGF-A sequestration and junctional VEGFR2 suppression are mechanistically coupled or independent functions of MMRN2 is unresolved\", \"Rab5c-dependent recycling characterized only in cultured endothelial cells\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extension of the CD93–MMRN2 axis to neural stem cells revealed a non-vascular function: MMRN2 engagement of CD93 activates β-Catenin, which induces ZFP503-mediated repression of GFAP to suppress astrogenesis, broadening MMRN2 biology beyond the endothelium.\",\n      \"evidence\": \"Cd93-KO mice, neural stem cell differentiation assays, β-Catenin nuclear translocation, ChIP on Gfap promoter, behavioral testing\",\n      \"pmids\": [\"32291340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MMRN2 is expressed by neural cells or supplied extrinsically not fully delineated\", \"Relevance to human neurodevelopmental conditions not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of miR-1910-5p as a direct post-transcriptional repressor of MMRN2 via its 3' UTR, downstream of CXCR4 signaling, revealed a regulatory input controlling MMRN2 levels and vascular barrier function in corneal neovascularization.\",\n      \"evidence\": \"Luciferase 3' UTR reporter, antagomir rescue in murine alkali-burn corneal neovascularization model, Western blotting, cell migration and tube formation assays\",\n      \"pmids\": [\"37040097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Additional miRNAs or transcription factors controlling MMRN2 expression not explored\", \"Whether CXCR4–miR-1910-5p–MMRN2 axis operates in tumor vasculature unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: (1) which MMRN2 domain mediates VEGF-A binding and whether VEGF sequestration and junctional barrier functions are mechanistically separable; (2) the atomic-resolution structure of MMRN2 and its receptor complexes; and (3) the in vivo significance of the CD248–MMRN2 interaction at the pericyte–endothelial interface.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure for MMRN2 or its complexes\", \"Relative contributions of VEGF-sequestration versus receptor-engagement pathways not dissected genetically\", \"CD248–MMRN2 axis lacks in vivo loss-of-function validation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 7, 8, 9, 12]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 10, 12]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"CD93–MMRN2–β1-integrin complex\"\n    ],\n    \"partners\": [\n      \"CD93\",\n      \"CLEC14A\",\n      \"CD248\",\n      \"VEGFA\",\n      \"ITGB1\",\n      \"RAB5C\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}