{"gene":"MMRN2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"EndoGlyx-1 (MMRN2) was molecularly cloned and characterized as an EMILIN-like pan-endothelial glycoprotein complex (~500 kDa) composed of four disulfide-bonded subunits (p110, p125, p140, p200) encoded by a single 2847-bp ORF (949 aa). The protein contains an N-terminal EMI domain, a central coiled-coil region, and a C-terminal C1q-like domain, and all subunits are exposed on the cell surface with N-linked and O-linked carbohydrates.","method":"Protein purification, peptide analysis, cDNA cloning, bioinformatic domain analysis, enzyme digestion for glycan characterization, cell surface biochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct purification, sequencing, and biochemical characterization of the protein and its subunits with multiple orthogonal methods","pmids":["11559704"],"is_preprint":false},{"year":1994,"finding":"EndoGlyx-1 (MMRN2) is expressed exclusively on the surface of endothelial cells (not on non-endothelial cell types) as a high-molecular-weight glycoprotein complex with disulfide-bonded subunits of ~190, 140, 125, and 110 kDa, and its expression is not altered by cytokine stimulation.","method":"Monoclonal antibody (mAbH572) generation, immunochemical characterization of endothelial cell extracts, cell surface expression assays","journal":"Laboratory investigation; a journal of technical methods and pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal immunochemical characterization with defined reagents, single lab, multiple cell/tissue types tested","pmids":["7933987"],"is_preprint":false},{"year":2011,"finding":"MMRN2 directly binds VEGF-A with an affinity of Kd ~50 nM, thereby sequestering VEGF-A and impairing its engagement with VEGFR1 and VEGFR2, leading to impaired endothelial cell migration, defective vessel network formation, and reduced tumor growth in vivo.","method":"Multiple binding assays (affinity estimation), endothelial migration assays, tube formation assays, VEGFR phosphorylation assays, in vivo tumor xenograft with MMRN2 overexpression and adenoviral MMRN2 construct, immunostaining for VEGF-A co-localization","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding affinity measured, multiple orthogonal functional assays, in vitro and in vivo validation, single lab","pmids":["22020326"],"is_preprint":false},{"year":2015,"finding":"MMRN2 binds to the extracellular region of CLEC14A; blocking this CLEC14A-MMRN2 interaction with a monoclonal antibody (clone C4) perturbs tube formation, endothelial sprouting in vitro and in vivo, and impairs tumor growth and vascular density in mice.","method":"Pull-down, co-immunoprecipitation, monoclonal antibody blocking assays, HUVEC spheroid sprouting assay, aortic ring assay, in vivo subcutaneous sponge and tumor models in clec14a+/+ and clec14a-/- mice","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KO mouse model, multiple in vitro and in vivo functional assays, antibody-mediated blocking","pmids":["25745997"],"is_preprint":false},{"year":2017,"finding":"MMRN2 is a specific extracellular matrix ligand for the transmembrane receptor CD93; their interaction is required for endothelial cell adhesion and migration. The coiled-coil domain of MMRN2 engages F238 of CD93, identified by site-directed mutagenesis and molecular docking.","method":"Co-expression analysis, binding assays, endothelial adhesion and migration assays with disruption of the interaction, site-directed mutagenesis, molecular modeling and docking","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — site-directed mutagenesis identifying binding residues, functional adhesion/migration assays, structural modeling, single lab with multiple orthogonal methods","pmids":["28912033"],"is_preprint":false},{"year":2017,"finding":"CLEC14A, CD93, and CD248 all directly bind MMRN2. CLEC14A and CD93 bind the same non-glycosylated coiled-coil region of MMRN2, and this binding requires a predicted long-loop region in their C-type lectin domain. CD248 binds a distinct, non-competing region of MMRN2. CLEC14A and CD248 can simultaneously bind MMRN2, spanning the endothelial-pericyte interface in human pancreatic cancer.","method":"Direct binding assays, mutation of C-type lectin domain, competition binding assays, recombinant MMRN2 peptide blocking of CLEC14A binding, HUVEC adhesion assays, in vitro and in vivo anti-angiogenic assays with MMRN2 peptide","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding with mutagenesis, competition assays establishing distinct binding sites, in vitro functional validation, replicated across multiple receptor family members","pmids":["28671670"],"is_preprint":false},{"year":2017,"finding":"During angiogenic stimulation, MMRN2 mRNA levels decrease and the deposited MMRN2 protein is proteolytically processed by MMP-9 (and to a lesser degree MMP-2), and this cleavage correlates with increased endothelial cell migration and increased pseudopodial formation at the migrating front. MMP-9 inhibitors attenuate the MMRN2 down-modulation phenotype.","method":"MMP cleavage assays, qRT-PCR for MMRN2 mRNA, endothelial cell migration assays, MMP-9 inhibitor treatment, immunofluorescence co-localization of MMP-9 and MMRN2 in tumor sections","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protease cleavage assays combined with functional migration readouts and inhibitor rescue, single lab","pmids":["28435016"],"is_preprint":false},{"year":2018,"finding":"MMRN2 stabilizes CD93 localization to endothelial 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 endothelial cells. Loss of CD93 in vivo (CD93-deficient mice) results in diminished β1 integrin activation and loss of fibronectin fibrillar organization in tumor vessels.","method":"Immunofluorescence/live imaging of endothelial filopodia, CD93-MMRN2 interaction assays, β1 integrin activation assay, FAK phosphorylation assay, fibronectin fibrillogenesis assay, CD93-deficient mouse tumor implantation model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (interaction, signaling, in vivo KO mouse model), functional readouts at multiple levels, replicated in vitro and in vivo","pmids":["29763414"],"is_preprint":false},{"year":2019,"finding":"MMRN2 is required to maintain vascular stability and permeability. RNAi knockdown of MMRN2 in endothelial cells causes cell-cell junctional instability and increased permeability via phosphorylation of VEGFR2 at Tyr951, activation of Src, and phosphorylation of VE-cadherin. Mmrn2-/- mice show junctional defects, elevated VEGFR2 phospho-Tyr949, impaired pericyte recruitment, increased vascular leakage, and defective tumor vessel function with reduced chemotherapy delivery.","method":"RNAi knockdown, VEGFR2/Src/VE-cadherin phosphorylation assays, vascular permeability assays, generation and phenotypic analysis of Mmrn2-/- mice, tumor xenograft experiments, chemotherapy efficacy assays","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — KO mouse model plus in vitro mechanistic pathway dissection with phospho-specific readouts, multiple orthogonal methods","pmids":["31422156"],"is_preprint":false},{"year":2020,"finding":"In neural stem cells of the developing mouse cerebral cortex, MMRN2 signals through CD93 to repress astrogenesis; CD93 responds to extracellular MMRN2 by triggering phosphorylation cascades that activate β-Catenin, which then translocates to the nucleus to activate Zfp503 transcription. The transcriptional repressor ZFP503 in turn binds the Gfap promoter (with Grg5) to inhibit Gfap transcription, suppressing astrocyte differentiation.","method":"Cd93 knockout mice, MMRN2 treatment of neural stem cells, phosphorylation assays, β-Catenin nuclear translocation assays, Zfp503 promoter reporter, ChIP at Gfap promoter, astrogenesis quantification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with defined molecular pathway (MMRN2→CD93→β-Catenin→ZFP503→Gfap), multiple orthogonal methods, clear phenotypic readout","pmids":["32291340"],"is_preprint":false},{"year":2013,"finding":"CLEC14A binds to MMRN2 in the endothelial extracellular matrix, identified by SILAC-based quantitative proteomics of the endothelial cell secretome during morphogenesis.","method":"SILAC spike-in quantitative proteomics, identification of extracellular matrix components secreted by endothelial cells, protein interaction identified in secretome","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — proteomics-based interaction identification, single method but replicated by later direct binding studies","pmids":["23979707"],"is_preprint":false},{"year":2023,"finding":"miR-1910-5p directly targets the 3' UTR of MMRN2 mRNA to suppress MMRN2 expression, causing extracellular junctional defects in endothelial cells and increased vascular permeability; antagomir-mediated inhibition of miR-1910-5p increases MMRN2 levels and decreases vascular leakage in a murine corneal neovascularization model.","method":"Luciferase 3'UTR reporter assay, miR-1910-5p antagomir in vivo, MMRN2 protein quantification by Western blot, vascular permeability and tube formation assays","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validates direct miRNA-3'UTR interaction, in vivo rescue with antagomir, single lab","pmids":["37040097"],"is_preprint":false},{"year":2023,"finding":"CD93 interacts with MMRN2 and integrin β1 in breast cancer cells; knockdown of CD93 or MMRN2 inhibits integrin β1 activation, thereby suppressing the PI3K/AKT/SP2 signaling pathway and reducing cancer cell migration, invasion, and vasculogenic mimicry.","method":"Co-immunoprecipitation, siRNA knockdown of CD93 and MMRN2, integrin β1 activation assays, PI3K/AKT/SP2 phosphorylation assays, Transwell migration/invasion assays, vasculogenic mimicry assay, in vivo xenograft","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional pathway assays with siRNA, single lab, in vitro and in vivo","pmids":["38511888"],"is_preprint":false},{"year":2024,"finding":"In type-H capillary endothelial cells, the Clec14a-Mmrn2 interaction regulates osteoblast maturation and mineralisation; antibody-mediated blockade of the Clec14a-Mmrn2 interaction recapitulates the Clec14a-/- phenotype of accelerated skeletal development, expanded osteoblast distribution, increased bone density, and enhanced osteoblast maturation.","method":"Clec14a-/- mouse model, antibody-mediated blockade of Clec14a-Mmrn2 interaction, histological and bone density analysis, osteoblast maturation and mineralisation assays","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model plus antibody blockade of specific interaction recapitulates phenotype, single lab","pmids":["39394430"],"is_preprint":false},{"year":2023,"finding":"In systemic sclerosis, MMRN2 expression is increased in skin endothelial cells while CD248 (expressed on SSc fibroblasts) binds MMRN2 and prevents VEGFR2 phosphorylation after VEGF stimulation, contributing to anti-angiogenic activity and endothelial cell apoptosis.","method":"Immunofluorescence of SSc skin, HC-ECs/SSc-FBs co-culture organotypic model, lentiviral CD248 shRNA loss-of-function, VEGFR2 phosphorylation by Western blot, apoptosis assay by immunofluorescence","journal":"Rheumatology (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular readout (VEGFR2 phosphorylation), in vitro co-culture model, single lab","pmids":["35916713"],"is_preprint":false}],"current_model":"MMRN2 (EndoGlyx-1) is a pan-endothelial extracellular matrix glycoprotein with an EMI domain, coiled-coil region, and C1q-like domain that functions as an angiostatic regulator by (1) directly binding VEGF-A (Kd ~50 nM) to sequester it from VEGFR2 signaling, (2) serving as the extracellular ligand for the group 14 C-type lectins CLEC14A, CD93, and CD248, with the coiled-coil domain engaging CD93/CLEC14A and a distinct region binding CD248; (3) the CD93-MMRN2 complex stabilizes CD93 in filopodia, activates β1 integrin and FAK to drive fibronectin fibrillogenesis and vascular maturation; (4) maintaining vascular stability and barrier integrity by suppressing VEGFR2 Tyr951 phosphorylation, Src activation, and VE-cadherin phosphorylation; (5) being proteolytically processed by MMP-9 during angiogenic stimuli to relieve its angiostatic effect; and (6) signaling through CD93 in neural stem cells to activate a β-Catenin→ZFP503 pathway that represses astrogenesis."},"narrative":{"mechanistic_narrative":"MMRN2 (EndoGlyx-1) is a pan-endothelial cell-surface extracellular matrix glycoprotein that acts as an angiostatic regulator controlling vascular maturation, stability, and barrier integrity [PMID:11559704, PMID:7933987, PMID:31422156]. Structurally it is a ~500 kDa disulfide-bonded complex built from a single ORF encoding an N-terminal EMI domain, a central coiled-coil region, and a C-terminal C1q-like domain, with all subunits exposed on the endothelial surface [PMID:11559704]. It restrains angiogenesis by directly binding VEGF-A (Kd ~50 nM), sequestering it from VEGFR1/VEGFR2 and thereby impairing endothelial migration, vessel network formation, and tumor growth [PMID:22020326]. MMRN2 is the extracellular ligand for the group 14 C-type lectins CLEC14A, CD93, and CD248: its non-glycosylated coiled-coil region engages CLEC14A and CD93 (via CD93 residue F238), while CD248 binds a distinct, non-competing region, allowing CLEC14A and CD248 to simultaneously bridge the endothelial-pericyte interface [PMID:25745997, PMID:28912033, PMID:28671670]. Through CD93 the complex localizes to endothelial filopodia and drives β1 integrin activation, FAK phosphorylation, and fibronectin fibrillogenesis to support vascular maturation [PMID:29763414]. MMRN2 maintains junctional stability by suppressing VEGFR2 Tyr951/Tyr949 phosphorylation, Src activation, and VE-cadherin phosphorylation; its loss causes junctional instability, increased permeability, and defective tumor vasculature [PMID:31422156]. Its angiostatic deposition is relieved during angiogenic stimulation through MMP-9-mediated proteolytic processing, and its abundance is post-transcriptionally tuned by miR-1910-5p [PMID:28435016, PMID:37040097]. Beyond the vasculature, MMRN2 signals through CD93 in cortical neural stem cells to activate a β-Catenin→ZFP503 cascade that represses Gfap transcription and astrogenesis [PMID:32291340].","teleology":[{"year":1994,"claim":"Establishing whether a defining endothelial surface marker existed, EndoGlyx-1/MMRN2 was identified as an endothelial-restricted high-molecular-weight glycoprotein, fixing it as a pan-endothelial protein.","evidence":"Monoclonal antibody (mAbH572) immunochemical characterization across endothelial and non-endothelial cells","pmids":["7933987"],"confidence":"Medium","gaps":["Molecular identity and sequence not yet defined","No function assigned beyond expression pattern"]},{"year":2001,"claim":"To define the protein's molecular architecture, cloning revealed a single ORF producing a disulfide-bonded multi-subunit complex with EMI, coiled-coil, and C1q-like domains, providing the framework for all later domain-function mapping.","evidence":"Protein purification, peptide sequencing, cDNA cloning, and bioinformatic domain analysis","pmids":["11559704"],"confidence":"High","gaps":["No ligands or receptors identified","Functional role of individual domains unknown"]},{"year":2011,"claim":"Addressing how a matrix protein could be angiostatic, MMRN2 was shown to directly bind VEGF-A and sequester it from VEGFRs, establishing a growth-factor-trapping mechanism.","evidence":"Binding affinity measurement, endothelial migration/tube assays, VEGFR phosphorylation, and tumor xenografts","pmids":["22020326"],"confidence":"High","gaps":["Domain of MMRN2 mediating VEGF-A binding not mapped","Receptor-side mechanism beyond ligand sequestration not addressed"]},{"year":2013,"claim":"Searching for endothelial matrix partners, secretome proteomics flagged CLEC14A as an MMRN2 interactor, nominating a receptor class for follow-up.","evidence":"SILAC quantitative proteomics of the endothelial secretome during morphogenesis","pmids":["23979707"],"confidence":"Medium","gaps":["Interaction not directly validated biochemically in this study","No functional consequence established"]},{"year":2015,"claim":"To test the functional relevance of the CLEC14A interaction, blocking the CLEC14A-MMRN2 bond was shown to impair sprouting and tumor vasculature, establishing a pro-angiogenic receptor-ligand axis.","evidence":"Pull-down/Co-IP, blocking antibody, sprouting and aortic ring assays, clec14a-/- mouse tumor models","pmids":["25745997"],"confidence":"High","gaps":["Binding region on MMRN2 not yet mapped","Downstream signaling not defined"]},{"year":2017,"claim":"To resolve the receptor repertoire and binding architecture, MMRN2 was shown to bind CLEC14A, CD93, and CD248 — with CLEC14A/CD93 sharing the coiled-coil site (CD93 F238) and CD248 occupying a distinct, simultaneously-engageable site — defining a multi-receptor scaffold spanning the endothelial-pericyte interface.","evidence":"Direct binding, site-directed mutagenesis, competition assays, molecular docking, adhesion/migration assays","pmids":["28912033","28671670"],"confidence":"High","gaps":["Intracellular signaling downstream of each receptor not fully resolved","Stoichiometry of multi-receptor complexes unknown"]},{"year":2017,"claim":"To explain how angiostatic MMRN2 is overcome during active angiogenesis, MMP-9 was shown to proteolytically process deposited MMRN2, correlating with increased endothelial migration.","evidence":"MMP cleavage assays, qRT-PCR, migration assays, MMP-9 inhibitor rescue, tumor section immunofluorescence","pmids":["28435016"],"confidence":"Medium","gaps":["Cleavage sites not mapped","Fate and activity of cleavage fragments not characterized"]},{"year":2018,"claim":"To define the maturation-promoting output of the CD93 axis, the CD93-MMRN2 complex was shown to stabilize CD93 in filopodia and drive β1 integrin/FAK activation and fibronectin fibrillogenesis, linking the interaction to matrix assembly and vessel maturation.","evidence":"Filopodia imaging, interaction assays, β1 integrin and FAK readouts, fibronectin fibrillogenesis, CD93-deficient mouse tumors","pmids":["29763414"],"confidence":"High","gaps":["Connection between integrin activation and downstream vessel phenotype incompletely defined","Role of EMI/C1q domains not addressed"]},{"year":2019,"claim":"To establish MMRN2's role in barrier function, loss-of-function in vitro and Mmrn2-/- mice revealed junctional instability via VEGFR2 Tyr951/Tyr949, Src, and VE-cadherin phosphorylation, defining MMRN2 as a suppressor of permeability signaling.","evidence":"RNAi, phospho-specific assays, permeability assays, Mmrn2-/- mice, tumor xenograft and chemotherapy delivery","pmids":["31422156"],"confidence":"High","gaps":["Receptor mediating the permeability-suppressing signal not pinpointed","Link between ligand sequestration and junctional signaling not unified"]},{"year":2020,"claim":"Extending MMRN2 beyond the vasculature, it was shown to signal through CD93 in cortical neural stem cells via β-Catenin→ZFP503 to repress Gfap and astrogenesis, demonstrating a developmental signaling role.","evidence":"Cd93 knockout mice, MMRN2 treatment, β-Catenin translocation, Zfp503 reporter, Gfap promoter ChIP, astrogenesis quantification","pmids":["32291340"],"confidence":"High","gaps":["Proximal phosphorylation events linking CD93 to β-Catenin not defined","Generality to other neural lineages unknown"]},{"year":2023,"claim":"To capture post-transcriptional and disease-context regulation, MMRN2 was shown to be repressed by miR-1910-5p (driving permeability) and to mediate CD248-dependent anti-angiogenic VEGFR2 suppression in systemic sclerosis.","evidence":"Luciferase 3'UTR reporter and antagomir corneal model; SSc skin immunofluorescence and CD248 shRNA co-culture with VEGFR2 readout","pmids":["37040097","35916713"],"confidence":"Medium","gaps":["Disease relevance largely model-based","Other regulators of MMRN2 abundance not characterized"]},{"year":2023,"claim":"To probe MMRN2 in cancer cell biology, CD93-MMRN2-integrin β1 signaling was shown to activate PI3K/AKT/SP2 driving migration, invasion, and vasculogenic mimicry in breast cancer.","evidence":"Co-IP, siRNA, integrin β1 activation, PI3K/AKT/SP2 phospho-assays, Transwell, vasculogenic mimicry, xenograft","pmids":["38511888"],"confidence":"Medium","gaps":["Single-lab Co-IP without reciprocal structural validation","Direct vs indirect role of MMRN2 in cancer-cell-intrinsic signaling unclear"]},{"year":2024,"claim":"Extending the CLEC14A-MMRN2 axis to skeletal biology, blockade of the interaction phenocopied Clec14a-/- accelerated osteoblast maturation and bone formation in type-H capillaries.","evidence":"Clec14a-/- mice, antibody blockade, bone density and osteoblast maturation assays","pmids":["39394430"],"confidence":"Medium","gaps":["Mechanism linking endothelial interaction to osteoblast maturation not defined","MMRN2-specific contribution vs CLEC14A not separated"]},{"year":null,"claim":"How the distinct receptor engagements (VEGF-A sequestration, CLEC14A, CD93, CD248) are integrated into a unified output controlling angiostasis versus maturation, and the structural basis of the multi-subunit complex, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of MMRN2 or its receptor complexes","Functional roles of the EMI and C1q-like domains not assigned","Integration of ligand-sequestration and receptor-signaling activities unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,4,5,9]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[5,6,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,13]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,4,5]}],"complexes":["CD93-MMRN2 complex"],"partners":["VEGFA","CLEC14A","CD93","CD248","ITGB1"],"other_free_text":[]}},"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":"29763414","id":"PMC_29763414","title":"CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29763414","citation_count":112,"is_preprint":false},{"pmid":"32166015","id":"PMC_32166015","title":"Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension.","date":"2020","source":"Pulmonary circulation","url":"https://pubmed.ncbi.nlm.nih.gov/32166015","citation_count":102,"is_preprint":false},{"pmid":"26544852","id":"PMC_26544852","title":"Proteomic Analysis of Urine to Identify Breast Cancer Biomarker Candidates Using a Label-Free LC-MS/MS Approach.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26544852","citation_count":89,"is_preprint":false},{"pmid":"22020326","id":"PMC_22020326","title":"MULTIMERIN2 impairs tumor angiogenesis and growth by interfering with VEGF-A/VEGFR2 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The protein contains an N-terminal EMI domain, a central coiled-coil region, and a C-terminal C1q-like domain, and all subunits are exposed on the cell surface with N-linked and O-linked carbohydrates.\",\n      \"method\": \"Protein purification, peptide analysis, cDNA cloning, bioinformatic domain analysis, enzyme digestion for glycan characterization, cell surface biochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct purification, sequencing, and biochemical characterization of the protein and its subunits with multiple orthogonal methods\",\n      \"pmids\": [\"11559704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"EndoGlyx-1 (MMRN2) is expressed exclusively on the surface of endothelial cells (not on non-endothelial cell types) as a high-molecular-weight glycoprotein complex with disulfide-bonded subunits of ~190, 140, 125, and 110 kDa, and its expression is not altered by cytokine stimulation.\",\n      \"method\": \"Monoclonal antibody (mAbH572) generation, immunochemical characterization of endothelial cell extracts, cell surface expression assays\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal immunochemical characterization with defined reagents, single lab, multiple cell/tissue types tested\",\n      \"pmids\": [\"7933987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MMRN2 directly binds VEGF-A with an affinity of Kd ~50 nM, thereby sequestering VEGF-A and impairing its engagement with VEGFR1 and VEGFR2, leading to impaired endothelial cell migration, defective vessel network formation, and reduced tumor growth in vivo.\",\n      \"method\": \"Multiple binding assays (affinity estimation), endothelial migration assays, tube formation assays, VEGFR phosphorylation assays, in vivo tumor xenograft with MMRN2 overexpression and adenoviral MMRN2 construct, immunostaining for VEGF-A co-localization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding affinity measured, multiple orthogonal functional assays, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"22020326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MMRN2 binds to the extracellular region of CLEC14A; blocking this CLEC14A-MMRN2 interaction with a monoclonal antibody (clone C4) perturbs tube formation, endothelial sprouting in vitro and in vivo, and impairs tumor growth and vascular density in mice.\",\n      \"method\": \"Pull-down, co-immunoprecipitation, monoclonal antibody blocking assays, HUVEC spheroid sprouting assay, aortic ring assay, in vivo subcutaneous sponge and tumor models in clec14a+/+ and clec14a-/- mice\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KO mouse model, multiple in vitro and in vivo functional assays, antibody-mediated blocking\",\n      \"pmids\": [\"25745997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MMRN2 is a specific extracellular matrix ligand for the transmembrane receptor CD93; their interaction is required for endothelial cell adhesion and migration. The coiled-coil domain of MMRN2 engages F238 of CD93, identified by site-directed mutagenesis and molecular docking.\",\n      \"method\": \"Co-expression analysis, binding assays, endothelial adhesion and migration assays with disruption of the interaction, site-directed mutagenesis, molecular modeling and docking\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-directed mutagenesis identifying binding residues, functional adhesion/migration assays, structural modeling, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28912033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CLEC14A, CD93, and CD248 all directly bind MMRN2. CLEC14A and CD93 bind the same non-glycosylated coiled-coil region of MMRN2, and this binding requires a predicted long-loop region in their C-type lectin domain. CD248 binds a distinct, non-competing region of MMRN2. CLEC14A and CD248 can simultaneously bind MMRN2, spanning the endothelial-pericyte interface in human pancreatic cancer.\",\n      \"method\": \"Direct binding assays, mutation of C-type lectin domain, competition binding assays, recombinant MMRN2 peptide blocking of CLEC14A binding, HUVEC adhesion assays, in vitro and in vivo anti-angiogenic assays with MMRN2 peptide\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding with mutagenesis, competition assays establishing distinct binding sites, in vitro functional validation, replicated across multiple receptor family members\",\n      \"pmids\": [\"28671670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"During angiogenic stimulation, MMRN2 mRNA levels decrease and the deposited MMRN2 protein is proteolytically processed by MMP-9 (and to a lesser degree MMP-2), and this cleavage correlates with increased endothelial cell migration and increased pseudopodial formation at the migrating front. MMP-9 inhibitors attenuate the MMRN2 down-modulation phenotype.\",\n      \"method\": \"MMP cleavage assays, qRT-PCR for MMRN2 mRNA, endothelial cell migration assays, MMP-9 inhibitor treatment, immunofluorescence co-localization of MMP-9 and MMRN2 in tumor sections\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protease cleavage assays combined with functional migration readouts and inhibitor rescue, single lab\",\n      \"pmids\": [\"28435016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MMRN2 stabilizes CD93 localization to endothelial 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 endothelial cells. Loss of CD93 in vivo (CD93-deficient mice) results in diminished β1 integrin activation and loss of fibronectin fibrillar organization in tumor vessels.\",\n      \"method\": \"Immunofluorescence/live imaging of endothelial filopodia, CD93-MMRN2 interaction assays, β1 integrin activation assay, FAK phosphorylation assay, fibronectin fibrillogenesis assay, CD93-deficient mouse tumor implantation model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (interaction, signaling, in vivo KO mouse model), functional readouts at multiple levels, replicated in vitro and in vivo\",\n      \"pmids\": [\"29763414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MMRN2 is required to maintain vascular stability and permeability. RNAi knockdown of MMRN2 in endothelial cells causes cell-cell junctional instability and increased permeability via phosphorylation of VEGFR2 at Tyr951, activation of Src, and phosphorylation of VE-cadherin. Mmrn2-/- mice show junctional defects, elevated VEGFR2 phospho-Tyr949, impaired pericyte recruitment, increased vascular leakage, and defective tumor vessel function with reduced chemotherapy delivery.\",\n      \"method\": \"RNAi knockdown, VEGFR2/Src/VE-cadherin phosphorylation assays, vascular permeability assays, generation and phenotypic analysis of Mmrn2-/- mice, tumor xenograft experiments, chemotherapy efficacy assays\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — KO mouse model plus in vitro mechanistic pathway dissection with phospho-specific readouts, multiple orthogonal methods\",\n      \"pmids\": [\"31422156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In neural stem cells of the developing mouse cerebral cortex, MMRN2 signals through CD93 to repress astrogenesis; CD93 responds to extracellular MMRN2 by triggering phosphorylation cascades that activate β-Catenin, which then translocates to the nucleus to activate Zfp503 transcription. The transcriptional repressor ZFP503 in turn binds the Gfap promoter (with Grg5) to inhibit Gfap transcription, suppressing astrocyte differentiation.\",\n      \"method\": \"Cd93 knockout mice, MMRN2 treatment of neural stem cells, phosphorylation assays, β-Catenin nuclear translocation assays, Zfp503 promoter reporter, ChIP at Gfap promoter, astrogenesis quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with defined molecular pathway (MMRN2→CD93→β-Catenin→ZFP503→Gfap), multiple orthogonal methods, clear phenotypic readout\",\n      \"pmids\": [\"32291340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CLEC14A binds to MMRN2 in the endothelial extracellular matrix, identified by SILAC-based quantitative proteomics of the endothelial cell secretome during morphogenesis.\",\n      \"method\": \"SILAC spike-in quantitative proteomics, identification of extracellular matrix components secreted by endothelial cells, protein interaction identified in secretome\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — proteomics-based interaction identification, single method but replicated by later direct binding studies\",\n      \"pmids\": [\"23979707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-1910-5p directly targets the 3' UTR of MMRN2 mRNA to suppress MMRN2 expression, causing extracellular junctional defects in endothelial cells and increased vascular permeability; antagomir-mediated inhibition of miR-1910-5p increases MMRN2 levels and decreases vascular leakage in a murine corneal neovascularization model.\",\n      \"method\": \"Luciferase 3'UTR reporter assay, miR-1910-5p antagomir in vivo, MMRN2 protein quantification by Western blot, vascular permeability and tube formation assays\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validates direct miRNA-3'UTR interaction, in vivo rescue with antagomir, single lab\",\n      \"pmids\": [\"37040097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD93 interacts with MMRN2 and integrin β1 in breast cancer cells; knockdown of CD93 or MMRN2 inhibits integrin β1 activation, thereby suppressing the PI3K/AKT/SP2 signaling pathway and reducing cancer cell migration, invasion, and vasculogenic mimicry.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of CD93 and MMRN2, integrin β1 activation assays, PI3K/AKT/SP2 phosphorylation assays, Transwell migration/invasion assays, vasculogenic mimicry assay, in vivo xenograft\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional pathway assays with siRNA, single lab, in vitro and in vivo\",\n      \"pmids\": [\"38511888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In type-H capillary endothelial cells, the Clec14a-Mmrn2 interaction regulates osteoblast maturation and mineralisation; antibody-mediated blockade of the Clec14a-Mmrn2 interaction recapitulates the Clec14a-/- phenotype of accelerated skeletal development, expanded osteoblast distribution, increased bone density, and enhanced osteoblast maturation.\",\n      \"method\": \"Clec14a-/- mouse model, antibody-mediated blockade of Clec14a-Mmrn2 interaction, histological and bone density analysis, osteoblast maturation and mineralisation assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model plus antibody blockade of specific interaction recapitulates phenotype, single lab\",\n      \"pmids\": [\"39394430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In systemic sclerosis, MMRN2 expression is increased in skin endothelial cells while CD248 (expressed on SSc fibroblasts) binds MMRN2 and prevents VEGFR2 phosphorylation after VEGF stimulation, contributing to anti-angiogenic activity and endothelial cell apoptosis.\",\n      \"method\": \"Immunofluorescence of SSc skin, HC-ECs/SSc-FBs co-culture organotypic model, lentiviral CD248 shRNA loss-of-function, VEGFR2 phosphorylation by Western blot, apoptosis assay by immunofluorescence\",\n      \"journal\": \"Rheumatology (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular readout (VEGFR2 phosphorylation), in vitro co-culture model, single lab\",\n      \"pmids\": [\"35916713\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MMRN2 (EndoGlyx-1) is a pan-endothelial extracellular matrix glycoprotein with an EMI domain, coiled-coil region, and C1q-like domain that functions as an angiostatic regulator by (1) directly binding VEGF-A (Kd ~50 nM) to sequester it from VEGFR2 signaling, (2) serving as the extracellular ligand for the group 14 C-type lectins CLEC14A, CD93, and CD248, with the coiled-coil domain engaging CD93/CLEC14A and a distinct region binding CD248; (3) the CD93-MMRN2 complex stabilizes CD93 in filopodia, activates β1 integrin and FAK to drive fibronectin fibrillogenesis and vascular maturation; (4) maintaining vascular stability and barrier integrity by suppressing VEGFR2 Tyr951 phosphorylation, Src activation, and VE-cadherin phosphorylation; (5) being proteolytically processed by MMP-9 during angiogenic stimuli to relieve its angiostatic effect; and (6) signaling through CD93 in neural stem cells to activate a β-Catenin→ZFP503 pathway that represses astrogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MMRN2 (EndoGlyx-1) is a pan-endothelial cell-surface extracellular matrix glycoprotein that acts as an angiostatic regulator controlling vascular maturation, stability, and barrier integrity [#0, #1, #8]. Structurally it is a ~500 kDa disulfide-bonded complex built from a single ORF encoding an N-terminal EMI domain, a central coiled-coil region, and a C-terminal C1q-like domain, with all subunits exposed on the endothelial surface [#0]. It restrains angiogenesis by directly binding VEGF-A (Kd ~50 nM), sequestering it from VEGFR1/VEGFR2 and thereby impairing endothelial migration, vessel network formation, and tumor growth [#2]. MMRN2 is the extracellular ligand for the group 14 C-type lectins CLEC14A, CD93, and CD248: its non-glycosylated coiled-coil region engages CLEC14A and CD93 (via CD93 residue F238), while CD248 binds a distinct, non-competing region, allowing CLEC14A and CD248 to simultaneously bridge the endothelial-pericyte interface [#3, #4, #5]. Through CD93 the complex localizes to endothelial filopodia and drives β1 integrin activation, FAK phosphorylation, and fibronectin fibrillogenesis to support vascular maturation [#7]. MMRN2 maintains junctional stability by suppressing VEGFR2 Tyr951/Tyr949 phosphorylation, Src activation, and VE-cadherin phosphorylation; its loss causes junctional instability, increased permeability, and defective tumor vasculature [#8]. Its angiostatic deposition is relieved during angiogenic stimulation through MMP-9-mediated proteolytic processing, and its abundance is post-transcriptionally tuned by miR-1910-5p [#6, #11]. Beyond the vasculature, MMRN2 signals through CD93 in cortical neural stem cells to activate a β-Catenin→ZFP503 cascade that represses Gfap transcription and astrogenesis [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing whether a defining endothelial surface marker existed, EndoGlyx-1/MMRN2 was identified as an endothelial-restricted high-molecular-weight glycoprotein, fixing it as a pan-endothelial protein.\",\n      \"evidence\": \"Monoclonal antibody (mAbH572) immunochemical characterization across endothelial and non-endothelial cells\",\n      \"pmids\": [\"7933987\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular identity and sequence not yet defined\", \"No function assigned beyond expression pattern\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"To define the protein's molecular architecture, cloning revealed a single ORF producing a disulfide-bonded multi-subunit complex with EMI, coiled-coil, and C1q-like domains, providing the framework for all later domain-function mapping.\",\n      \"evidence\": \"Protein purification, peptide sequencing, cDNA cloning, and bioinformatic domain analysis\",\n      \"pmids\": [\"11559704\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No ligands or receptors identified\", \"Functional role of individual domains unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Addressing how a matrix protein could be angiostatic, MMRN2 was shown to directly bind VEGF-A and sequester it from VEGFRs, establishing a growth-factor-trapping mechanism.\",\n      \"evidence\": \"Binding affinity measurement, endothelial migration/tube assays, VEGFR phosphorylation, and tumor xenografts\",\n      \"pmids\": [\"22020326\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Domain of MMRN2 mediating VEGF-A binding not mapped\", \"Receptor-side mechanism beyond ligand sequestration not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Searching for endothelial matrix partners, secretome proteomics flagged CLEC14A as an MMRN2 interactor, nominating a receptor class for follow-up.\",\n      \"evidence\": \"SILAC quantitative proteomics of the endothelial secretome during morphogenesis\",\n      \"pmids\": [\"23979707\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Interaction not directly validated biochemically in this study\", \"No functional consequence established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"To test the functional relevance of the CLEC14A interaction, blocking the CLEC14A-MMRN2 bond was shown to impair sprouting and tumor vasculature, establishing a pro-angiogenic receptor-ligand axis.\",\n      \"evidence\": \"Pull-down/Co-IP, blocking antibody, sprouting and aortic ring assays, clec14a-/- mouse tumor models\",\n      \"pmids\": [\"25745997\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Binding region on MMRN2 not yet mapped\", \"Downstream signaling not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"To resolve the receptor repertoire and binding architecture, MMRN2 was shown to bind CLEC14A, CD93, and CD248 — with CLEC14A/CD93 sharing the coiled-coil site (CD93 F238) and CD248 occupying a distinct, simultaneously-engageable site — defining a multi-receptor scaffold spanning the endothelial-pericyte interface.\",\n      \"evidence\": \"Direct binding, site-directed mutagenesis, competition assays, molecular docking, adhesion/migration assays\",\n      \"pmids\": [\"28912033\", \"28671670\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Intracellular signaling downstream of each receptor not fully resolved\", \"Stoichiometry of multi-receptor complexes unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"To explain how angiostatic MMRN2 is overcome during active angiogenesis, MMP-9 was shown to proteolytically process deposited MMRN2, correlating with increased endothelial migration.\",\n      \"evidence\": \"MMP cleavage assays, qRT-PCR, migration assays, MMP-9 inhibitor rescue, tumor section immunofluorescence\",\n      \"pmids\": [\"28435016\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cleavage sites not mapped\", \"Fate and activity of cleavage fragments not characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"To define the maturation-promoting output of the CD93 axis, the CD93-MMRN2 complex was shown to stabilize CD93 in filopodia and drive β1 integrin/FAK activation and fibronectin fibrillogenesis, linking the interaction to matrix assembly and vessel maturation.\",\n      \"evidence\": \"Filopodia imaging, interaction assays, β1 integrin and FAK readouts, fibronectin fibrillogenesis, CD93-deficient mouse tumors\",\n      \"pmids\": [\"29763414\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Connection between integrin activation and downstream vessel phenotype incompletely defined\", \"Role of EMI/C1q domains not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"To establish MMRN2's role in barrier function, loss-of-function in vitro and Mmrn2-/- mice revealed junctional instability via VEGFR2 Tyr951/Tyr949, Src, and VE-cadherin phosphorylation, defining MMRN2 as a suppressor of permeability signaling.\",\n      \"evidence\": \"RNAi, phospho-specific assays, permeability assays, Mmrn2-/- mice, tumor xenograft and chemotherapy delivery\",\n      \"pmids\": [\"31422156\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor mediating the permeability-suppressing signal not pinpointed\", \"Link between ligand sequestration and junctional signaling not unified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extending MMRN2 beyond the vasculature, it was shown to signal through CD93 in cortical neural stem cells via β-Catenin→ZFP503 to repress Gfap and astrogenesis, demonstrating a developmental signaling role.\",\n      \"evidence\": \"Cd93 knockout mice, MMRN2 treatment, β-Catenin translocation, Zfp503 reporter, Gfap promoter ChIP, astrogenesis quantification\",\n      \"pmids\": [\"32291340\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Proximal phosphorylation events linking CD93 to β-Catenin not defined\", \"Generality to other neural lineages unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To capture post-transcriptional and disease-context regulation, MMRN2 was shown to be repressed by miR-1910-5p (driving permeability) and to mediate CD248-dependent anti-angiogenic VEGFR2 suppression in systemic sclerosis.\",\n      \"evidence\": \"Luciferase 3'UTR reporter and antagomir corneal model; SSc skin immunofluorescence and CD248 shRNA co-culture with VEGFR2 readout\",\n      \"pmids\": [\"37040097\", \"35916713\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Disease relevance largely model-based\", \"Other regulators of MMRN2 abundance not characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To probe MMRN2 in cancer cell biology, CD93-MMRN2-integrin β1 signaling was shown to activate PI3K/AKT/SP2 driving migration, invasion, and vasculogenic mimicry in breast cancer.\",\n      \"evidence\": \"Co-IP, siRNA, integrin β1 activation, PI3K/AKT/SP2 phospho-assays, Transwell, vasculogenic mimicry, xenograft\",\n      \"pmids\": [\"38511888\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single-lab Co-IP without reciprocal structural validation\", \"Direct vs indirect role of MMRN2 in cancer-cell-intrinsic signaling unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extending the CLEC14A-MMRN2 axis to skeletal biology, blockade of the interaction phenocopied Clec14a-/- accelerated osteoblast maturation and bone formation in type-H capillaries.\",\n      \"evidence\": \"Clec14a-/- mice, antibody blockade, bone density and osteoblast maturation assays\",\n      \"pmids\": [\"39394430\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism linking endothelial interaction to osteoblast maturation not defined\", \"MMRN2-specific contribution vs CLEC14A not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct receptor engagements (VEGF-A sequestration, CLEC14A, CD93, CD248) are integrated into a unified output controlling angiostasis versus maturation, and the structural basis of the multi-subunit complex, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No high-resolution structure of MMRN2 or its receptor complexes\", \"Functional roles of the EMI and C1q-like domains not assigned\", \"Integration of ligand-sequestration and receptor-signaling activities unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 4, 5, 9]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 4, 5]}\n    ],\n    \"complexes\": [\"CD93-MMRN2 complex\"],\n    \"partners\": [\"VEGFA\", \"CLEC14A\", \"CD93\", \"CD248\", \"ITGB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}