{"gene":"EMILIN2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2001,"finding":"EMILIN2 was isolated using the EMILIN1 gC1q domain as bait in a yeast two-hybrid screen, establishing that EMILIN2 is an extracellular matrix glycoprotein with domain organization superimposable to EMILIN1 (EMI domain, coiled-coil region, collagenous stalk, C-terminal gC1q domain), secreted extracellularly by in vitro-grown cells, and partially co-localizes with EMILIN1 in vitro.","method":"Yeast two-hybrid, cDNA cloning, protein secretion assay, immunolocalization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (Y2H, secretion assay, immunolocalization) in single foundational paper establishing basic biochemistry","pmids":["11278945"],"is_preprint":false},{"year":2007,"finding":"EMILIN2 triggers apoptosis in multiple cell lines by directly binding death receptors DR4 (and to a lesser extent DR5), leading to receptor clustering, colocalization with lipid rafts, death-inducing signaling complex (DISC) assembly, and caspase activation via the extrinsic apoptotic pathway. Knockdown of EMILIN2 increases transformed cell survival; overexpression impairs clonogenicity.","method":"Binding assays (EMILIN2–DR4/DR5 interaction), lipid raft fractionation, DISC assembly assay, caspase activation assay, siRNA knockdown, overexpression in soft agar and 3D matrix assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (receptor binding, DISC assembly, caspase activation, KD and OE phenotypes) in single rigorous study; novel mechanism well-supported","pmids":["17698584"],"is_preprint":false},{"year":2014,"finding":"EMILIN2 directly binds the Wnt1 ligand (interaction demonstrated by co-immunoprecipitation), leading to decreased LRP6 phosphorylation and down-modulation of β-catenin, TAZ, and their target genes, thereby attenuating Wnt signaling. This interaction requires the EMI domain of EMILIN2, as a deletion mutant lacking the EMI domain shows no effect. EMILIN2 does not affect Wnt signaling downstream of Wnt-Frizzled interaction (no effect on GSK3 inhibitor-activated pathway).","method":"Co-immunoprecipitation (EMILIN2–Wnt1 binding), LRP6 phosphorylation assay, β-catenin/TAZ western blot, EMI domain deletion mutant, GSK3 inhibitor rescue, in vivo xenograft, 2D and 3D cell viability/migration assays","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated by Co-IP, domain mutant validates mechanism, in vivo rescue, multiple orthogonal functional readouts, single rigorous study","pmids":["24374807"],"is_preprint":false},{"year":2014,"finding":"EMILIN1 and EMILIN2 interact via their gC1q and EMI domains: gC1q domains self-interact and interact with EMI domains, but no EMI-EMI self-interactions were detected. Full-length EMILIN1 and EMILIN2 form non-covalent homo- and hetero-multimers, consistent with head-to-tail and tail-to-tail assemblies in tissues.","method":"Qualitative and quantitative yeast two-hybrid, co-immunoprecipitation from co-transfected 293-EBNA cells, immunofluorescence on mouse cell cultures and tissue sections","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and Y2H in same study, multiple domain constructs tested, single lab","pmids":["25445627"],"is_preprint":false},{"year":2015,"finding":"EMILIN2 promotes platelet aggregation and clot retraction: EMILIN2-deficient platelets and EMILIN2-deficient plasma both contribute to impaired aggregation responses to ADP, collagen, and thrombin. Purified EMILIN2 accelerates platelet aggregation and reduces clotting time. Platelet-specific EMILIN2 deficiency doubles carotid occlusion time. In vitro clot retraction is markedly decreased in EMILIN2-deficient mice, indicating that platelet outside-in signaling depends on EMILIN2. EMILIN1 and EMILIN2 have opposing effects on clot retraction.","method":"EMILIN2 knockout and platelet-specific KO mice, platelet aggregation assays (ADP/collagen/thrombin), purified protein add-back, carotid ferric chloride injury model, in vitro clot retraction assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (global and platelet-specific KO), purified protein rescue, multiple functional assays, single rigorous study","pmids":["25658937"],"is_preprint":false},{"year":2016,"finding":"EMILIN-1 and EMILIN-2 are targeted to fibrillin microfibrils in the skin; their deposition requires fibronectin during wound healing and in vitro matrix assembly. Disruption of microfibrils in fibrillin-1-deficient mice leads to fragmentation of EMILIN-1 and EMILIN-2 networks, establishing fibrillin as required for proper EMILIN2 ECM incorporation.","method":"Immunoelectron microscopy, immunofluorescence microscopy, biochemical ECM extraction, fibrillin-1 knockout mouse analysis, primary dermal fibroblast cultures","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple imaging modalities and genetic model, single lab, no reconstitution of direct fibrillin-EMILIN2 binding","pmids":["26945878"],"is_preprint":false},{"year":2018,"finding":"EMILIN2 promotes angiogenesis by directly binding EGFR, which enhances IL-8 (MIP-2) production; IL-8 in turn stimulates proliferation and migration of vascular endothelial cells. Emilin2 null mice show delayed retinal vascular development rescued by exogenous MIP-2 administration.","method":"EGFR binding assay, IL-8/MIP-2 ELISA, Emilin2 knockout mice, retinal vascular development assay, MIP-2 rescue experiment, tumor growth and vascular density analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct EGFR binding demonstrated, genetic rescue with cytokine, multiple in vivo readouts, single rigorous study with orthogonal methods","pmids":["29483644"],"is_preprint":false},{"year":2022,"finding":"EMILIN-2 activates the TLR-4/MyD88/NF-κB pathway in macrophages, promoting their polarization towards the M1 phenotype. Loss of EMILIN-2 in Emilin-2 null mice results in decreased M1 and increased M2 macrophages in colorectal tumors, and earlier MDSC-rich infiltration. Ex vivo macrophage cultures from knockout mice were used to validate the molecular pathway.","method":"Emilin-2 knockout mouse AOM/DSS colorectal cancer model, flow cytometry of immune subpopulations, ex vivo monocyte/macrophage cultures, immunohistochemistry, immunofluorescence, western blot for TLR-4/MyD88/NF-κB pathway","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with ex vivo mechanistic validation of pathway, single lab, pathway confirmed in cultured macrophages","pmids":["35148799"],"is_preprint":false},{"year":2022,"finding":"Emilin-2 is expressed and secreted by bone marrow mesenchymal stem cells, inhibits their adipogenic differentiation, and is required for normal hematopoietic stem/progenitor cell frequency in bone marrow during aging, as shown in Emilin-2 null mice.","method":"Immunodetection in bone marrow sections, primary and immortalized MSC cultures, adipogenic differentiation assay, flow cytometry of HSPCs in wild-type vs. Emilin-2 null mice","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with cellular phenotype readouts and in vitro differentiation assay, single lab","pmids":["35012633"],"is_preprint":false},{"year":2023,"finding":"Emilin2 promotes pericyte recruitment and vascular stabilization via multiple mechanisms: (1) stimulating endothelial cells to produce PDGF-BB and HB-EGF; (2) serving as a direct adhesion substrate and haptotactic stimulus for pericytes by engaging α5β1 and α6β1 integrins on pericytes; (3) increasing N-cadherin expression in pericytes via the sphingosine-1-phosphate receptor, enhancing endothelial-pericyte interconnection.","method":"Recombinant Emilin2 stimulation of primary endothelial cells (PDGF-BB/HB-EGF ELISA), integrin binding/blocking assays, haptotaxis migration assay, N-cadherin western blot, sphingosine-1-phosphate receptor inhibition, Emilin2-/- tumor vascular analysis, drug delivery assay","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal mechanisms tested with recombinant protein and genetic KO, integrin identification by blocking experiments, in vivo validation, single rigorous study","pmids":["37579864"],"is_preprint":false},{"year":2024,"finding":"HPV-18 E6 oncoprotein enhances the interaction between EMILIN2 and SNX27 (a retromer complex PDZ-domain protein), blocking EMILIN2 secretion in a PBM-dependent manner. E6 prevents EMILIN2 from interacting with Wnt1 ligand, thereby enhancing Wnt1 signaling and promoting cell proliferation.","method":"SNX27 proteome interaction profiling (GFP-SNX27 pulldown/MS), co-immunoprecipitation, HPV-18 E6 expression and PBM mutant analysis, Wnt1 binding assay, cell proliferation assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome plus Co-IP and functional Wnt binding assay, single lab, mechanistically novel finding","pmids":["38874360"],"is_preprint":false},{"year":2024,"finding":"Macrophages produce Emilin2 in response to bone injury, and the secreted Emilin2 acts as a chemoattractant for mesenchymal cells. Emilin2-/- mice show delayed bone regeneration with decreased mesenchymal cell accumulation at injury sites; local administration of recombinant Emilin2 enhances bone regeneration.","method":"Migration assay, LC-MS/MS protein identification, Emilin2-/- mouse bone injury model, endoscopy/histology, recombinant protein rescue experiment","journal":"Inflammation and regeneration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemoattractant activity confirmed by migration assay and genetic KO with recombinant protein rescue, single lab","pmids":["38831448"],"is_preprint":false}],"current_model":"EMILIN2 is a multifunctional extracellular matrix glycoprotein that: (1) directly binds and clusters death receptors DR4/DR5 to activate the extrinsic apoptotic pathway via DISC assembly and caspase activation; (2) sequesters Wnt1 ligand extracellularly through its EMI domain to attenuate LRP6/β-catenin/TAZ signaling; (3) directly engages EGFR to drive IL-8 production and promote angiogenesis; (4) fosters vascular stabilization by stimulating endothelial PDGF-BB/HB-EGF production and by acting as an α5β1/α6β1 integrin ligand and sphingosine-1-phosphate-dependent N-cadherin inducer in pericytes; (5) activates TLR-4/MyD88/NF-κB signaling in macrophages to drive M1 polarization; (6) acts as a macrophage-secreted chemoattractant for mesenchymal progenitors during bone repair; (7) promotes platelet aggregation and outside-in signaling for clot retraction; and (8) is incorporated into fibrillin microfibril networks in the ECM through interactions requiring fibronectin."},"narrative":{"mechanistic_narrative":"EMILIN2 is a secreted extracellular matrix glycoprotein with an EMILIN1-like domain architecture (EMI domain, coiled-coil, collagenous stalk, C-terminal gC1q domain) that is incorporated into fibrillin microfibril networks and acts as a multifunctional regulator of apoptosis, growth-factor signaling, vascularization, and immune and hematopoietic processes [PMID:11278945, PMID:26945878]. Its ECM deposition depends on fibronectin and intact fibrillin microfibrils, and it self-associates and hetero-associates with EMILIN1 through reciprocal gC1q–gC1q and gC1q–EMI domain contacts [PMID:25445627, PMID:26945878]. A central activity is pro-apoptotic signaling: EMILIN2 directly binds the death receptor DR4 (and to a lesser extent DR5), driving receptor clustering, lipid-raft colocalization, DISC assembly, and caspase activation through the extrinsic pathway, so that its loss promotes transformed-cell survival [PMID:17698584]. EMILIN2 also restrains canonical Wnt signaling by using its EMI domain to bind and sequester Wnt1, reducing LRP6 phosphorylation and β-catenin/TAZ activity [PMID:24374807]; this tumor-suppressive function is subverted by HPV-18 E6, which promotes an EMILIN2–SNX27 interaction that blocks EMILIN2 secretion and relieves Wnt1 inhibition [PMID:38874360]. In the vasculature, EMILIN2 promotes angiogenesis by directly engaging EGFR to drive IL-8/MIP-2 production, and supports vessel maturation by stimulating endothelial PDGF-BB and HB-EGF, serving as an α5β1/α6β1 integrin adhesion and haptotactic substrate for pericytes, and inducing pericyte N-cadherin via the sphingosine-1-phosphate receptor [PMID:29483644, PMID:37579864]. Beyond these roles, EMILIN2 promotes platelet aggregation and outside-in signaling for clot retraction [PMID:25658937], activates TLR-4/MyD88/NF-κB signaling to drive macrophage M1 polarization [PMID:35148799], and acts as a macrophage-secreted chemoattractant for mesenchymal cells during bone regeneration while restraining MSC adipogenesis in marrow [PMID:35012633, PMID:38831448].","teleology":[{"year":2001,"claim":"Establishing EMILIN2 as a distinct secreted ECM glycoprotein with an EMILIN1-like multidomain architecture defined the molecular framework for all subsequent functional studies.","evidence":"Yeast two-hybrid using EMILIN1 gC1q as bait, cDNA cloning, secretion assay, and immunolocalization","pmids":["11278945"],"confidence":"Medium","gaps":["No function assigned to any domain","Tissue distribution and physiological role unaddressed"]},{"year":2007,"claim":"Identifying direct DR4/DR5 binding and DISC-dependent caspase activation revealed EMILIN2 as a pro-apoptotic ECM ligand engaging the extrinsic death pathway.","evidence":"Receptor binding assays, lipid raft fractionation, DISC and caspase assays, siRNA knockdown and overexpression in transformed cells","pmids":["17698584"],"confidence":"High","gaps":["Domain mediating death-receptor binding not mapped","In vivo relevance of apoptotic role not tested"]},{"year":2014,"claim":"Demonstrating EMI-domain-dependent Wnt1 sequestration showed EMILIN2 inhibits canonical Wnt/β-catenin/TAZ signaling at the ligand-receptor step, providing a tumor-suppressive mechanism.","evidence":"Co-IP, LRP6 phosphorylation and β-catenin/TAZ blots, EMI-deletion mutant, GSK3-inhibitor rescue, xenografts","pmids":["24374807"],"confidence":"High","gaps":["Stoichiometry of Wnt1 sequestration unresolved","Cross-talk with apoptotic signaling unaddressed"]},{"year":2014,"claim":"Mapping the domain basis of EMILIN1–EMILIN2 assembly clarified how these proteins build homo- and hetero-multimeric ECM networks.","evidence":"Quantitative Y2H, reciprocal Co-IP from co-transfected cells, immunofluorescence on cells and tissue","pmids":["25445627"],"confidence":"Medium","gaps":["No high-resolution structure of multimers","Functional consequence of hetero-multimerization not tested"]},{"year":2015,"claim":"Genetic and add-back studies defined EMILIN2 as a positive regulator of platelet aggregation and clot retraction via outside-in signaling, opposing EMILIN1.","evidence":"Global and platelet-specific KO mice, aggregation assays, purified protein add-back, ferric chloride injury, clot retraction assay","pmids":["25658937"],"confidence":"High","gaps":["Platelet receptor for EMILIN2 not identified","Molecular basis of opposing EMILIN1/EMILIN2 effects unknown"]},{"year":2016,"claim":"Showing that EMILIN2 deposition requires fibronectin and intact fibrillin microfibrils established how the protein is integrated into the ECM scaffold.","evidence":"Immunoelectron and immunofluorescence microscopy, ECM extraction, fibrillin-1 KO mice, dermal fibroblasts","pmids":["26945878"],"confidence":"Medium","gaps":["Direct fibrillin–EMILIN2 binding not reconstituted","Domain mediating microfibril targeting not defined"]},{"year":2018,"claim":"Identifying direct EGFR binding and downstream IL-8/MIP-2 induction established EMILIN2 as a pro-angiogenic factor with an in vivo rescuable phenotype.","evidence":"EGFR binding assay, IL-8/MIP-2 ELISA, Emilin2 KO retinal vascular development, MIP-2 rescue, tumor vascular analysis","pmids":["29483644"],"confidence":"High","gaps":["EGFR-binding domain unmapped","Relationship between pro-angiogenic and pro-apoptotic activities unresolved"]},{"year":2022,"claim":"Linking EMILIN2 to TLR-4/MyD88/NF-κB signaling defined it as a driver of macrophage M1 polarization shaping the tumor immune microenvironment.","evidence":"Emilin-2 KO AOM/DSS colorectal model, flow cytometry, ex vivo macrophage cultures, western blot for the pathway","pmids":["35148799"],"confidence":"Medium","gaps":["Direct TLR-4 binding not demonstrated","Domain engaging TLR-4 unknown"]},{"year":2022,"claim":"Bone-marrow studies showed EMILIN2 is MSC-secreted, restrains adipogenic differentiation, and supports HSPC frequency during aging.","evidence":"Bone marrow immunodetection, MSC cultures, adipogenic differentiation assay, HSPC flow cytometry in WT vs KO mice","pmids":["35012633"],"confidence":"Medium","gaps":["Receptor/pathway mediating adipogenic inhibition unknown","Mechanism of HSPC support undefined"]},{"year":2023,"claim":"Dissecting endothelial growth-factor induction, integrin engagement, and S1P-dependent N-cadherin induction established EMILIN2 as a multi-mechanism driver of pericyte recruitment and vascular stabilization.","evidence":"Recombinant Emilin2 endothelial stimulation, integrin binding/blocking, haptotaxis, N-cadherin blots, S1P receptor inhibition, KO tumor vascular analysis","pmids":["37579864"],"confidence":"High","gaps":["Domains mediating integrin and S1P-axis effects not mapped","Integration with EGFR-driven angiogenesis unresolved"]},{"year":2024,"claim":"Identifying E6-enhanced EMILIN2–SNX27 interaction revealed a viral mechanism that blocks EMILIN2 secretion to relieve Wnt1 inhibition and promote proliferation.","evidence":"GFP-SNX27 pulldown/MS, Co-IP, HPV-18 E6 PBM-mutant analysis, Wnt1 binding and proliferation assays","pmids":["38874360"],"confidence":"Medium","gaps":["Trafficking fate of retained EMILIN2 not resolved","Generalizability beyond HPV-18 E6 untested"]},{"year":2024,"claim":"Demonstrating macrophage-derived EMILIN2 as a chemoattractant for mesenchymal cells established its role in recruiting progenitors during bone regeneration.","evidence":"Migration assays, LC-MS/MS identification, Emilin2 KO bone injury model, histology, recombinant protein rescue","pmids":["38831448"],"confidence":"Medium","gaps":["Receptor mediating mesenchymal chemotaxis unidentified","Relationship to MSC adipogenic and integrin functions unclear"]},{"year":null,"claim":"How EMILIN2's individual domains are partitioned among its many ligands (DR4/DR5, Wnt1, EGFR, integrins, TLR-4) and how these activities are coordinated in a single ECM protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the full-length protein with its receptors","Domain-resolved ligand map incomplete for most partners","No human Mendelian disease link established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,2,6,9]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[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":[0,5]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,11]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[5]}],"complexes":["death-inducing signaling complex (DISC)","fibrillin microfibril network"],"partners":["EMILIN1","DR4","DR5","WNT1","EGFR","SNX27","FN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BXX0","full_name":"EMILIN-2","aliases":["Elastin microfibril interface-located protein 2","Elastin microfibril interfacer 2","Protein FOAP-10"],"length_aa":1053,"mass_kda":115.7,"function":"May be responsible for anchoring smooth muscle cells to elastic fibers, and may be involved not only in the formation of the elastic fiber, but also in the processes that regulate vessel assembly. Has cell adhesive capacity","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q9BXX0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EMILIN2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EMILIN2","total_profiled":1310},"omim":[{"mim_id":"608929","title":"ELASTIN MICROFIBRIL INTERFACER 3; EMILIN3","url":"https://www.omim.org/entry/608929"},{"mim_id":"608928","title":"ELASTIN MICROFIBRIL INTERFACER 2; EMILIN2","url":"https://www.omim.org/entry/608928"},{"mim_id":"130660","title":"ELASTIN MICROFIBRIL INTERFACER 1; EMILIN1","url":"https://www.omim.org/entry/130660"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"parathyroid gland","ntpm":71.6}],"url":"https://www.proteinatlas.org/search/EMILIN2"},"hgnc":{"alias_symbol":["FLJ33200","FOAP-10"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXX0","domains":[{"cath_id":"-","chopping":"48-110","consensus_level":"high","plddt":78.6614,"start":48,"end":110},{"cath_id":"2.60.120.40","chopping":"908-1049","consensus_level":"high","plddt":82.0813,"start":908,"end":1049}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXX0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXX0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXX0-F1-predicted_aligned_error_v6.png","plddt_mean":65.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EMILIN2","jax_strain_url":"https://www.jax.org/strain/search?query=EMILIN2"},"sequence":{"accession":"Q9BXX0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXX0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXX0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXX0"}},"corpus_meta":[{"pmid":"17698584","id":"PMC_17698584","title":"Regulation of the extrinsic apoptotic pathway by the extracellular matrix glycoprotein EMILIN2.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17698584","citation_count":61,"is_preprint":false},{"pmid":"24374807","id":"PMC_24374807","title":"EMILIN2 down-modulates the Wnt signalling pathway and suppresses breast cancer cell growth and migration.","date":"2014","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24374807","citation_count":51,"is_preprint":false},{"pmid":"29483644","id":"PMC_29483644","title":"The ablation of the matricellular protein EMILIN2 causes defective vascularization due to impaired EGFR-dependent IL-8 production affecting tumor growth.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29483644","citation_count":50,"is_preprint":false},{"pmid":"11278945","id":"PMC_11278945","title":"Isolation and characterization of EMILIN-2, a new component of the growing EMILINs family and a member of the EMI domain-containing superfamily.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278945","citation_count":50,"is_preprint":false},{"pmid":"26945878","id":"PMC_26945878","title":"Targeting of EMILIN-1 and EMILIN-2 to Fibrillin Microfibrils Facilitates their Incorporation into the Extracellular Matrix.","date":"2016","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/26945878","citation_count":40,"is_preprint":false},{"pmid":"35148799","id":"PMC_35148799","title":"Colorectal cancer development is affected by the ECM molecule EMILIN-2 hinging on macrophage polarization via the TLR-4/MyD88 pathway.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35148799","citation_count":27,"is_preprint":false},{"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},{"pmid":"25445627","id":"PMC_25445627","title":"Multiple-interactions among EMILIN1 and EMILIN2 N- and C-terminal domains.","date":"2014","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/25445627","citation_count":20,"is_preprint":false},{"pmid":"33543026","id":"PMC_33543026","title":"Deregulated expression of Elastin Microfibril Interfacer 2 (EMILIN2) in gastric cancer affects tumor growth and angiogenesis.","date":"2020","source":"Matrix biology plus","url":"https://pubmed.ncbi.nlm.nih.gov/33543026","citation_count":18,"is_preprint":false},{"pmid":"25658937","id":"PMC_25658937","title":"EMILIN2 regulates platelet activation, thrombus formation, and clot retraction.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25658937","citation_count":17,"is_preprint":false},{"pmid":"21569335","id":"PMC_21569335","title":"EMILIN2 (Elastin microfibril interface located protein), potential modifier of thrombosis.","date":"2011","source":"Thrombosis journal","url":"https://pubmed.ncbi.nlm.nih.gov/21569335","citation_count":15,"is_preprint":false},{"pmid":"34299131","id":"PMC_34299131","title":"The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34299131","citation_count":15,"is_preprint":false},{"pmid":"35012633","id":"PMC_35012633","title":"Emilin-2 is a component of bone marrow extracellular matrix regulating mesenchymal stem cell differentiation and hematopoietic progenitors.","date":"2022","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35012633","citation_count":13,"is_preprint":false},{"pmid":"23593459","id":"PMC_23593459","title":"Identification of an interstitial 18p11.32-p11.31 duplication including the EMILIN2 gene in a family with porokeratosis of Mibelli.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23593459","citation_count":10,"is_preprint":false},{"pmid":"37579864","id":"PMC_37579864","title":"Emilin2 fosters vascular stability by promoting pericyte recruitment.","date":"2023","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/37579864","citation_count":9,"is_preprint":false},{"pmid":"38831448","id":"PMC_38831448","title":"Emilin2 marks the target region for mesenchymal cell accumulation in bone regeneration.","date":"2024","source":"Inflammation and regeneration","url":"https://pubmed.ncbi.nlm.nih.gov/38831448","citation_count":3,"is_preprint":false},{"pmid":"38874360","id":"PMC_38874360","title":"HPV-18 E6 enhances the interaction between EMILIN2 and SNX27 to promote WNT signaling.","date":"2024","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/38874360","citation_count":1,"is_preprint":false},{"pmid":"41426194","id":"PMC_41426194","title":"Retraction notice to \"Deregulated expression of Elastin Microfibril Interfacer 2 (EMILIN2) in gastric cancer affects tumor growth and angiogenesis.\" [Matrix Biol. Plus 6-7 (2020) 100029].","date":"2025","source":"Matrix biology plus","url":"https://pubmed.ncbi.nlm.nih.gov/41426194","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11282,"output_tokens":3703,"usd":0.044695,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11360,"output_tokens":4282,"usd":0.081925,"stage2_stop_reason":"end_turn"},"total_usd":0.12662,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"EMILIN2 was isolated using the EMILIN1 gC1q domain as bait in a yeast two-hybrid screen, establishing that EMILIN2 is an extracellular matrix glycoprotein with domain organization superimposable to EMILIN1 (EMI domain, coiled-coil region, collagenous stalk, C-terminal gC1q domain), secreted extracellularly by in vitro-grown cells, and partially co-localizes with EMILIN1 in vitro.\",\n      \"method\": \"Yeast two-hybrid, cDNA cloning, protein secretion assay, immunolocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (Y2H, secretion assay, immunolocalization) in single foundational paper establishing basic biochemistry\",\n      \"pmids\": [\"11278945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EMILIN2 triggers apoptosis in multiple cell lines by directly binding death receptors DR4 (and to a lesser extent DR5), leading to receptor clustering, colocalization with lipid rafts, death-inducing signaling complex (DISC) assembly, and caspase activation via the extrinsic apoptotic pathway. Knockdown of EMILIN2 increases transformed cell survival; overexpression impairs clonogenicity.\",\n      \"method\": \"Binding assays (EMILIN2–DR4/DR5 interaction), lipid raft fractionation, DISC assembly assay, caspase activation assay, siRNA knockdown, overexpression in soft agar and 3D matrix assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (receptor binding, DISC assembly, caspase activation, KD and OE phenotypes) in single rigorous study; novel mechanism well-supported\",\n      \"pmids\": [\"17698584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EMILIN2 directly binds the Wnt1 ligand (interaction demonstrated by co-immunoprecipitation), leading to decreased LRP6 phosphorylation and down-modulation of β-catenin, TAZ, and their target genes, thereby attenuating Wnt signaling. This interaction requires the EMI domain of EMILIN2, as a deletion mutant lacking the EMI domain shows no effect. EMILIN2 does not affect Wnt signaling downstream of Wnt-Frizzled interaction (no effect on GSK3 inhibitor-activated pathway).\",\n      \"method\": \"Co-immunoprecipitation (EMILIN2–Wnt1 binding), LRP6 phosphorylation assay, β-catenin/TAZ western blot, EMI domain deletion mutant, GSK3 inhibitor rescue, in vivo xenograft, 2D and 3D cell viability/migration assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated by Co-IP, domain mutant validates mechanism, in vivo rescue, multiple orthogonal functional readouts, single rigorous study\",\n      \"pmids\": [\"24374807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EMILIN1 and EMILIN2 interact via their gC1q and EMI domains: gC1q domains self-interact and interact with EMI domains, but no EMI-EMI self-interactions were detected. Full-length EMILIN1 and EMILIN2 form non-covalent homo- and hetero-multimers, consistent with head-to-tail and tail-to-tail assemblies in tissues.\",\n      \"method\": \"Qualitative and quantitative yeast two-hybrid, co-immunoprecipitation from co-transfected 293-EBNA cells, immunofluorescence on mouse cell cultures and tissue sections\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and Y2H in same study, multiple domain constructs tested, single lab\",\n      \"pmids\": [\"25445627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EMILIN2 promotes platelet aggregation and clot retraction: EMILIN2-deficient platelets and EMILIN2-deficient plasma both contribute to impaired aggregation responses to ADP, collagen, and thrombin. Purified EMILIN2 accelerates platelet aggregation and reduces clotting time. Platelet-specific EMILIN2 deficiency doubles carotid occlusion time. In vitro clot retraction is markedly decreased in EMILIN2-deficient mice, indicating that platelet outside-in signaling depends on EMILIN2. EMILIN1 and EMILIN2 have opposing effects on clot retraction.\",\n      \"method\": \"EMILIN2 knockout and platelet-specific KO mice, platelet aggregation assays (ADP/collagen/thrombin), purified protein add-back, carotid ferric chloride injury model, in vitro clot retraction assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (global and platelet-specific KO), purified protein rescue, multiple functional assays, single rigorous study\",\n      \"pmids\": [\"25658937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EMILIN-1 and EMILIN-2 are targeted to fibrillin microfibrils in the skin; their deposition requires fibronectin during wound healing and in vitro matrix assembly. Disruption of microfibrils in fibrillin-1-deficient mice leads to fragmentation of EMILIN-1 and EMILIN-2 networks, establishing fibrillin as required for proper EMILIN2 ECM incorporation.\",\n      \"method\": \"Immunoelectron microscopy, immunofluorescence microscopy, biochemical ECM extraction, fibrillin-1 knockout mouse analysis, primary dermal fibroblast cultures\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple imaging modalities and genetic model, single lab, no reconstitution of direct fibrillin-EMILIN2 binding\",\n      \"pmids\": [\"26945878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EMILIN2 promotes angiogenesis by directly binding EGFR, which enhances IL-8 (MIP-2) production; IL-8 in turn stimulates proliferation and migration of vascular endothelial cells. Emilin2 null mice show delayed retinal vascular development rescued by exogenous MIP-2 administration.\",\n      \"method\": \"EGFR binding assay, IL-8/MIP-2 ELISA, Emilin2 knockout mice, retinal vascular development assay, MIP-2 rescue experiment, tumor growth and vascular density analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct EGFR binding demonstrated, genetic rescue with cytokine, multiple in vivo readouts, single rigorous study with orthogonal methods\",\n      \"pmids\": [\"29483644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EMILIN-2 activates the TLR-4/MyD88/NF-κB pathway in macrophages, promoting their polarization towards the M1 phenotype. Loss of EMILIN-2 in Emilin-2 null mice results in decreased M1 and increased M2 macrophages in colorectal tumors, and earlier MDSC-rich infiltration. Ex vivo macrophage cultures from knockout mice were used to validate the molecular pathway.\",\n      \"method\": \"Emilin-2 knockout mouse AOM/DSS colorectal cancer model, flow cytometry of immune subpopulations, ex vivo monocyte/macrophage cultures, immunohistochemistry, immunofluorescence, western blot for TLR-4/MyD88/NF-κB pathway\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with ex vivo mechanistic validation of pathway, single lab, pathway confirmed in cultured macrophages\",\n      \"pmids\": [\"35148799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Emilin-2 is expressed and secreted by bone marrow mesenchymal stem cells, inhibits their adipogenic differentiation, and is required for normal hematopoietic stem/progenitor cell frequency in bone marrow during aging, as shown in Emilin-2 null mice.\",\n      \"method\": \"Immunodetection in bone marrow sections, primary and immortalized MSC cultures, adipogenic differentiation assay, flow cytometry of HSPCs in wild-type vs. Emilin-2 null mice\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with cellular phenotype readouts and in vitro differentiation assay, single lab\",\n      \"pmids\": [\"35012633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Emilin2 promotes pericyte recruitment and vascular stabilization via multiple mechanisms: (1) stimulating endothelial cells to produce PDGF-BB and HB-EGF; (2) serving as a direct adhesion substrate and haptotactic stimulus for pericytes by engaging α5β1 and α6β1 integrins on pericytes; (3) increasing N-cadherin expression in pericytes via the sphingosine-1-phosphate receptor, enhancing endothelial-pericyte interconnection.\",\n      \"method\": \"Recombinant Emilin2 stimulation of primary endothelial cells (PDGF-BB/HB-EGF ELISA), integrin binding/blocking assays, haptotaxis migration assay, N-cadherin western blot, sphingosine-1-phosphate receptor inhibition, Emilin2-/- tumor vascular analysis, drug delivery assay\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal mechanisms tested with recombinant protein and genetic KO, integrin identification by blocking experiments, in vivo validation, single rigorous study\",\n      \"pmids\": [\"37579864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HPV-18 E6 oncoprotein enhances the interaction between EMILIN2 and SNX27 (a retromer complex PDZ-domain protein), blocking EMILIN2 secretion in a PBM-dependent manner. E6 prevents EMILIN2 from interacting with Wnt1 ligand, thereby enhancing Wnt1 signaling and promoting cell proliferation.\",\n      \"method\": \"SNX27 proteome interaction profiling (GFP-SNX27 pulldown/MS), co-immunoprecipitation, HPV-18 E6 expression and PBM mutant analysis, Wnt1 binding assay, cell proliferation assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome plus Co-IP and functional Wnt binding assay, single lab, mechanistically novel finding\",\n      \"pmids\": [\"38874360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Macrophages produce Emilin2 in response to bone injury, and the secreted Emilin2 acts as a chemoattractant for mesenchymal cells. Emilin2-/- mice show delayed bone regeneration with decreased mesenchymal cell accumulation at injury sites; local administration of recombinant Emilin2 enhances bone regeneration.\",\n      \"method\": \"Migration assay, LC-MS/MS protein identification, Emilin2-/- mouse bone injury model, endoscopy/histology, recombinant protein rescue experiment\",\n      \"journal\": \"Inflammation and regeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemoattractant activity confirmed by migration assay and genetic KO with recombinant protein rescue, single lab\",\n      \"pmids\": [\"38831448\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EMILIN2 is a multifunctional extracellular matrix glycoprotein that: (1) directly binds and clusters death receptors DR4/DR5 to activate the extrinsic apoptotic pathway via DISC assembly and caspase activation; (2) sequesters Wnt1 ligand extracellularly through its EMI domain to attenuate LRP6/β-catenin/TAZ signaling; (3) directly engages EGFR to drive IL-8 production and promote angiogenesis; (4) fosters vascular stabilization by stimulating endothelial PDGF-BB/HB-EGF production and by acting as an α5β1/α6β1 integrin ligand and sphingosine-1-phosphate-dependent N-cadherin inducer in pericytes; (5) activates TLR-4/MyD88/NF-κB signaling in macrophages to drive M1 polarization; (6) acts as a macrophage-secreted chemoattractant for mesenchymal progenitors during bone repair; (7) promotes platelet aggregation and outside-in signaling for clot retraction; and (8) is incorporated into fibrillin microfibril networks in the ECM through interactions requiring fibronectin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EMILIN2 is a secreted extracellular matrix glycoprotein with an EMILIN1-like domain architecture (EMI domain, coiled-coil, collagenous stalk, C-terminal gC1q domain) that is incorporated into fibrillin microfibril networks and acts as a multifunctional regulator of apoptosis, growth-factor signaling, vascularization, and immune and hematopoietic processes [#0, #5]. Its ECM deposition depends on fibronectin and intact fibrillin microfibrils, and it self-associates and hetero-associates with EMILIN1 through reciprocal gC1q–gC1q and gC1q–EMI domain contacts [#3, #5]. A central activity is pro-apoptotic signaling: EMILIN2 directly binds the death receptor DR4 (and to a lesser extent DR5), driving receptor clustering, lipid-raft colocalization, DISC assembly, and caspase activation through the extrinsic pathway, so that its loss promotes transformed-cell survival [#1]. EMILIN2 also restrains canonical Wnt signaling by using its EMI domain to bind and sequester Wnt1, reducing LRP6 phosphorylation and β-catenin/TAZ activity [#2]; this tumor-suppressive function is subverted by HPV-18 E6, which promotes an EMILIN2–SNX27 interaction that blocks EMILIN2 secretion and relieves Wnt1 inhibition [#10]. In the vasculature, EMILIN2 promotes angiogenesis by directly engaging EGFR to drive IL-8/MIP-2 production, and supports vessel maturation by stimulating endothelial PDGF-BB and HB-EGF, serving as an α5β1/α6β1 integrin adhesion and haptotactic substrate for pericytes, and inducing pericyte N-cadherin via the sphingosine-1-phosphate receptor [#6, #9]. Beyond these roles, EMILIN2 promotes platelet aggregation and outside-in signaling for clot retraction [#4], activates TLR-4/MyD88/NF-κB signaling to drive macrophage M1 polarization [#7], and acts as a macrophage-secreted chemoattractant for mesenchymal cells during bone regeneration while restraining MSC adipogenesis in marrow [#8, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing EMILIN2 as a distinct secreted ECM glycoprotein with an EMILIN1-like multidomain architecture defined the molecular framework for all subsequent functional studies.\",\n      \"evidence\": \"Yeast two-hybrid using EMILIN1 gC1q as bait, cDNA cloning, secretion assay, and immunolocalization\",\n      \"pmids\": [\"11278945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No function assigned to any domain\", \"Tissue distribution and physiological role unaddressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying direct DR4/DR5 binding and DISC-dependent caspase activation revealed EMILIN2 as a pro-apoptotic ECM ligand engaging the extrinsic death pathway.\",\n      \"evidence\": \"Receptor binding assays, lipid raft fractionation, DISC and caspase assays, siRNA knockdown and overexpression in transformed cells\",\n      \"pmids\": [\"17698584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain mediating death-receptor binding not mapped\", \"In vivo relevance of apoptotic role not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating EMI-domain-dependent Wnt1 sequestration showed EMILIN2 inhibits canonical Wnt/β-catenin/TAZ signaling at the ligand-receptor step, providing a tumor-suppressive mechanism.\",\n      \"evidence\": \"Co-IP, LRP6 phosphorylation and β-catenin/TAZ blots, EMI-deletion mutant, GSK3-inhibitor rescue, xenografts\",\n      \"pmids\": [\"24374807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of Wnt1 sequestration unresolved\", \"Cross-talk with apoptotic signaling unaddressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping the domain basis of EMILIN1–EMILIN2 assembly clarified how these proteins build homo- and hetero-multimeric ECM networks.\",\n      \"evidence\": \"Quantitative Y2H, reciprocal Co-IP from co-transfected cells, immunofluorescence on cells and tissue\",\n      \"pmids\": [\"25445627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of multimers\", \"Functional consequence of hetero-multimerization not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetic and add-back studies defined EMILIN2 as a positive regulator of platelet aggregation and clot retraction via outside-in signaling, opposing EMILIN1.\",\n      \"evidence\": \"Global and platelet-specific KO mice, aggregation assays, purified protein add-back, ferric chloride injury, clot retraction assay\",\n      \"pmids\": [\"25658937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Platelet receptor for EMILIN2 not identified\", \"Molecular basis of opposing EMILIN1/EMILIN2 effects unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that EMILIN2 deposition requires fibronectin and intact fibrillin microfibrils established how the protein is integrated into the ECM scaffold.\",\n      \"evidence\": \"Immunoelectron and immunofluorescence microscopy, ECM extraction, fibrillin-1 KO mice, dermal fibroblasts\",\n      \"pmids\": [\"26945878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct fibrillin–EMILIN2 binding not reconstituted\", \"Domain mediating microfibril targeting not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying direct EGFR binding and downstream IL-8/MIP-2 induction established EMILIN2 as a pro-angiogenic factor with an in vivo rescuable phenotype.\",\n      \"evidence\": \"EGFR binding assay, IL-8/MIP-2 ELISA, Emilin2 KO retinal vascular development, MIP-2 rescue, tumor vascular analysis\",\n      \"pmids\": [\"29483644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EGFR-binding domain unmapped\", \"Relationship between pro-angiogenic and pro-apoptotic activities unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking EMILIN2 to TLR-4/MyD88/NF-κB signaling defined it as a driver of macrophage M1 polarization shaping the tumor immune microenvironment.\",\n      \"evidence\": \"Emilin-2 KO AOM/DSS colorectal model, flow cytometry, ex vivo macrophage cultures, western blot for the pathway\",\n      \"pmids\": [\"35148799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TLR-4 binding not demonstrated\", \"Domain engaging TLR-4 unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Bone-marrow studies showed EMILIN2 is MSC-secreted, restrains adipogenic differentiation, and supports HSPC frequency during aging.\",\n      \"evidence\": \"Bone marrow immunodetection, MSC cultures, adipogenic differentiation assay, HSPC flow cytometry in WT vs KO mice\",\n      \"pmids\": [\"35012633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/pathway mediating adipogenic inhibition unknown\", \"Mechanism of HSPC support undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Dissecting endothelial growth-factor induction, integrin engagement, and S1P-dependent N-cadherin induction established EMILIN2 as a multi-mechanism driver of pericyte recruitment and vascular stabilization.\",\n      \"evidence\": \"Recombinant Emilin2 endothelial stimulation, integrin binding/blocking, haptotaxis, N-cadherin blots, S1P receptor inhibition, KO tumor vascular analysis\",\n      \"pmids\": [\"37579864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domains mediating integrin and S1P-axis effects not mapped\", \"Integration with EGFR-driven angiogenesis unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying E6-enhanced EMILIN2–SNX27 interaction revealed a viral mechanism that blocks EMILIN2 secretion to relieve Wnt1 inhibition and promote proliferation.\",\n      \"evidence\": \"GFP-SNX27 pulldown/MS, Co-IP, HPV-18 E6 PBM-mutant analysis, Wnt1 binding and proliferation assays\",\n      \"pmids\": [\"38874360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking fate of retained EMILIN2 not resolved\", \"Generalizability beyond HPV-18 E6 untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating macrophage-derived EMILIN2 as a chemoattractant for mesenchymal cells established its role in recruiting progenitors during bone regeneration.\",\n      \"evidence\": \"Migration assays, LC-MS/MS identification, Emilin2 KO bone injury model, histology, recombinant protein rescue\",\n      \"pmids\": [\"38831448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating mesenchymal chemotaxis unidentified\", \"Relationship to MSC adipogenic and integrin functions unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EMILIN2's individual domains are partitioned among its many ligands (DR4/DR5, Wnt1, EGFR, integrins, TLR-4) and how these activities are coordinated in a single ECM protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the full-length protein with its receptors\", \"Domain-resolved ligand map incomplete for most partners\", \"No human Mendelian disease link established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 2, 6, 9]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"death-inducing signaling complex (DISC)\",\n      \"fibrillin microfibril network\"\n    ],\n    \"partners\": [\n      \"EMILIN1\",\n      \"DR4\",\n      \"DR5\",\n      \"WNT1\",\n      \"EGFR\",\n      \"SNX27\",\n      \"FN1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}