{"gene":"EMILIN1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1993,"finding":"EMILIN-1 (then called 'emilin') localizes preferentially at the elastin-microfibril interface within elastic fibers, and anti-emilin antibodies added to culture medium severely alter elastin deposition by aorta cells, demonstrating a direct role in elastogenesis.","method":"Immunoelectron microscopy (post- and pre-embedding immunolabeling), quantitative gold-particle distribution analysis, and antibody inhibition in cell culture","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization by immunoelectron microscopy with quantitative analysis, functionally validated by antibody perturbation of elastin deposition, replicated across multiple tissues","pmids":["8458869"],"is_preprint":false},{"year":1999,"finding":"Human EMILIN-1 encodes a 1016-aa protein with a C-terminal gC1q-like globular domain (adopting high β-sheet content by CD), a collagenous stalk, coiled-coil/leucine-zipper region, and an N-terminal cysteine-rich (EMI) domain; the recombinant gC1q domain promotes cell adhesion.","method":"cDNA cloning, RT-PCR, peptide sequencing, CD spectroscopy, recombinant protein expression, cell adhesion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical and structural methods in one study; domain architecture and adhesion activity directly demonstrated","pmids":["10358019"],"is_preprint":false},{"year":2000,"finding":"The EMILIN-1 gC1q domain self-assembles into homotrimers (demonstrated by yeast two-hybrid and native gel migration) and the full-length protein forms large disulfide-bonded multimers of many millions of daltons; the C-terminal gC1q and collagenous domains are essential for trimer formation.","method":"Yeast two-hybrid, native PAGE, reducing/non-reducing agarose gels, recombinant domain expression, truncation constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — yeast two-hybrid in vivo interaction confirmed biochemically by native gel oligomeric state; truncation mutants establish domain requirements","pmids":["10821830"],"is_preprint":false},{"year":2002,"finding":"Cell adhesion to EMILIN-1 is mediated by the gC1q domain engaging the α4β1 integrin; a function-blocking anti-gC1q mAb completely blocks attachment, and only α4-transfected K562 cells (not wild-type K562) adhere to EMILIN-1. Cells on EMILIN-1 show ruffled morphology without stress fibers, consistent with promotion of cell motility rather than strong adhesion.","method":"Monoclonal antibody inhibition assays, cell adhesion kinetics, adhesion-strength centrifugation, K562 α4-transfection, actin cytoskeleton imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional blocking with mAbs and gain-of-function transfection with integrin α4; multiple orthogonal methods in one study","pmids":["12456677"],"is_preprint":false},{"year":2004,"finding":"Emilin1-/- mice show abnormal elastic fiber formation in aorta and skin, and altered morphology and anchorage of endothelial and smooth muscle cells to elastic lamellae, demonstrating EMILIN-1's role in elastogenesis and vascular cell maintenance.","method":"Mouse gene targeting (knockout), histology, ultrastructural analysis by electron microscopy, embryonic fibroblast cultures","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive KO with defined structural and cellular phenotypes, multiple tissues examined, replicated in cultured fibroblasts","pmids":["14701737"],"is_preprint":false},{"year":2006,"finding":"EMILIN-1 acts as a negative regulator of TGF-β processing and signaling in the vasculature; Emilin1-/- mice display elevated blood pressure due to increased TGF-β activity. EMILIN-1 inhibits pro-TGF-β proteolysis, limiting TGF-β bioavailability.","method":"Emilin1-/- mouse model, blood pressure measurement, vascular TGF-β signaling assays (referenced in Cell commentary citing Zacchigna et al. 2006 paper); rescue experiments with anti-TGF-β antibodies (PMID 22814752)","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse phenotype (hypertension) rescued by anti-TGF-β antibody neutralization, independently replicated and mechanistically elaborated in multiple subsequent papers","pmids":["16530037","22814752"],"is_preprint":false},{"year":2006,"finding":"EMILIN-1 in the uterine stroma promotes α4β1 integrin-dependent haptotactic migration of extravillous trophoblasts; function-blocking anti-α4 and anti-EMILIN-1 mAbs and EMILIN-1 siRNA each block trophoblast interaction with EMILIN-1/gC1q. Co-culture upregulates MT1-MMP and MMP-2.","method":"Haptotaxis assays with freshly isolated EVT and HTR-8/SVneo cells, function-blocking mAbs, siRNA knockdown, co-culture MMP assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — three orthogonal inhibitory approaches (mAb, siRNA, receptor-blocking) converging on the same α4β1-gC1q mechanism","pmids":["17074837"],"is_preprint":false},{"year":2008,"finding":"The NMR solution structure of the EMILIN-1 gC1q homotrimer reveals a nine-stranded β-sandwich (missing one strand versus typical 10-stranded gC1q fold), with a unique disordered 19-residue protruding loop at the trimer apex; site-directed mutagenesis of Glu933 within this loop abrogates α4β1 integrin binding, T-cell adhesion under static and flow conditions, and endothelial cell haptotactic migration.","method":"NMR-based homology modeling, TROSY NMR, site-directed mutagenesis (E933A), Jurkat T-cell and EA.hy926 endothelial cell adhesion assays under static and flow conditions","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional validation by mutagenesis across multiple cell types and assay conditions","pmids":["18463100"],"is_preprint":false},{"year":2008,"finding":"Emilin1 deficiency leads to lymphatic vessel hyperplasia, enlargement, irregular patterning, reduction of anchoring filaments, enhanced lymphangioma formation, lymphedema, and compromised lymph drainage, identifying EMILIN-1 as a regulator of lymphatic vessel growth and integrity.","method":"Emilin1-/- mouse model (CD1 and C57BL/6 backgrounds), histology, ultrastructural analysis, lymphangiography, lymph drainage assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse phenotype characterized across two genetic backgrounds with functional lymphatic drainage measurements","pmids":["18411305"],"is_preprint":false},{"year":2011,"finding":"EMILIN-1 directly engages α4β1 and α9β1 integrins via its gC1q domain (E933 residue) to inhibit dermal fibroblast and keratinocyte proliferation; loss of this interaction in Emilin1-/- skin causes dermal/epidermal hyperproliferation via reduced PTEN, activation of PI3K/Akt and Erk1/2, and Erk1/2-mediated inhibitory phosphorylation of Smad2 at Ser245/250/255, suppressing TGF-β/Smad signaling.","method":"Emilin1-/- KO mouse, wound closure assays, function-blocking mAbs against α4 and α9 integrins, pathway analysis (phospho-immunoblots for Akt, Erk1/2, PTEN, Smad2), identification of EMILIN-1 as novel α9β1 ligand in keratinocytes","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO phenotype plus antibody blocking plus signaling pathway dissection, multiple orthogonal methods identifying the downstream cascade","pmids":["21949412"],"is_preprint":false},{"year":2012,"finding":"Vascular smooth muscle cell-derived EMILIN-1 (not endothelial cell-derived) is the functional source controlling resting blood pressure; its mechanism involves suppression of arteriolar myogenic tone through restraint of TGF-β activity, as shown by TGF-β antibody normalization of BP in Emilin1-/- mice and selective SMC-restricted transgenic rescue.","method":"Cell-type-specific transgenic rescue in Emilin1-/- background (SMC vs. endothelial promoters), anti-TGF-β antibody treatment, ex vivo resistance artery myogenic tone measurement","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific transgenic rescue plus pharmacological TGF-β neutralization, multiple functional readouts","pmids":["22814752"],"is_preprint":false},{"year":2013,"finding":"EMILIN-1 interaction with α9β1 integrin, mediated by the E933 residue of the gC1q domain, is required for lymphatic valve formation and maintenance; mice expressing E933A-mutant EMILIN-1 (unable to engage α4/α9 integrins) display defective lymphatic valve structure and lymph flow, caused by deranged lymphatic endothelial cell proliferation and migration.","method":"Emilin1-/- KO mouse, E933A transgenic knock-in mouse, morphometric in vitro and in vivo assays, lymphangiography, cell proliferation and migration assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two complementary transgenic models (KO and point mutant) with functional lymphatic assays and in vitro mechanistic validation","pmids":["24019067"],"is_preprint":false},{"year":2014,"finding":"Neutrophil elastase cleaves EMILIN-1 into three-to-four fragments, abolishing its anti-proliferative function; this cleavage mechanism is operative in sarcomas and ovarian cancers where PMN infiltration and elastase positivity are detected.","method":"In vitro protease cleavage assay with neutrophil elastase, SDS-PAGE fragment analysis, proliferation assays with cleaved versus intact EMILIN-1, immunostaining of tumor specimens for elastase and EMILIN-1","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic cleavage assay linked to functional loss, corroborated by pathological specimens","pmids":["24513040"],"is_preprint":false},{"year":2014,"finding":"In the Emilin1-/- aortic valve, early elastic fiber fragmentation is followed by aberrant angiogenesis and late fibrosis; constitutive canonical TGF-β (pSmad2/3) signaling is upregulated from birth, while non-canonical TGF-β (pErk1/2 MAPK) signaling progressively increases, mediating advanced fibrotic disease.","method":"Emilin1-/- mouse model, histology, immunohistochemistry, electron microscopy, quantitative gene expression, immunoblotting, echocardiography","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple analytical methods but signaling pathway assignment based on correlative immunoblot; single lab","pmids":["25056700"],"is_preprint":false},{"year":2015,"finding":"A heterozygous missense mutation p.A22T in EMILIN-1 (mapping near the signal peptide cleavage site) causes impaired protein secretion with accumulation in the endoplasmic reticulum, reduced extracellular deposition, and disorganized fibrillar architecture in patient skin, segregating with an autosomal-dominant connective tissue disorder.","method":"Trio exome sequencing, Sanger sequencing for familial segregation, transfection of mutant construct with ER localization assessment, skin biopsy immunostaining","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay (transfection showing ER retention) plus patient skin biopsy, single lab, one family","pmids":["26462740"],"is_preprint":false},{"year":2016,"finding":"EMILIN-1 and EMILIN-2 are incorporated into fibrillin microfibril networks in skin; fibrillin-1 deficiency disrupts EMILIN-1/2 networks. EMILIN-1/2 deposition during wound healing also requires fibronectin as an assembly scaffold.","method":"Immunoelectron microscopy, immunofluorescence, biochemical extraction, analysis of fibrillin-1-deficient mouse skin, wound healing model, embryonic fibroblast matrix assembly","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal localization methods plus fibrillin-1 KO disruption experiment and fibronectin dependency demonstrated in two experimental systems","pmids":["26945878"],"is_preprint":false},{"year":2016,"finding":"In a mouse post-surgical tail lymphedema model, neutrophil elastase released by infiltrating neutrophils degrades EMILIN-1 in the acute phase, weakening lymphatic endothelial cell junctions and impairing drainage; local administration of the NE inhibitor sivelestat prevents EMILIN-1 cleavage and reduces lymphedema. Cleaved EMILIN-1 fragments with NE-dependent patterns are also detected in human secondary lymphedema.","method":"Mouse tail lymphedema model, NE inhibitor (sivelestat) treatment, EMILIN-1 integrity immunoblot, lymphatic junction analysis, lymph drainage assay, human lymphedema biopsy immunostaining","journal":"Clinical science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo pharmacological intervention (NE inhibitor) rescuing both EMILIN-1 integrity and lymphatic function, validated in human samples","pmids":["26920215"],"is_preprint":false},{"year":2017,"finding":"Neutrophil elastase cleaves the EMILIN-1 gC1q domain at the S913-R914 peptide bond (outside the E933 integrin-binding site), disrupting gC1q structural conformation and abolishing α4β1 integrin interaction; the R914W mutant is resistant to NE cleavage and retains integrin-binding and anti-proliferative activity. MMP-3 and MT1-MMP partially cleave EMILIN-1 but do not impair gC1q-α4β1 function.","method":"In vitro protease cleavage assays (NE, MMP-3, MMP-9, MT1-MMP), site-directed mutagenesis (R914W NE-resistant mutant), cell adhesion and proliferation assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — precise cleavage site mapped by mutagenesis, function rescued with resistant mutant, multiple proteases tested comparatively","pmids":["28074935"],"is_preprint":false},{"year":2017,"finding":"EMILIN-1 gC1q silences the RAS-ERK proliferative pathway via α4β1 integrin through ubiquitination of HRas-GTP; α4 integrin co-immunoprecipitates ubiquitinated HRas only when ligated by gC1q, and this anti-proliferative effect requires the intact cytoplasmic tail of the α4 integrin chain.","method":"Cell plating on gC1q, phospho-ERK immunoblots, HRas-GTP pull-down with ubiquitinated HRas detection, co-immunoprecipitation, α4 truncation mutant transfection, salirasib (Ras inhibitor) pharmacology","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of ubiquitinated HRas with α4, pharmacological and genetic (truncation) dissection of the signaling pathway, multiple orthogonal approaches","pmids":["28177903"],"is_preprint":false},{"year":2017,"finding":"EMILIN-1 depletion from osteoblasts by RNAi selectively abolishes fibulin-4 matrix deposition without affecting other fibulins or LTBPs; direct interaction between EMILIN-1 and fibulin-4 was confirmed by immunoprecipitation and ELISA-style binding assay.","method":"RNAi knockdown in primary calvarial osteoblasts and MC3T3-E1 cells, immunofluorescence, electron microscopy, immunoprecipitation, ELISA-style binding assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding confirmed by two orthogonal biochemical methods, functional consequence (selective fibulin-4 loss) established by KD","pmids":["28717224"],"is_preprint":false},{"year":2017,"finding":"The α4β1-EMILIN-1 gC1q interaction requires all three E933 residues of the homotrimer simultaneously; molecular docking of the NMR gC1q structure onto a virtual α4β1 model shows the three E933 residues coordinate the Mg²⁺ ion at the βI MIDAS site, and R904 acts as a synergistic residue via intra-chain salt bridges with E928/E930.","method":"Site-directed mutagenesis, cell adhesion assays, docking of NMR structure to virtual α4β1 crystal structure, structural modelling","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 1 (NMR structure + mutagenesis) / Moderate — single lab; MIDAS coordination model is computational but mutagenesis is experimental","pmids":["29037761"],"is_preprint":false},{"year":2018,"finding":"Loss of smooth muscle cell EMILIN-1 in adult mice via conditional gene targeting increases blood pressure through enhanced arteriolar myogenic tone; mechanistically, higher TGF-β in smooth muscle cells drives HB-EGF expression and EGFR transactivation, which recruits TRPC6 and TRPM4 channels to potentiate voltage-dependent calcium channels and myogenic tone. Reduced EMILIN-1 and enhanced TGF-β-EGFR signaling are found in resistance arteries from hypertensive patients.","method":"Conditional SMC-specific Emilin1 knockout, ex vivo myogenic tone measurement, immunoblotting for TGF-β, HB-EGF, pEGFR, TRPC6/TRPM4 signaling, pharmacological EGFR and TRP channel inhibition, human hypertensive patient biopsy","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus pharmacological pathway dissection plus human validation; multiple orthogonal experiments in one study","pmids":["30354220"],"is_preprint":false},{"year":2018,"finding":"The EMILIN-1 gC1q/E933-integrin interaction is required for normal lymphangiogenesis; E933A-mutant transgenic mice show abnormal dense, tortuous lymphatic networks, reduced anchoring filaments, aberrant narrowed collecting valves, impaired lymph transport, and enhanced lymph node metastasis. Lymphatic endothelial cells from E1-E933A mice have severely reduced sprouting capacity in ex vivo thoracic duct ring assays.","method":"E933A transgenic knock-in mouse, lymphangiography, morphometry, ex vivo thoracic duct ring assay, in vitro tubulogenesis assay, lymph node metastasis assay","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise point mutant abrogating integrin binding with multiple in vivo and ex vivo functional readouts; reciprocal confirmation with Emilin1-/- data","pmids":["30408617"],"is_preprint":false},{"year":2010,"finding":"EMILIN-1 is colocalized with fibrillin-1 in periodontal ligament cells, co-immunoprecipitates with fibrillin-1, and siRNA-mediated knockdown of EMILIN-1 reduces fibrillin-1 extracellular deposition to 23% of control, indicating EMILIN-1 regulates oxytalan fiber/microfibril formation.","method":"siRNA knockdown in PDL cell culture, immunofluorescence quantification of fibrillin-1 deposition, co-immunoprecipitation","journal":"Connective tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional KD demonstrating deposition requirement, single lab","pmids":["20701466"],"is_preprint":false},{"year":2012,"finding":"The EMILIN-1 gC1q and EMI domains can interact with each other and self-interact (gC1q-gC1q); full-length EMILIN-1 and EMILIN-2 can form non-covalent homo- and hetero-multimers, suggesting head-to-tail and tail-to-tail assemblies.","method":"Yeast two-hybrid (qualitative and quantitative), co-immunoprecipitation from co-transfected cell extracts, immunofluorescence co-localization","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP, single lab","pmids":["25445627"],"is_preprint":false},{"year":2012,"finding":"CNGA3 cyclic nucleotide-gated channel binds to the intracellular C-terminus domain of EMILIN-1; this interaction was identified by yeast two-hybrid and confirmed by surface plasmon resonance with Ca²⁺-dependent kinetics (Kd ~10⁻⁶–10⁻⁷ M) and pull-down assays in inner ear hair cell and organ of Corti systems.","method":"Yeast two-hybrid, surface plasmon resonance, pull-down assay, immunolocalization in saccular hair cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by SPR (quantitative binding) and pull-down; single lab, intracellular domain interaction context unusual for an ECM protein","pmids":["22248097"],"is_preprint":false},{"year":2019,"finding":"Loss of EMILIN-1/β1 integrin interaction (via Emilin1-/- or E933A knock-in mice) promotes AOM-DSS colon tumor development with higher incidence and larger adenomas, increased lymphangiogenesis with dysfunctional lymphatics, and increased inflammatory infiltrates, demonstrating EMILIN-1-integrin interaction restrains colitis-associated carcinogenesis and maintains lymphatic drainage of inflammatory cells.","method":"AOM-DSS carcinogenesis protocol in Emilin1-/- and E1-E933A transgenic mice, histopathology, lymphatic vessel functional assessment, inflammatory cell scoring","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two complementary genetic models (KO and point mutant) with multiple in vivo functional endpoints","pmids":["31479698"],"is_preprint":false},{"year":2019,"finding":"Co-immunoprecipitation and immunofluorescence in gastric cancer cells demonstrate that EMILIN-1 and TSPAN9 interact and co-localize; EMILIN-1 overexpression boosts TSPAN9 expression and synergistically enhances the TSPAN9-dependent inhibition of gastric cancer cell migration and invasion.","method":"Co-immunoprecipitation, immunofluorescence co-localization, overexpression and knockdown functional assays (wound healing, invasion), Western blot","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP interaction plus functional assays; single lab with two orthogonal methods","pmids":["31242895"],"is_preprint":false},{"year":2019,"finding":"EMILIN-1 co-immunoprecipitates with elastin and collagen IV in human skin fibroblasts; it colocalizes with elastin, fibrillin-1, and collagen IV including at the basement membrane. siRNA knockdown of EMILIN-1 downregulates FGFR2 expression and COL6A1.","method":"Co-immunoprecipitation, multiphoton microscopy co-localization, confocal microscopy, siRNA knockdown with gene expression analysis","journal":"International journal of cosmetic science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP interactions confirmed by microscopy, siRNA downstream effects observed, single lab","pmids":["30843221"],"is_preprint":false},{"year":2020,"finding":"A heterozygous EMILIN-1 mutation p.R250C in the coiled-coil region causes reduced extracellular deposition with disorganized fibrillar network in patient skin and fibroblasts; zebrafish emilin1a knockdown produces locomotion defects and abnormal motor neuron axonal arborization, partially rescued by wild-type but not mutant EMILIN-1 cRNA, establishing a role in peripheral nervous system development.","method":"Whole exome sequencing, immunofluorescence of patient skin/fibroblasts, zebrafish morpholino knockdown, rescue by human wild-type vs. mutant EMILIN-1 cRNA injection, locomotion assay, motor neuron imaging","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino KD with cRNA rescue (wild-type vs. mutant) in zebrafish; single lab, patient data support","pmids":["31978608"],"is_preprint":false},{"year":2022,"finding":"Bi-allelic EMILIN-1 loss-of-function in humans and Emilin1-/- mice impairs EFEMP2 (fibulin-4) ECM deposition and LOX activity, resulting in reduced collagen crosslinking, aberrant collagen fibril ultrastructure, impaired elastogenesis, and abnormal trabecular bone formation, connecting elastic fiber assembly to collagen fibrillogenesis.","method":"Human genetics (bi-allelic variants), Emilin1-/- mouse analysis, EFEMP2 ECM deposition assay, LOX activity measurement, collagen crosslinking biochemistry, electron microscopy of collagen ultrastructure, bone histomorphometry","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple biochemical assays (LOX activity, crosslinking, EFEMP2 deposition) plus structural electron microscopy in both human and mouse; replicated across tissues","pmids":["36351433"],"is_preprint":false},{"year":2022,"finding":"EMILIN-1 deficiency (null or E933A mutant) in psoriasis promotes macrophage recruitment, shifts polarization toward M1 via myofibroblast induction, and alters non-canonical TGF-β signaling through both the EMI and gC1q domains; the gC1q/integrin interaction controls skin homeostasis in keratinocytes and fibroblasts.","method":"IMQ-induced psoriasis in Emilin1-/- and E1-E933A mice, flow cytometry for macrophage subsets, immunoblotting for TGF-β pathway components, histopathology, human psoriatic lesion immunostaining","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two genetic models with immunological and signaling readouts; single lab","pmids":["35764213"],"is_preprint":false},{"year":2021,"finding":"EMILIN-1 gC1q domain engages VLA-4 (α4β1) in CLL cells, promoting adhesion and pro-survival signaling (ERK and AKT phosphorylation) and impairment of in vitro apoptosis; the absence of neutrophil elastase in CLL bone marrow biopsies indicates EMILIN-1 remains structurally intact and functionally active in this context.","method":"Cell adhesion assays, phospho-ERK and phospho-AKT immunoblotting, apoptosis assay, immunohistochemistry of bone marrow biopsies, NE immunostaining","journal":"Hematological oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional adhesion and signaling assays in CLL cells; single lab","pmids":["34783040"],"is_preprint":false},{"year":2021,"finding":"In melanoma lymph node metastatic cells, EMILIN-1 is proteolyzed and packaged into small extracellular vesicles as a mechanism to reduce its intracellular levels; EMILIN-1 has intrinsic anti-proliferative, anti-migratory, and anti-tumor properties that are disabled by this proteolysis/EV secretion pathway.","method":"Small EV isolation and proteomics, EMILIN-1 overexpression and knockdown, migration assay, viability assay, primary tumor growth and metastasis in mouse model","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays linking EV secretion of EMILIN-1 to tumor suppression; single lab","pmids":["34299025"],"is_preprint":false},{"year":2023,"finding":"EMILIN-1 knockdown reduces dental pulp stem cell (hDPSC) proliferation and osteo/odontogenic differentiation, while exogenous recombinant EMILIN-1 enhances both, establishing a functional role for EMILIN-1 in osteodifferentiation of hDPSCs.","method":"siRNA knockdown, exogenous rhEMILIN-1 addition, CCK-8 proliferation assay, ALP staining, alizarin red staining, qPCR and Western blot for differentiation markers","journal":"BMC oral health","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — paired loss-of-function (siRNA) and gain-of-function (recombinant protein) in the same cell system; single lab","pmids":["37024847"],"is_preprint":false},{"year":2019,"finding":"Depletion of EMILIN-1 from ECM of renal epithelial cells (by siRNA knockdown) reduces adhesion strength and decreases focal adhesion points and stress fibers without affecting cell growth, but promotes migration.","method":"siRNA knockdown of EMILIN-1 in ECM layer (novel cell-secreted ECM anchorage methodology), adhesion strength assay, focal adhesion immunostaining, migration assay","journal":"Matrix biology plus","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific functional knockdown of ECM-deposited EMILIN-1, phenotype characterized by multiple readouts; single lab","pmids":["33543009"],"is_preprint":false},{"year":2025,"finding":"EMILIN-1 overexpression in HNSCC cells decreases proliferation, migration, and invasion, while EMILIN-1 knockdown in cancer-associated fibroblasts promotes these phenotypes; the anti-proliferative mechanism involves downregulation of cell cycle and aurora kinase signaling pathways, confirmed by RNA-sequencing and protein-level validation. In ovo CAM model confirms reduced tumor size, Ki-67, and increased cleaved caspase-3 with EMILIN-1 overexpression.","method":"Overexpression and siRNA knockdown, co-culture assay, conditioned medium assay, RNA-seq pathway analysis, immunoblotting, in ovo CAM tumor model, Ki-67 and cleaved caspase-3 immunostaining","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — paired gain/loss-of-function with in vitro and in vivo validation; RNA-seq pathway assignment supported at protein level; single lab","pmids":["39892781"],"is_preprint":false},{"year":2025,"finding":"Extravillous trophoblasts (EVTs) secrete EMILIN-1 (and Gremlin-1) as TGF-β antagonists that reverse decidual myofibroblast activation, reduce high collagen production, and functionally reverse acquired decidual resistance to trophoblast invasion.","method":"HTR8 and differentiated EVT from trophectoderm stem cells, conditioned medium assays, TGF-β signaling readouts, collagen production assays, trophoblast invasion assays","journal":"Cells & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — secreted EMILIN-1 functionally linked to TGF-β antagonism and invasion; single lab","pmids":["39756583"],"is_preprint":false}],"current_model":"EMILIN-1 is a homotrimeric extracellular matrix glycoprotein that localizes at the elastin-microfibril interface where its EMI domain regulates elastogenesis (including fibulin-4 and fibrillin deposition) and its C-terminal gC1q domain engages α4β1 and α9β1 integrins via a unique disordered loop exposing Glu933; this integrin interaction inhibits cell proliferation by silencing the HRas/MAPK-ERK pathway and reducing PTEN, maintains lymphatic vessel architecture and valve formation, and restrains TGF-β bioavailability in the vascular wall—thereby controlling blood pressure through suppression of smooth muscle cell arteriolar myogenic tone via a TGF-β→HB-EGF→EGFR→TRPC6/TRPM4 cascade—while neutrophil elastase cleavage at S913-R914 can inactivate these functions in pathological contexts."},"narrative":{"mechanistic_narrative":"EMILIN-1 is a homotrimeric extracellular matrix glycoprotein that localizes at the elastin-microfibril interface of elastic fibers, where it controls elastogenesis, vascular and lymphatic architecture, and cell proliferation [PMID:8458869, PMID:14701737]. Its modular architecture comprises an N-terminal cysteine-rich EMI domain, a coiled-coil/leucine-zipper stalk, a collagenous region, and a C-terminal gC1q globular domain; the gC1q and collagenous domains drive self-assembly into homotrimers and large disulfide-bonded multimers [PMID:10358019, PMID:10821830]. EMILIN-1 organizes the elastic fiber matrix by incorporating into fibrillin microfibril networks (in a fibrillin-1- and fibronectin-dependent manner) and by directly binding fibulin-4/EFEMP2 to enable its matrix deposition, LOX activity, and collagen crosslinking, thereby coupling elastogenesis to collagen fibrillogenesis [PMID:26945878, PMID:28717224, PMID:36351433]. The gC1q domain adopts a nine-stranded β-sandwich bearing a unique disordered apical loop that exposes Glu933; all three E933 residues of the trimer coordinate the integrin MIDAS to engage α4β1 and α9β1 integrins, mediating cell adhesion and migration [PMID:18463100, PMID:29037761, PMID:12456677]. Through this gC1q–integrin engagement, EMILIN-1 inhibits cell proliferation by silencing the RAS-ERK pathway via ubiquitination of HRas-GTP and by reducing PTEN, an effect requiring the intact α4 integrin cytoplasmic tail [PMID:28177903, PMID:21949412]. EMILIN-1 also acts as a negative regulator of TGF-β by inhibiting pro-TGF-β proteolysis, and smooth-muscle-cell-derived EMILIN-1 controls resting blood pressure by restraining arteriolar myogenic tone through a TGF-β→HB-EGF→EGFR→TRPC6/TRPM4 cascade [PMID:16530037, PMID:22814752, PMID:30354220]. The same integrin interaction maintains lymphatic vessel patterning, valve formation, and lymphangiogenesis [PMID:18411305, PMID:24019067, PMID:30408617]. Neutrophil elastase cleaves EMILIN-1 within the gC1q domain at the S913-R914 bond, disrupting its conformation and abolishing α4β1 binding and anti-proliferative activity, a mechanism operative in tumors and lymphedema [PMID:28074935, PMID:24513040, PMID:26920215]. Heterozygous and bi-allelic EMILIN-1 mutations cause autosomal connective tissue disorders with impaired secretion or matrix deposition and disorganized fibrillar architecture [PMID:26462740, PMID:36351433, PMID:31978608].","teleology":[{"year":1993,"claim":"Established EMILIN-1 as a structural constituent of elastic fibers with a functional role in elastogenesis, the founding observation for the gene.","evidence":"Immunoelectron microscopy with quantitative gold-particle analysis and antibody inhibition of elastin deposition in aorta cell culture","pmids":["8458869"],"confidence":"High","gaps":["Molecular partners mediating elastin deposition not yet defined","Domain responsible for elastogenic activity unknown at this stage"]},{"year":1999,"claim":"Defined the multidomain architecture and showed the gC1q domain mediates cell adhesion, framing EMILIN-1 as both a structural and cell-interactive ECM protein.","evidence":"cDNA cloning, CD spectroscopy, recombinant gC1q expression and cell adhesion assay","pmids":["10358019"],"confidence":"High","gaps":["Adhesion receptor not yet identified","Functional roles of EMI and coiled-coil domains undefined"]},{"year":2000,"claim":"Resolved how EMILIN-1 oligomerizes, showing the gC1q and collagenous domains drive homotrimer and high-order multimer assembly.","evidence":"Yeast two-hybrid, native PAGE, and truncation constructs","pmids":["10821830"],"confidence":"High","gaps":["Stoichiometry of disulfide-bonded multimers not fully mapped","Relationship between assembly state and matrix incorporation unresolved"]},{"year":2002,"claim":"Identified α4β1 integrin as the gC1q adhesion receptor, establishing the cell-surface link that underlies EMILIN-1's signaling functions.","evidence":"Function-blocking mAbs, K562 α4-transfection gain-of-function, and actin imaging","pmids":["12456677"],"confidence":"High","gaps":["Precise integrin-binding residue not yet mapped","Downstream signaling consequences unexplored"]},{"year":2004,"claim":"In vivo knockout confirmed EMILIN-1's requirement for elastic fiber formation and vascular cell anchorage.","evidence":"Emilin1-/- mouse histology, electron microscopy, and fibroblast culture","pmids":["14701737"],"confidence":"High","gaps":["Molecular pathway linking loss to phenotype not yet defined","No physiological vascular readout (blood pressure) examined"]},{"year":2006,"claim":"Connected EMILIN-1 to TGF-β biology and blood pressure, showing it restrains pro-TGF-β proteolysis to limit TGF-β bioavailability.","evidence":"Emilin1-/- mouse blood pressure measurement and anti-TGF-β antibody rescue","pmids":["16530037","22814752"],"confidence":"High","gaps":["Mechanism of pro-TGF-β proteolysis inhibition not biochemically resolved","Cellular source of functional EMILIN-1 not yet identified"]},{"year":2006,"claim":"Demonstrated the α4β1-gC1q axis drives directed cell migration in a physiological tissue context (trophoblast invasion).","evidence":"Haptotaxis assays with EVT cells, function-blocking mAbs, siRNA, and MMP co-culture assays","pmids":["17074837"],"confidence":"High","gaps":["Whether migration vs. proliferation outcomes depend on cell type unresolved","Signaling downstream of α4β1 not dissected"]},{"year":2008,"claim":"Solved the gC1q structure and pinpointed Glu933 in a disordered apical loop as the essential integrin-binding residue, providing the structural basis for EMILIN-1's cell-interactive functions.","evidence":"TROSY NMR structure, E933A mutagenesis, and adhesion/migration assays under static and flow conditions","pmids":["18463100"],"confidence":"High","gaps":["Atomic-level integrin docking geometry not yet defined","Whether E933 mediates α9β1 as well as α4β1 not yet tested"]},{"year":2008,"claim":"Extended EMILIN-1 function to the lymphatic system, identifying it as a regulator of lymphatic vessel growth and integrity.","evidence":"Emilin1-/- mouse lymphangiography, ultrastructure, and lymph drainage assays across two backgrounds","pmids":["18411305"],"confidence":"High","gaps":["Receptor and signaling pathway for lymphatic phenotype not yet established","Distinction between valve and vessel defects unresolved"]},{"year":2011,"claim":"Established the anti-proliferative signaling mechanism, showing gC1q-α4β1/α9β1 engagement raises PTEN and dampens PI3K/Akt and Erk1/2 to restrain epidermal/dermal proliferation.","evidence":"Emilin1-/- skin, function-blocking anti-α4/α9 mAbs, and phospho-pathway immunoblots","pmids":["21949412"],"confidence":"High","gaps":["Direct mechanism connecting integrin to PTEN levels undefined","How Erk1/2-Smad2 crosstalk is initiated unresolved"]},{"year":2012,"claim":"Localized the functional source of blood-pressure control to smooth muscle cell EMILIN-1 acting through suppression of arteriolar myogenic tone.","evidence":"Cell-type-specific transgenic rescue (SMC vs. endothelial) and anti-TGF-β treatment with ex vivo myogenic tone measurement","pmids":["22814752"],"confidence":"High","gaps":["Downstream effectors of TGF-β in SMC tone not yet identified","Channel-level mechanism of myogenic tone unresolved"]},{"year":2012,"claim":"Showed EMILIN-1 can self-assemble through gC1q and EMI domains and form hetero-multimers with EMILIN-2, expanding the matrix-assembly model.","evidence":"Yeast two-hybrid, co-IP from co-transfected cells, and immunofluorescence colocalization","pmids":["25445627"],"confidence":"Medium","gaps":["Yeast two-hybrid/co-IP not reconstituted with purified proteins","Functional significance of EMILIN-1/2 heteromers unknown"]},{"year":2012,"claim":"Reported an unexpected intracellular interaction between the EMILIN-1 C-terminus and the CNGA3 channel in hair cells.","evidence":"Yeast two-hybrid, surface plasmon resonance with Ca2+-dependent kinetics, and pull-down in organ of Corti systems","pmids":["22248097"],"confidence":"Medium","gaps":["Intracellular interaction context unusual for a secreted ECM protein and not independently confirmed","Physiological consequence in hearing not established"]},{"year":2010,"claim":"Demonstrated EMILIN-1 is required for fibrillin-1 microfibril deposition, linking it to oxytalan fiber assembly.","evidence":"Co-IP and siRNA knockdown reducing fibrillin-1 deposition in periodontal ligament cells","pmids":["20701466"],"confidence":"Medium","gaps":["Direct binding not distinguished from indirect assembly dependence","Single cell system"]},{"year":2014,"claim":"Identified neutrophil elastase cleavage as a pathological inactivation mechanism that abolishes EMILIN-1's anti-proliferative function in tumors.","evidence":"In vitro NE cleavage, fragment analysis, proliferation assays, and tumor specimen immunostaining","pmids":["24513040"],"confidence":"High","gaps":["Cleavage site not yet mapped at this stage","Causality in tumor progression in vivo not established"]},{"year":2014,"claim":"Distinguished canonical and non-canonical TGF-β contributions to EMILIN-1-deficient aortic valve disease over time.","evidence":"Emilin1-/- mouse histology, immunoblotting, and echocardiography","pmids":["25056700"],"confidence":"Medium","gaps":["Pathway assignment based on correlative immunoblot","Single lab; causal manipulation of pSmad vs pErk not performed"]},{"year":2015,"claim":"First human disease link: a heterozygous p.A22T mutation near the signal peptide impairs secretion, causing ER retention and an autosomal-dominant connective tissue disorder.","evidence":"Trio exome sequencing, familial segregation, mutant transfection ER-retention assay, and patient skin biopsy","pmids":["26462740"],"confidence":"Medium","gaps":["Single family","Mechanism connecting reduced deposition to tissue phenotype not dissected"]},{"year":2016,"claim":"Defined the assembly hierarchy placing EMILIN-1 within fibrillin microfibril networks dependent on fibrillin-1 and fibronectin scaffolds.","evidence":"Immunoelectron microscopy, fibrillin-1-deficient mouse skin, and wound-healing matrix assembly","pmids":["26945878"],"confidence":"High","gaps":["Order of recruitment among EMILIN-1, fibronectin, and fibrillin not fully resolved","Direct binding interfaces not mapped"]},{"year":2016,"claim":"Linked NE-mediated EMILIN-1 degradation to lymphedema pathogenesis and showed pharmacological NE inhibition is protective.","evidence":"Mouse tail lymphedema model with sivelestat treatment, EMILIN-1 integrity immunoblot, and human biopsy validation","pmids":["26920215"],"confidence":"High","gaps":["How EMILIN-1 loss weakens LEC junctions mechanistically unresolved","Cleavage site not yet defined here"]},{"year":2017,"claim":"Mapped the precise NE cleavage site (S913-R914) within gC1q and showed an NE-resistant R914W mutant preserves integrin binding and anti-proliferative activity, defining the molecular basis of functional inactivation.","evidence":"Comparative in vitro protease assays (NE, MMP-3, MMP-9, MT1-MMP), R914W mutagenesis, and adhesion/proliferation assays","pmids":["28074935"],"confidence":"High","gaps":["In vivo relevance of R914W resistance not tested","Why MMP cleavage spares gC1q function not structurally explained"]},{"year":2017,"claim":"Resolved the anti-proliferative signaling node, showing gC1q-α4β1 engagement drives ubiquitination of HRas-GTP requiring the α4 cytoplasmic tail.","evidence":"gC1q plating, HRas-GTP/ubiquitination pull-down, co-IP, α4 truncation mutants, and salirasib pharmacology","pmids":["28177903"],"confidence":"High","gaps":["Identity of the ubiquitin ligase acting on HRas unknown","Link to PTEN regulation not unified"]},{"year":2017,"claim":"Showed EMILIN-1 selectively governs fibulin-4 matrix deposition through direct binding, distinguishing it from effects on other fibulins or LTBPs.","evidence":"RNAi in osteoblasts, immunoprecipitation, and ELISA-style binding assay","pmids":["28717224"],"confidence":"High","gaps":["Binding interface between EMILIN-1 and fibulin-4 not mapped","Connection to downstream LOX/collagen biology not yet made here"]},{"year":2017,"claim":"Provided an atomic model of the gC1q-α4β1 interface, showing all three trimeric E933 residues coordinate the MIDAS Mg2+ with R904 as a synergistic residue.","evidence":"Site-directed mutagenesis, adhesion assays, and docking of the NMR structure onto a virtual α4β1 model","pmids":["29037761"],"confidence":"Medium","gaps":["MIDAS coordination model is computational","No co-crystal or cryo-EM structure of the complex"]},{"year":2018,"claim":"Defined the SMC blood-pressure mechanism in adults, mapping TGF-β→HB-EGF→EGFR→TRPC6/TRPM4 channel recruitment that potentiates myogenic tone, with human hypertensive validation.","evidence":"Conditional SMC-specific Emilin1 knockout, ex vivo myogenic tone, signaling immunoblots, pharmacological inhibition, and patient biopsy","pmids":["30354220"],"confidence":"High","gaps":["Direct biochemical link from TGF-β to HB-EGF induction not fully resolved","Whether the same cascade operates in non-resistance vessels untested"]},{"year":2018,"claim":"Demonstrated the gC1q/E933-integrin interaction is required for normal lymphangiogenesis and restrains lymph node metastasis using a point-mutant model.","evidence":"E933A knock-in mouse, lymphangiography, ex vivo thoracic duct ring assay, and metastasis assay","pmids":["30408617"],"confidence":"High","gaps":["Signaling pathway in LECs downstream of integrin not dissected","Mechanism linking lymphatic dysfunction to metastasis unresolved"]},{"year":2019,"claim":"Showed EMILIN-1-integrin interaction restrains colitis-associated carcinogenesis and maintains inflammatory-cell lymphatic drainage.","evidence":"AOM-DSS carcinogenesis in Emilin1-/- and E933A mice with histopathology and lymphatic functional assessment","pmids":["31479698"],"confidence":"High","gaps":["Whether tumor suppression is cell-autonomous or microenvironmental unresolved","Specific integrin-bearing cells responsible not identified"]},{"year":2019,"claim":"Identified a TSPAN9 interaction through which EMILIN-1 enhances suppression of gastric cancer cell migration and invasion.","evidence":"Co-IP, immunofluorescence, and overexpression/knockdown functional assays","pmids":["31242895"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation in a second system","Whether interaction is direct unknown"]},{"year":2019,"claim":"Documented EMILIN-1 associations with elastin and collagen IV in skin fibroblasts and downstream effects on FGFR2 and COL6A1.","evidence":"Co-IP, multiphoton/confocal colocalization, and siRNA with expression analysis","pmids":["30843221"],"confidence":"Medium","gaps":["Direct vs. matrix-mediated association not distinguished","Single lab"]},{"year":2019,"claim":"Showed ECM-deposited EMILIN-1 sets adhesion strength and focal adhesion/stress fiber content in renal epithelial cells while permitting migration.","evidence":"siRNA knockdown of ECM EMILIN-1, adhesion strength assay, focal adhesion staining, and migration assay","pmids":["33543009"],"confidence":"Medium","gaps":["Receptor mediating renal epithelial adhesion not identified","Single lab"]},{"year":2020,"claim":"Extended human disease to a coiled-coil p.R250C mutation with a zebrafish model revealing a role in peripheral nervous system/motor neuron development.","evidence":"Exome sequencing, patient skin/fibroblast immunofluorescence, and zebrafish morpholino knockdown with wild-type vs. mutant cRNA rescue","pmids":["31978608"],"confidence":"Medium","gaps":["Mechanism linking EMILIN-1 to motor neuron arborization unresolved","Morpholino-based; single family"]},{"year":2021,"claim":"Showed in chronic lymphocytic leukemia the intact gC1q-VLA-4 interaction can be pro-survival, with EMILIN-1 remaining uncleaved due to absence of NE.","evidence":"Adhesion assays, phospho-ERK/AKT immunoblots, apoptosis assays, and bone marrow NE immunostaining","pmids":["34783040"],"confidence":"Medium","gaps":["Context-dependent switch between anti-proliferative and pro-survival signaling unexplained","Single lab"]},{"year":2021,"claim":"Identified proteolysis and EV packaging as a mechanism by which melanoma cells lower intracellular EMILIN-1 to evade its anti-tumor properties.","evidence":"Small EV proteomics, overexpression/knockdown, migration/viability assays, and mouse tumor/metastasis model","pmids":["34299025"],"confidence":"Medium","gaps":["Protease responsible for EV-associated cleavage not identified","Mechanism of EV sorting unknown"]},{"year":2022,"claim":"Unified elastogenesis with collagen biology, showing EMILIN-1 loss impairs fibulin-4 deposition and LOX activity, reducing collagen crosslinking and causing bone phenotypes in humans and mice.","evidence":"Human bi-allelic variants, Emilin1-/- mice, EFEMP2 deposition, LOX activity, crosslinking biochemistry, electron microscopy, and bone histomorphometry","pmids":["36351433"],"confidence":"High","gaps":["Whether EMILIN-1 directly modulates LOX or acts via fibulin-4 not separated","Tissue specificity of bone phenotype not fully explained"]},{"year":2022,"claim":"Connected EMILIN-1 loss to inflammatory skin disease, showing both EMI and gC1q domains shape macrophage recruitment and non-canonical TGF-β signaling in psoriasis.","evidence":"IMQ psoriasis in Emilin1-/- and E933A mice, flow cytometry, TGF-β immunoblotting, and human lesion immunostaining","pmids":["35764213"],"confidence":"Medium","gaps":["Separate contributions of EMI vs gC1q domains not cleanly resolved","Single lab"]},{"year":2023,"claim":"Showed EMILIN-1 promotes proliferation and osteo/odontogenic differentiation of dental pulp stem cells.","evidence":"siRNA knockdown and recombinant EMILIN-1 addition with proliferation, mineralization, and differentiation marker assays","pmids":["37024847"],"confidence":"Medium","gaps":["Receptor and signaling pathway in hDPSCs not identified","Apparent pro-proliferative role contrasts with anti-proliferative integrin signaling and is unreconciled"]},{"year":2025,"claim":"Demonstrated tumor-suppressive activity in HNSCC and cancer-associated fibroblasts through downregulation of cell cycle and aurora kinase signaling.","evidence":"Overexpression/knockdown, co-culture, RNA-seq, immunoblotting, and in ovo CAM tumor model with Ki-67/cleaved caspase-3 staining","pmids":["39892781"],"confidence":"Medium","gaps":["Whether the aurora kinase axis links to the gC1q-integrin pathway unresolved","Single lab"]},{"year":2025,"claim":"Showed extravillous trophoblast-secreted EMILIN-1 acts as a TGF-β antagonist that reverses decidual myofibroblast activation and resistance to invasion.","evidence":"EVT conditioned medium assays, TGF-β signaling readouts, collagen production, and invasion assays","pmids":["39756583"],"confidence":"Medium","gaps":["Molecular basis of TGF-β antagonism by secreted EMILIN-1 not defined","Single lab"]},{"year":null,"claim":"How EMILIN-1 mechanistically inhibits pro-TGF-β proteolysis, and how the same gC1q-integrin interaction yields opposite (anti-proliferative vs pro-survival) outcomes across cell contexts, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No biochemical mechanism for pro-TGF-β proteolysis inhibition","Context-dependent signaling switch unexplained","No experimental high-resolution structure of the gC1q-integrin complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,7,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,9,18]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,7,18]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,4,15,19,30]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,14,37]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,4,15,19,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,18,21]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,14,26,36]}],"complexes":["fibrillin microfibril network","elastic fiber"],"partners":["ITGA4","ITGA9","EFEMP2","FBN1","EMILIN2","TSPAN9","CNGA3","HRAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6C2","full_name":"EMILIN-1","aliases":["Elastin microfibril interface-located protein 1","Elastin microfibril interfacer 1"],"length_aa":1016,"mass_kda":106.7,"function":"Involved in elastic and collagen fibers formation. It is required for EFEMP2 deposition into the extracellular matrix, and collagen network assembly and cross-linking via protein-lysine 6-oxidase/LOX activity (PubMed:36351433). May be responsible for anchoring smooth muscle cells to elastic fibers, and may be involved in the processes that regulate vessel assembly. Has cell adhesive capacity","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q9Y6C2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EMILIN1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EMILIN1","total_profiled":1310},"omim":[{"mim_id":"620908","title":"ARTERIAL TORTUOSITY-BONE FRAGILITY SYNDROME; ATBFS","url":"https://www.omim.org/entry/620908"},{"mim_id":"620080","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 10; HMND10","url":"https://www.omim.org/entry/620080"},{"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":"604633","title":"EGF-CONTAINING FIBULIN-LIKE EXTRACELLULAR MATRIX PROTEIN 2; EFEMP2","url":"https://www.omim.org/entry/604633"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EMILIN1"},"hgnc":{"alias_symbol":["DKFZp586M121","gp115","EMILIN"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6C2","domains":[{"cath_id":"-","chopping":"60-121","consensus_level":"high","plddt":79.0405,"start":60,"end":121},{"cath_id":"2.60.120.40","chopping":"873-948_965-1016","consensus_level":"high","plddt":83.7548,"start":873,"end":1016}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6C2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6C2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6C2-F1-predicted_aligned_error_v6.png","plddt_mean":62.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EMILIN1","jax_strain_url":"https://www.jax.org/strain/search?query=EMILIN1"},"sequence":{"accession":"Q9Y6C2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6C2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6C2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6C2"}},"corpus_meta":[{"pmid":"14701737","id":"PMC_14701737","title":"EMILIN-1 deficiency induces elastogenesis and vascular cell defects.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14701737","citation_count":136,"is_preprint":false},{"pmid":"8458869","id":"PMC_8458869","title":"Emilin, a component of elastic fibers preferentially located at the elastin-microfibrils interface.","date":"1993","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8458869","citation_count":134,"is_preprint":false},{"pmid":"18411305","id":"PMC_18411305","title":"Emilin1 deficiency causes structural and functional defects of lymphatic vasculature.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18411305","citation_count":106,"is_preprint":false},{"pmid":"8458831","id":"PMC_8458831","title":"Physiological analysis of mutants indicates involvement of the Saccharomyces cerevisiae GPI-anchored protein gp115 in morphogenesis and cell separation.","date":"1993","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8458831","citation_count":100,"is_preprint":false},{"pmid":"22566882","id":"PMC_22566882","title":"The EMILIN/Multimerin family.","date":"2012","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22566882","citation_count":94,"is_preprint":false},{"pmid":"10963989","id":"PMC_10963989","title":"The EMILIN protein family.","date":"2000","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/10963989","citation_count":89,"is_preprint":false},{"pmid":"21949412","id":"PMC_21949412","title":"EMILIN1-α4/α9 integrin interaction inhibits dermal fibroblast and keratinocyte proliferation.","date":"2011","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21949412","citation_count":87,"is_preprint":false},{"pmid":"2061310","id":"PMC_2061310","title":"Isolation and deduced amino acid sequence of the gene encoding gp115, a yeast glycophospholipid-anchored protein containing a serine-rich region.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2061310","citation_count":83,"is_preprint":false},{"pmid":"12456677","id":"PMC_12456677","title":"beta 1 Integrin-dependent cell adhesion to EMILIN-1 is mediated by the gC1q domain.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12456677","citation_count":81,"is_preprint":false},{"pmid":"10358019","id":"PMC_10358019","title":"EMILIN, a component of the elastic fiber and a new member of the C1q/tumor necrosis factor superfamily of proteins.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10358019","citation_count":71,"is_preprint":false},{"pmid":"24019067","id":"PMC_24019067","title":"EMILIN1/α9β1 integrin interaction is crucial in lymphatic valve formation and maintenance.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24019067","citation_count":64,"is_preprint":false},{"pmid":"17074837","id":"PMC_17074837","title":"EMILIN1 represents a major stromal element determining human trophoblast invasion of the uterine wall.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17074837","citation_count":62,"is_preprint":false},{"pmid":"10821830","id":"PMC_10821830","title":"Self-assembly and supramolecular organization of EMILIN.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10821830","citation_count":56,"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":"25056700","id":"PMC_25056700","title":"TGF-β mediates early angiogenesis and latent fibrosis in an Emilin1-deficient mouse model of aortic valve disease.","date":"2014","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/25056700","citation_count":49,"is_preprint":false},{"pmid":"11559704","id":"PMC_11559704","title":"Molecular cloning and characterization of EndoGlyx-1, an EMILIN-like multisubunit glycoprotein of vascular endothelium.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11559704","citation_count":49,"is_preprint":false},{"pmid":"14996434","id":"PMC_14996434","title":"Overlapping, complementary and site-specific expression pattern of genes of the EMILIN/Multimerin family.","date":"2004","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/14996434","citation_count":47,"is_preprint":false},{"pmid":"22334695","id":"PMC_22334695","title":"EMILIN-3, peculiar member of elastin microfibril interface-located protein (EMILIN) family, has distinct expression pattern, forms oligomeric assemblies, and serves as transforming growth factor β (TGF-β) antagonist.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22334695","citation_count":43,"is_preprint":false},{"pmid":"38505604","id":"PMC_38505604","title":"Cancer-associated fibroblast spatial heterogeneity and EMILIN1 expression in the tumor microenvironment modulate TGF-β activity and CD8+ T-cell infiltration in breast cancer.","date":"2024","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/38505604","citation_count":42,"is_preprint":false},{"pmid":"2160276","id":"PMC_2160276","title":"The cell cycle modulated glycoprotein GP115 is one of the major yeast proteins 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pre-embedding immunolabeling), quantitative gold-particle distribution analysis, and antibody inhibition in cell culture\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization by immunoelectron microscopy with quantitative analysis, functionally validated by antibody perturbation of elastin deposition, replicated across multiple tissues\",\n      \"pmids\": [\"8458869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human EMILIN-1 encodes a 1016-aa protein with a C-terminal gC1q-like globular domain (adopting high β-sheet content by CD), a collagenous stalk, coiled-coil/leucine-zipper region, and an N-terminal cysteine-rich (EMI) domain; the recombinant gC1q domain promotes cell adhesion.\",\n      \"method\": \"cDNA cloning, RT-PCR, peptide sequencing, CD spectroscopy, recombinant protein expression, cell adhesion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical and structural methods in one study; domain architecture and adhesion activity directly demonstrated\",\n      \"pmids\": [\"10358019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The EMILIN-1 gC1q domain self-assembles into homotrimers (demonstrated by yeast two-hybrid and native gel migration) and the full-length protein forms large disulfide-bonded multimers of many millions of daltons; the C-terminal gC1q and collagenous domains are essential for trimer formation.\",\n      \"method\": \"Yeast two-hybrid, native PAGE, reducing/non-reducing agarose gels, recombinant domain expression, truncation constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — yeast two-hybrid in vivo interaction confirmed biochemically by native gel oligomeric state; truncation mutants establish domain requirements\",\n      \"pmids\": [\"10821830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Cell adhesion to EMILIN-1 is mediated by the gC1q domain engaging the α4β1 integrin; a function-blocking anti-gC1q mAb completely blocks attachment, and only α4-transfected K562 cells (not wild-type K562) adhere to EMILIN-1. Cells on EMILIN-1 show ruffled morphology without stress fibers, consistent with promotion of cell motility rather than strong adhesion.\",\n      \"method\": \"Monoclonal antibody inhibition assays, cell adhesion kinetics, adhesion-strength centrifugation, K562 α4-transfection, actin cytoskeleton imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional blocking with mAbs and gain-of-function transfection with integrin α4; multiple orthogonal methods in one study\",\n      \"pmids\": [\"12456677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Emilin1-/- mice show abnormal elastic fiber formation in aorta and skin, and altered morphology and anchorage of endothelial and smooth muscle cells to elastic lamellae, demonstrating EMILIN-1's role in elastogenesis and vascular cell maintenance.\",\n      \"method\": \"Mouse gene targeting (knockout), histology, ultrastructural analysis by electron microscopy, embryonic fibroblast cultures\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive KO with defined structural and cellular phenotypes, multiple tissues examined, replicated in cultured fibroblasts\",\n      \"pmids\": [\"14701737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EMILIN-1 acts as a negative regulator of TGF-β processing and signaling in the vasculature; Emilin1-/- mice display elevated blood pressure due to increased TGF-β activity. EMILIN-1 inhibits pro-TGF-β proteolysis, limiting TGF-β bioavailability.\",\n      \"method\": \"Emilin1-/- mouse model, blood pressure measurement, vascular TGF-β signaling assays (referenced in Cell commentary citing Zacchigna et al. 2006 paper); rescue experiments with anti-TGF-β antibodies (PMID 22814752)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse phenotype (hypertension) rescued by anti-TGF-β antibody neutralization, independently replicated and mechanistically elaborated in multiple subsequent papers\",\n      \"pmids\": [\"16530037\", \"22814752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EMILIN-1 in the uterine stroma promotes α4β1 integrin-dependent haptotactic migration of extravillous trophoblasts; function-blocking anti-α4 and anti-EMILIN-1 mAbs and EMILIN-1 siRNA each block trophoblast interaction with EMILIN-1/gC1q. Co-culture upregulates MT1-MMP and MMP-2.\",\n      \"method\": \"Haptotaxis assays with freshly isolated EVT and HTR-8/SVneo cells, function-blocking mAbs, siRNA knockdown, co-culture MMP assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three orthogonal inhibitory approaches (mAb, siRNA, receptor-blocking) converging on the same α4β1-gC1q mechanism\",\n      \"pmids\": [\"17074837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The NMR solution structure of the EMILIN-1 gC1q homotrimer reveals a nine-stranded β-sandwich (missing one strand versus typical 10-stranded gC1q fold), with a unique disordered 19-residue protruding loop at the trimer apex; site-directed mutagenesis of Glu933 within this loop abrogates α4β1 integrin binding, T-cell adhesion under static and flow conditions, and endothelial cell haptotactic migration.\",\n      \"method\": \"NMR-based homology modeling, TROSY NMR, site-directed mutagenesis (E933A), Jurkat T-cell and EA.hy926 endothelial cell adhesion assays under static and flow conditions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional validation by mutagenesis across multiple cell types and assay conditions\",\n      \"pmids\": [\"18463100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Emilin1 deficiency leads to lymphatic vessel hyperplasia, enlargement, irregular patterning, reduction of anchoring filaments, enhanced lymphangioma formation, lymphedema, and compromised lymph drainage, identifying EMILIN-1 as a regulator of lymphatic vessel growth and integrity.\",\n      \"method\": \"Emilin1-/- mouse model (CD1 and C57BL/6 backgrounds), histology, ultrastructural analysis, lymphangiography, lymph drainage assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse phenotype characterized across two genetic backgrounds with functional lymphatic drainage measurements\",\n      \"pmids\": [\"18411305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EMILIN-1 directly engages α4β1 and α9β1 integrins via its gC1q domain (E933 residue) to inhibit dermal fibroblast and keratinocyte proliferation; loss of this interaction in Emilin1-/- skin causes dermal/epidermal hyperproliferation via reduced PTEN, activation of PI3K/Akt and Erk1/2, and Erk1/2-mediated inhibitory phosphorylation of Smad2 at Ser245/250/255, suppressing TGF-β/Smad signaling.\",\n      \"method\": \"Emilin1-/- KO mouse, wound closure assays, function-blocking mAbs against α4 and α9 integrins, pathway analysis (phospho-immunoblots for Akt, Erk1/2, PTEN, Smad2), identification of EMILIN-1 as novel α9β1 ligand in keratinocytes\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO phenotype plus antibody blocking plus signaling pathway dissection, multiple orthogonal methods identifying the downstream cascade\",\n      \"pmids\": [\"21949412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Vascular smooth muscle cell-derived EMILIN-1 (not endothelial cell-derived) is the functional source controlling resting blood pressure; its mechanism involves suppression of arteriolar myogenic tone through restraint of TGF-β activity, as shown by TGF-β antibody normalization of BP in Emilin1-/- mice and selective SMC-restricted transgenic rescue.\",\n      \"method\": \"Cell-type-specific transgenic rescue in Emilin1-/- background (SMC vs. endothelial promoters), anti-TGF-β antibody treatment, ex vivo resistance artery myogenic tone measurement\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific transgenic rescue plus pharmacological TGF-β neutralization, multiple functional readouts\",\n      \"pmids\": [\"22814752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EMILIN-1 interaction with α9β1 integrin, mediated by the E933 residue of the gC1q domain, is required for lymphatic valve formation and maintenance; mice expressing E933A-mutant EMILIN-1 (unable to engage α4/α9 integrins) display defective lymphatic valve structure and lymph flow, caused by deranged lymphatic endothelial cell proliferation and migration.\",\n      \"method\": \"Emilin1-/- KO mouse, E933A transgenic knock-in mouse, morphometric in vitro and in vivo assays, lymphangiography, cell proliferation and migration assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two complementary transgenic models (KO and point mutant) with functional lymphatic assays and in vitro mechanistic validation\",\n      \"pmids\": [\"24019067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Neutrophil elastase cleaves EMILIN-1 into three-to-four fragments, abolishing its anti-proliferative function; this cleavage mechanism is operative in sarcomas and ovarian cancers where PMN infiltration and elastase positivity are detected.\",\n      \"method\": \"In vitro protease cleavage assay with neutrophil elastase, SDS-PAGE fragment analysis, proliferation assays with cleaved versus intact EMILIN-1, immunostaining of tumor specimens for elastase and EMILIN-1\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic cleavage assay linked to functional loss, corroborated by pathological specimens\",\n      \"pmids\": [\"24513040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In the Emilin1-/- aortic valve, early elastic fiber fragmentation is followed by aberrant angiogenesis and late fibrosis; constitutive canonical TGF-β (pSmad2/3) signaling is upregulated from birth, while non-canonical TGF-β (pErk1/2 MAPK) signaling progressively increases, mediating advanced fibrotic disease.\",\n      \"method\": \"Emilin1-/- mouse model, histology, immunohistochemistry, electron microscopy, quantitative gene expression, immunoblotting, echocardiography\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple analytical methods but signaling pathway assignment based on correlative immunoblot; single lab\",\n      \"pmids\": [\"25056700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A heterozygous missense mutation p.A22T in EMILIN-1 (mapping near the signal peptide cleavage site) causes impaired protein secretion with accumulation in the endoplasmic reticulum, reduced extracellular deposition, and disorganized fibrillar architecture in patient skin, segregating with an autosomal-dominant connective tissue disorder.\",\n      \"method\": \"Trio exome sequencing, Sanger sequencing for familial segregation, transfection of mutant construct with ER localization assessment, skin biopsy immunostaining\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay (transfection showing ER retention) plus patient skin biopsy, single lab, one family\",\n      \"pmids\": [\"26462740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EMILIN-1 and EMILIN-2 are incorporated into fibrillin microfibril networks in skin; fibrillin-1 deficiency disrupts EMILIN-1/2 networks. EMILIN-1/2 deposition during wound healing also requires fibronectin as an assembly scaffold.\",\n      \"method\": \"Immunoelectron microscopy, immunofluorescence, biochemical extraction, analysis of fibrillin-1-deficient mouse skin, wound healing model, embryonic fibroblast matrix assembly\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal localization methods plus fibrillin-1 KO disruption experiment and fibronectin dependency demonstrated in two experimental systems\",\n      \"pmids\": [\"26945878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In a mouse post-surgical tail lymphedema model, neutrophil elastase released by infiltrating neutrophils degrades EMILIN-1 in the acute phase, weakening lymphatic endothelial cell junctions and impairing drainage; local administration of the NE inhibitor sivelestat prevents EMILIN-1 cleavage and reduces lymphedema. Cleaved EMILIN-1 fragments with NE-dependent patterns are also detected in human secondary lymphedema.\",\n      \"method\": \"Mouse tail lymphedema model, NE inhibitor (sivelestat) treatment, EMILIN-1 integrity immunoblot, lymphatic junction analysis, lymph drainage assay, human lymphedema biopsy immunostaining\",\n      \"journal\": \"Clinical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo pharmacological intervention (NE inhibitor) rescuing both EMILIN-1 integrity and lymphatic function, validated in human samples\",\n      \"pmids\": [\"26920215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Neutrophil elastase cleaves the EMILIN-1 gC1q domain at the S913-R914 peptide bond (outside the E933 integrin-binding site), disrupting gC1q structural conformation and abolishing α4β1 integrin interaction; the R914W mutant is resistant to NE cleavage and retains integrin-binding and anti-proliferative activity. MMP-3 and MT1-MMP partially cleave EMILIN-1 but do not impair gC1q-α4β1 function.\",\n      \"method\": \"In vitro protease cleavage assays (NE, MMP-3, MMP-9, MT1-MMP), site-directed mutagenesis (R914W NE-resistant mutant), cell adhesion and proliferation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — precise cleavage site mapped by mutagenesis, function rescued with resistant mutant, multiple proteases tested comparatively\",\n      \"pmids\": [\"28074935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EMILIN-1 gC1q silences the RAS-ERK proliferative pathway via α4β1 integrin through ubiquitination of HRas-GTP; α4 integrin co-immunoprecipitates ubiquitinated HRas only when ligated by gC1q, and this anti-proliferative effect requires the intact cytoplasmic tail of the α4 integrin chain.\",\n      \"method\": \"Cell plating on gC1q, phospho-ERK immunoblots, HRas-GTP pull-down with ubiquitinated HRas detection, co-immunoprecipitation, α4 truncation mutant transfection, salirasib (Ras inhibitor) pharmacology\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of ubiquitinated HRas with α4, pharmacological and genetic (truncation) dissection of the signaling pathway, multiple orthogonal approaches\",\n      \"pmids\": [\"28177903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EMILIN-1 depletion from osteoblasts by RNAi selectively abolishes fibulin-4 matrix deposition without affecting other fibulins or LTBPs; direct interaction between EMILIN-1 and fibulin-4 was confirmed by immunoprecipitation and ELISA-style binding assay.\",\n      \"method\": \"RNAi knockdown in primary calvarial osteoblasts and MC3T3-E1 cells, immunofluorescence, electron microscopy, immunoprecipitation, ELISA-style binding assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding confirmed by two orthogonal biochemical methods, functional consequence (selective fibulin-4 loss) established by KD\",\n      \"pmids\": [\"28717224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The α4β1-EMILIN-1 gC1q interaction requires all three E933 residues of the homotrimer simultaneously; molecular docking of the NMR gC1q structure onto a virtual α4β1 model shows the three E933 residues coordinate the Mg²⁺ ion at the βI MIDAS site, and R904 acts as a synergistic residue via intra-chain salt bridges with E928/E930.\",\n      \"method\": \"Site-directed mutagenesis, cell adhesion assays, docking of NMR structure to virtual α4β1 crystal structure, structural modelling\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (NMR structure + mutagenesis) / Moderate — single lab; MIDAS coordination model is computational but mutagenesis is experimental\",\n      \"pmids\": [\"29037761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of smooth muscle cell EMILIN-1 in adult mice via conditional gene targeting increases blood pressure through enhanced arteriolar myogenic tone; mechanistically, higher TGF-β in smooth muscle cells drives HB-EGF expression and EGFR transactivation, which recruits TRPC6 and TRPM4 channels to potentiate voltage-dependent calcium channels and myogenic tone. Reduced EMILIN-1 and enhanced TGF-β-EGFR signaling are found in resistance arteries from hypertensive patients.\",\n      \"method\": \"Conditional SMC-specific Emilin1 knockout, ex vivo myogenic tone measurement, immunoblotting for TGF-β, HB-EGF, pEGFR, TRPC6/TRPM4 signaling, pharmacological EGFR and TRP channel inhibition, human hypertensive patient biopsy\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus pharmacological pathway dissection plus human validation; multiple orthogonal experiments in one study\",\n      \"pmids\": [\"30354220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The EMILIN-1 gC1q/E933-integrin interaction is required for normal lymphangiogenesis; E933A-mutant transgenic mice show abnormal dense, tortuous lymphatic networks, reduced anchoring filaments, aberrant narrowed collecting valves, impaired lymph transport, and enhanced lymph node metastasis. Lymphatic endothelial cells from E1-E933A mice have severely reduced sprouting capacity in ex vivo thoracic duct ring assays.\",\n      \"method\": \"E933A transgenic knock-in mouse, lymphangiography, morphometry, ex vivo thoracic duct ring assay, in vitro tubulogenesis assay, lymph node metastasis assay\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise point mutant abrogating integrin binding with multiple in vivo and ex vivo functional readouts; reciprocal confirmation with Emilin1-/- data\",\n      \"pmids\": [\"30408617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EMILIN-1 is colocalized with fibrillin-1 in periodontal ligament cells, co-immunoprecipitates with fibrillin-1, and siRNA-mediated knockdown of EMILIN-1 reduces fibrillin-1 extracellular deposition to 23% of control, indicating EMILIN-1 regulates oxytalan fiber/microfibril formation.\",\n      \"method\": \"siRNA knockdown in PDL cell culture, immunofluorescence quantification of fibrillin-1 deposition, co-immunoprecipitation\",\n      \"journal\": \"Connective tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional KD demonstrating deposition requirement, single lab\",\n      \"pmids\": [\"20701466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The EMILIN-1 gC1q and EMI domains can interact with each other and self-interact (gC1q-gC1q); full-length EMILIN-1 and EMILIN-2 can form non-covalent homo- and hetero-multimers, suggesting head-to-tail and tail-to-tail assemblies.\",\n      \"method\": \"Yeast two-hybrid (qualitative and quantitative), co-immunoprecipitation from co-transfected cell extracts, immunofluorescence co-localization\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP, single lab\",\n      \"pmids\": [\"25445627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CNGA3 cyclic nucleotide-gated channel binds to the intracellular C-terminus domain of EMILIN-1; this interaction was identified by yeast two-hybrid and confirmed by surface plasmon resonance with Ca²⁺-dependent kinetics (Kd ~10⁻⁶–10⁻⁷ M) and pull-down assays in inner ear hair cell and organ of Corti systems.\",\n      \"method\": \"Yeast two-hybrid, surface plasmon resonance, pull-down assay, immunolocalization in saccular hair cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by SPR (quantitative binding) and pull-down; single lab, intracellular domain interaction context unusual for an ECM protein\",\n      \"pmids\": [\"22248097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of EMILIN-1/β1 integrin interaction (via Emilin1-/- or E933A knock-in mice) promotes AOM-DSS colon tumor development with higher incidence and larger adenomas, increased lymphangiogenesis with dysfunctional lymphatics, and increased inflammatory infiltrates, demonstrating EMILIN-1-integrin interaction restrains colitis-associated carcinogenesis and maintains lymphatic drainage of inflammatory cells.\",\n      \"method\": \"AOM-DSS carcinogenesis protocol in Emilin1-/- and E1-E933A transgenic mice, histopathology, lymphatic vessel functional assessment, inflammatory cell scoring\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two complementary genetic models (KO and point mutant) with multiple in vivo functional endpoints\",\n      \"pmids\": [\"31479698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Co-immunoprecipitation and immunofluorescence in gastric cancer cells demonstrate that EMILIN-1 and TSPAN9 interact and co-localize; EMILIN-1 overexpression boosts TSPAN9 expression and synergistically enhances the TSPAN9-dependent inhibition of gastric cancer cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, overexpression and knockdown functional assays (wound healing, invasion), Western blot\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP interaction plus functional assays; single lab with two orthogonal methods\",\n      \"pmids\": [\"31242895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EMILIN-1 co-immunoprecipitates with elastin and collagen IV in human skin fibroblasts; it colocalizes with elastin, fibrillin-1, and collagen IV including at the basement membrane. siRNA knockdown of EMILIN-1 downregulates FGFR2 expression and COL6A1.\",\n      \"method\": \"Co-immunoprecipitation, multiphoton microscopy co-localization, confocal microscopy, siRNA knockdown with gene expression analysis\",\n      \"journal\": \"International journal of cosmetic science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP interactions confirmed by microscopy, siRNA downstream effects observed, single lab\",\n      \"pmids\": [\"30843221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A heterozygous EMILIN-1 mutation p.R250C in the coiled-coil region causes reduced extracellular deposition with disorganized fibrillar network in patient skin and fibroblasts; zebrafish emilin1a knockdown produces locomotion defects and abnormal motor neuron axonal arborization, partially rescued by wild-type but not mutant EMILIN-1 cRNA, establishing a role in peripheral nervous system development.\",\n      \"method\": \"Whole exome sequencing, immunofluorescence of patient skin/fibroblasts, zebrafish morpholino knockdown, rescue by human wild-type vs. mutant EMILIN-1 cRNA injection, locomotion assay, motor neuron imaging\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with cRNA rescue (wild-type vs. mutant) in zebrafish; single lab, patient data support\",\n      \"pmids\": [\"31978608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Bi-allelic EMILIN-1 loss-of-function in humans and Emilin1-/- mice impairs EFEMP2 (fibulin-4) ECM deposition and LOX activity, resulting in reduced collagen crosslinking, aberrant collagen fibril ultrastructure, impaired elastogenesis, and abnormal trabecular bone formation, connecting elastic fiber assembly to collagen fibrillogenesis.\",\n      \"method\": \"Human genetics (bi-allelic variants), Emilin1-/- mouse analysis, EFEMP2 ECM deposition assay, LOX activity measurement, collagen crosslinking biochemistry, electron microscopy of collagen ultrastructure, bone histomorphometry\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple biochemical assays (LOX activity, crosslinking, EFEMP2 deposition) plus structural electron microscopy in both human and mouse; replicated across tissues\",\n      \"pmids\": [\"36351433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EMILIN-1 deficiency (null or E933A mutant) in psoriasis promotes macrophage recruitment, shifts polarization toward M1 via myofibroblast induction, and alters non-canonical TGF-β signaling through both the EMI and gC1q domains; the gC1q/integrin interaction controls skin homeostasis in keratinocytes and fibroblasts.\",\n      \"method\": \"IMQ-induced psoriasis in Emilin1-/- and E1-E933A mice, flow cytometry for macrophage subsets, immunoblotting for TGF-β pathway components, histopathology, human psoriatic lesion immunostaining\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two genetic models with immunological and signaling readouts; single lab\",\n      \"pmids\": [\"35764213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EMILIN-1 gC1q domain engages VLA-4 (α4β1) in CLL cells, promoting adhesion and pro-survival signaling (ERK and AKT phosphorylation) and impairment of in vitro apoptosis; the absence of neutrophil elastase in CLL bone marrow biopsies indicates EMILIN-1 remains structurally intact and functionally active in this context.\",\n      \"method\": \"Cell adhesion assays, phospho-ERK and phospho-AKT immunoblotting, apoptosis assay, immunohistochemistry of bone marrow biopsies, NE immunostaining\",\n      \"journal\": \"Hematological oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional adhesion and signaling assays in CLL cells; single lab\",\n      \"pmids\": [\"34783040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In melanoma lymph node metastatic cells, EMILIN-1 is proteolyzed and packaged into small extracellular vesicles as a mechanism to reduce its intracellular levels; EMILIN-1 has intrinsic anti-proliferative, anti-migratory, and anti-tumor properties that are disabled by this proteolysis/EV secretion pathway.\",\n      \"method\": \"Small EV isolation and proteomics, EMILIN-1 overexpression and knockdown, migration assay, viability assay, primary tumor growth and metastasis in mouse model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays linking EV secretion of EMILIN-1 to tumor suppression; single lab\",\n      \"pmids\": [\"34299025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EMILIN-1 knockdown reduces dental pulp stem cell (hDPSC) proliferation and osteo/odontogenic differentiation, while exogenous recombinant EMILIN-1 enhances both, establishing a functional role for EMILIN-1 in osteodifferentiation of hDPSCs.\",\n      \"method\": \"siRNA knockdown, exogenous rhEMILIN-1 addition, CCK-8 proliferation assay, ALP staining, alizarin red staining, qPCR and Western blot for differentiation markers\",\n      \"journal\": \"BMC oral health\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — paired loss-of-function (siRNA) and gain-of-function (recombinant protein) in the same cell system; single lab\",\n      \"pmids\": [\"37024847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Depletion of EMILIN-1 from ECM of renal epithelial cells (by siRNA knockdown) reduces adhesion strength and decreases focal adhesion points and stress fibers without affecting cell growth, but promotes migration.\",\n      \"method\": \"siRNA knockdown of EMILIN-1 in ECM layer (novel cell-secreted ECM anchorage methodology), adhesion strength assay, focal adhesion immunostaining, migration assay\",\n      \"journal\": \"Matrix biology plus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific functional knockdown of ECM-deposited EMILIN-1, phenotype characterized by multiple readouts; single lab\",\n      \"pmids\": [\"33543009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EMILIN-1 overexpression in HNSCC cells decreases proliferation, migration, and invasion, while EMILIN-1 knockdown in cancer-associated fibroblasts promotes these phenotypes; the anti-proliferative mechanism involves downregulation of cell cycle and aurora kinase signaling pathways, confirmed by RNA-sequencing and protein-level validation. In ovo CAM model confirms reduced tumor size, Ki-67, and increased cleaved caspase-3 with EMILIN-1 overexpression.\",\n      \"method\": \"Overexpression and siRNA knockdown, co-culture assay, conditioned medium assay, RNA-seq pathway analysis, immunoblotting, in ovo CAM tumor model, Ki-67 and cleaved caspase-3 immunostaining\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — paired gain/loss-of-function with in vitro and in vivo validation; RNA-seq pathway assignment supported at protein level; single lab\",\n      \"pmids\": [\"39892781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Extravillous trophoblasts (EVTs) secrete EMILIN-1 (and Gremlin-1) as TGF-β antagonists that reverse decidual myofibroblast activation, reduce high collagen production, and functionally reverse acquired decidual resistance to trophoblast invasion.\",\n      \"method\": \"HTR8 and differentiated EVT from trophectoderm stem cells, conditioned medium assays, TGF-β signaling readouts, collagen production assays, trophoblast invasion assays\",\n      \"journal\": \"Cells & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — secreted EMILIN-1 functionally linked to TGF-β antagonism and invasion; single lab\",\n      \"pmids\": [\"39756583\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EMILIN-1 is a homotrimeric extracellular matrix glycoprotein that localizes at the elastin-microfibril interface where its EMI domain regulates elastogenesis (including fibulin-4 and fibrillin deposition) and its C-terminal gC1q domain engages α4β1 and α9β1 integrins via a unique disordered loop exposing Glu933; this integrin interaction inhibits cell proliferation by silencing the HRas/MAPK-ERK pathway and reducing PTEN, maintains lymphatic vessel architecture and valve formation, and restrains TGF-β bioavailability in the vascular wall—thereby controlling blood pressure through suppression of smooth muscle cell arteriolar myogenic tone via a TGF-β→HB-EGF→EGFR→TRPC6/TRPM4 cascade—while neutrophil elastase cleavage at S913-R914 can inactivate these functions in pathological contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EMILIN-1 is a homotrimeric extracellular matrix glycoprotein that localizes at the elastin-microfibril interface of elastic fibers, where it controls elastogenesis, vascular and lymphatic architecture, and cell proliferation [#0, #4]. Its modular architecture comprises an N-terminal cysteine-rich EMI domain, a coiled-coil/leucine-zipper stalk, a collagenous region, and a C-terminal gC1q globular domain; the gC1q and collagenous domains drive self-assembly into homotrimers and large disulfide-bonded multimers [#1, #2]. EMILIN-1 organizes the elastic fiber matrix by incorporating into fibrillin microfibril networks (in a fibrillin-1- and fibronectin-dependent manner) and by directly binding fibulin-4/EFEMP2 to enable its matrix deposition, LOX activity, and collagen crosslinking, thereby coupling elastogenesis to collagen fibrillogenesis [#15, #19, #30]. The gC1q domain adopts a nine-stranded β-sandwich bearing a unique disordered apical loop that exposes Glu933; all three E933 residues of the trimer coordinate the integrin MIDAS to engage α4β1 and α9β1 integrins, mediating cell adhesion and migration [#7, #20, #3]. Through this gC1q–integrin engagement, EMILIN-1 inhibits cell proliferation by silencing the RAS-ERK pathway via ubiquitination of HRas-GTP and by reducing PTEN, an effect requiring the intact α4 integrin cytoplasmic tail [#18, #9]. EMILIN-1 also acts as a negative regulator of TGF-β by inhibiting pro-TGF-β proteolysis, and smooth-muscle-cell-derived EMILIN-1 controls resting blood pressure by restraining arteriolar myogenic tone through a TGF-β→HB-EGF→EGFR→TRPC6/TRPM4 cascade [#5, #10, #21]. The same integrin interaction maintains lymphatic vessel patterning, valve formation, and lymphangiogenesis [#8, #11, #22]. Neutrophil elastase cleaves EMILIN-1 within the gC1q domain at the S913-R914 bond, disrupting its conformation and abolishing α4β1 binding and anti-proliferative activity, a mechanism operative in tumors and lymphedema [#17, #12, #16]. Heterozygous and bi-allelic EMILIN-1 mutations cause autosomal connective tissue disorders with impaired secretion or matrix deposition and disorganized fibrillar architecture [#14, #30, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established EMILIN-1 as a structural constituent of elastic fibers with a functional role in elastogenesis, the founding observation for the gene.\",\n      \"evidence\": \"Immunoelectron microscopy with quantitative gold-particle analysis and antibody inhibition of elastin deposition in aorta cell culture\",\n      \"pmids\": [\"8458869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners mediating elastin deposition not yet defined\", \"Domain responsible for elastogenic activity unknown at this stage\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the multidomain architecture and showed the gC1q domain mediates cell adhesion, framing EMILIN-1 as both a structural and cell-interactive ECM protein.\",\n      \"evidence\": \"cDNA cloning, CD spectroscopy, recombinant gC1q expression and cell adhesion assay\",\n      \"pmids\": [\"10358019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adhesion receptor not yet identified\", \"Functional roles of EMI and coiled-coil domains undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Resolved how EMILIN-1 oligomerizes, showing the gC1q and collagenous domains drive homotrimer and high-order multimer assembly.\",\n      \"evidence\": \"Yeast two-hybrid, native PAGE, and truncation constructs\",\n      \"pmids\": [\"10821830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of disulfide-bonded multimers not fully mapped\", \"Relationship between assembly state and matrix incorporation unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified α4β1 integrin as the gC1q adhesion receptor, establishing the cell-surface link that underlies EMILIN-1's signaling functions.\",\n      \"evidence\": \"Function-blocking mAbs, K562 α4-transfection gain-of-function, and actin imaging\",\n      \"pmids\": [\"12456677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise integrin-binding residue not yet mapped\", \"Downstream signaling consequences unexplored\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"In vivo knockout confirmed EMILIN-1's requirement for elastic fiber formation and vascular cell anchorage.\",\n      \"evidence\": \"Emilin1-/- mouse histology, electron microscopy, and fibroblast culture\",\n      \"pmids\": [\"14701737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway linking loss to phenotype not yet defined\", \"No physiological vascular readout (blood pressure) examined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected EMILIN-1 to TGF-β biology and blood pressure, showing it restrains pro-TGF-β proteolysis to limit TGF-β bioavailability.\",\n      \"evidence\": \"Emilin1-/- mouse blood pressure measurement and anti-TGF-β antibody rescue\",\n      \"pmids\": [\"16530037\", \"22814752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of pro-TGF-β proteolysis inhibition not biochemically resolved\", \"Cellular source of functional EMILIN-1 not yet identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated the α4β1-gC1q axis drives directed cell migration in a physiological tissue context (trophoblast invasion).\",\n      \"evidence\": \"Haptotaxis assays with EVT cells, function-blocking mAbs, siRNA, and MMP co-culture assays\",\n      \"pmids\": [\"17074837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether migration vs. proliferation outcomes depend on cell type unresolved\", \"Signaling downstream of α4β1 not dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Solved the gC1q structure and pinpointed Glu933 in a disordered apical loop as the essential integrin-binding residue, providing the structural basis for EMILIN-1's cell-interactive functions.\",\n      \"evidence\": \"TROSY NMR structure, E933A mutagenesis, and adhesion/migration assays under static and flow conditions\",\n      \"pmids\": [\"18463100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-level integrin docking geometry not yet defined\", \"Whether E933 mediates α9β1 as well as α4β1 not yet tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended EMILIN-1 function to the lymphatic system, identifying it as a regulator of lymphatic vessel growth and integrity.\",\n      \"evidence\": \"Emilin1-/- mouse lymphangiography, ultrastructure, and lymph drainage assays across two backgrounds\",\n      \"pmids\": [\"18411305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor and signaling pathway for lymphatic phenotype not yet established\", \"Distinction between valve and vessel defects unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established the anti-proliferative signaling mechanism, showing gC1q-α4β1/α9β1 engagement raises PTEN and dampens PI3K/Akt and Erk1/2 to restrain epidermal/dermal proliferation.\",\n      \"evidence\": \"Emilin1-/- skin, function-blocking anti-α4/α9 mAbs, and phospho-pathway immunoblots\",\n      \"pmids\": [\"21949412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism connecting integrin to PTEN levels undefined\", \"How Erk1/2-Smad2 crosstalk is initiated unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Localized the functional source of blood-pressure control to smooth muscle cell EMILIN-1 acting through suppression of arteriolar myogenic tone.\",\n      \"evidence\": \"Cell-type-specific transgenic rescue (SMC vs. endothelial) and anti-TGF-β treatment with ex vivo myogenic tone measurement\",\n      \"pmids\": [\"22814752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of TGF-β in SMC tone not yet identified\", \"Channel-level mechanism of myogenic tone unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed EMILIN-1 can self-assemble through gC1q and EMI domains and form hetero-multimers with EMILIN-2, expanding the matrix-assembly model.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP from co-transfected cells, and immunofluorescence colocalization\",\n      \"pmids\": [\"25445627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Yeast two-hybrid/co-IP not reconstituted with purified proteins\", \"Functional significance of EMILIN-1/2 heteromers unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reported an unexpected intracellular interaction between the EMILIN-1 C-terminus and the CNGA3 channel in hair cells.\",\n      \"evidence\": \"Yeast two-hybrid, surface plasmon resonance with Ca2+-dependent kinetics, and pull-down in organ of Corti systems\",\n      \"pmids\": [\"22248097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular interaction context unusual for a secreted ECM protein and not independently confirmed\", \"Physiological consequence in hearing not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated EMILIN-1 is required for fibrillin-1 microfibril deposition, linking it to oxytalan fiber assembly.\",\n      \"evidence\": \"Co-IP and siRNA knockdown reducing fibrillin-1 deposition in periodontal ligament cells\",\n      \"pmids\": [\"20701466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding not distinguished from indirect assembly dependence\", \"Single cell system\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified neutrophil elastase cleavage as a pathological inactivation mechanism that abolishes EMILIN-1's anti-proliferative function in tumors.\",\n      \"evidence\": \"In vitro NE cleavage, fragment analysis, proliferation assays, and tumor specimen immunostaining\",\n      \"pmids\": [\"24513040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site not yet mapped at this stage\", \"Causality in tumor progression in vivo not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Distinguished canonical and non-canonical TGF-β contributions to EMILIN-1-deficient aortic valve disease over time.\",\n      \"evidence\": \"Emilin1-/- mouse histology, immunoblotting, and echocardiography\",\n      \"pmids\": [\"25056700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway assignment based on correlative immunoblot\", \"Single lab; causal manipulation of pSmad vs pErk not performed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"First human disease link: a heterozygous p.A22T mutation near the signal peptide impairs secretion, causing ER retention and an autosomal-dominant connective tissue disorder.\",\n      \"evidence\": \"Trio exome sequencing, familial segregation, mutant transfection ER-retention assay, and patient skin biopsy\",\n      \"pmids\": [\"26462740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family\", \"Mechanism connecting reduced deposition to tissue phenotype not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the assembly hierarchy placing EMILIN-1 within fibrillin microfibril networks dependent on fibrillin-1 and fibronectin scaffolds.\",\n      \"evidence\": \"Immunoelectron microscopy, fibrillin-1-deficient mouse skin, and wound-healing matrix assembly\",\n      \"pmids\": [\"26945878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of recruitment among EMILIN-1, fibronectin, and fibrillin not fully resolved\", \"Direct binding interfaces not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked NE-mediated EMILIN-1 degradation to lymphedema pathogenesis and showed pharmacological NE inhibition is protective.\",\n      \"evidence\": \"Mouse tail lymphedema model with sivelestat treatment, EMILIN-1 integrity immunoblot, and human biopsy validation\",\n      \"pmids\": [\"26920215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EMILIN-1 loss weakens LEC junctions mechanistically unresolved\", \"Cleavage site not yet defined here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped the precise NE cleavage site (S913-R914) within gC1q and showed an NE-resistant R914W mutant preserves integrin binding and anti-proliferative activity, defining the molecular basis of functional inactivation.\",\n      \"evidence\": \"Comparative in vitro protease assays (NE, MMP-3, MMP-9, MT1-MMP), R914W mutagenesis, and adhesion/proliferation assays\",\n      \"pmids\": [\"28074935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of R914W resistance not tested\", \"Why MMP cleavage spares gC1q function not structurally explained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the anti-proliferative signaling node, showing gC1q-α4β1 engagement drives ubiquitination of HRas-GTP requiring the α4 cytoplasmic tail.\",\n      \"evidence\": \"gC1q plating, HRas-GTP/ubiquitination pull-down, co-IP, α4 truncation mutants, and salirasib pharmacology\",\n      \"pmids\": [\"28177903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the ubiquitin ligase acting on HRas unknown\", \"Link to PTEN regulation not unified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed EMILIN-1 selectively governs fibulin-4 matrix deposition through direct binding, distinguishing it from effects on other fibulins or LTBPs.\",\n      \"evidence\": \"RNAi in osteoblasts, immunoprecipitation, and ELISA-style binding assay\",\n      \"pmids\": [\"28717224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface between EMILIN-1 and fibulin-4 not mapped\", \"Connection to downstream LOX/collagen biology not yet made here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided an atomic model of the gC1q-α4β1 interface, showing all three trimeric E933 residues coordinate the MIDAS Mg2+ with R904 as a synergistic residue.\",\n      \"evidence\": \"Site-directed mutagenesis, adhesion assays, and docking of the NMR structure onto a virtual α4β1 model\",\n      \"pmids\": [\"29037761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MIDAS coordination model is computational\", \"No co-crystal or cryo-EM structure of the complex\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the SMC blood-pressure mechanism in adults, mapping TGF-β→HB-EGF→EGFR→TRPC6/TRPM4 channel recruitment that potentiates myogenic tone, with human hypertensive validation.\",\n      \"evidence\": \"Conditional SMC-specific Emilin1 knockout, ex vivo myogenic tone, signaling immunoblots, pharmacological inhibition, and patient biopsy\",\n      \"pmids\": [\"30354220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link from TGF-β to HB-EGF induction not fully resolved\", \"Whether the same cascade operates in non-resistance vessels untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated the gC1q/E933-integrin interaction is required for normal lymphangiogenesis and restrains lymph node metastasis using a point-mutant model.\",\n      \"evidence\": \"E933A knock-in mouse, lymphangiography, ex vivo thoracic duct ring assay, and metastasis assay\",\n      \"pmids\": [\"30408617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway in LECs downstream of integrin not dissected\", \"Mechanism linking lymphatic dysfunction to metastasis unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed EMILIN-1-integrin interaction restrains colitis-associated carcinogenesis and maintains inflammatory-cell lymphatic drainage.\",\n      \"evidence\": \"AOM-DSS carcinogenesis in Emilin1-/- and E933A mice with histopathology and lymphatic functional assessment\",\n      \"pmids\": [\"31479698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tumor suppression is cell-autonomous or microenvironmental unresolved\", \"Specific integrin-bearing cells responsible not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a TSPAN9 interaction through which EMILIN-1 enhances suppression of gastric cancer cell migration and invasion.\",\n      \"evidence\": \"Co-IP, immunofluorescence, and overexpression/knockdown functional assays\",\n      \"pmids\": [\"31242895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation in a second system\", \"Whether interaction is direct unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Documented EMILIN-1 associations with elastin and collagen IV in skin fibroblasts and downstream effects on FGFR2 and COL6A1.\",\n      \"evidence\": \"Co-IP, multiphoton/confocal colocalization, and siRNA with expression analysis\",\n      \"pmids\": [\"30843221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. matrix-mediated association not distinguished\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed ECM-deposited EMILIN-1 sets adhesion strength and focal adhesion/stress fiber content in renal epithelial cells while permitting migration.\",\n      \"evidence\": \"siRNA knockdown of ECM EMILIN-1, adhesion strength assay, focal adhesion staining, and migration assay\",\n      \"pmids\": [\"33543009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating renal epithelial adhesion not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended human disease to a coiled-coil p.R250C mutation with a zebrafish model revealing a role in peripheral nervous system/motor neuron development.\",\n      \"evidence\": \"Exome sequencing, patient skin/fibroblast immunofluorescence, and zebrafish morpholino knockdown with wild-type vs. mutant cRNA rescue\",\n      \"pmids\": [\"31978608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking EMILIN-1 to motor neuron arborization unresolved\", \"Morpholino-based; single family\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed in chronic lymphocytic leukemia the intact gC1q-VLA-4 interaction can be pro-survival, with EMILIN-1 remaining uncleaved due to absence of NE.\",\n      \"evidence\": \"Adhesion assays, phospho-ERK/AKT immunoblots, apoptosis assays, and bone marrow NE immunostaining\",\n      \"pmids\": [\"34783040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent switch between anti-proliferative and pro-survival signaling unexplained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified proteolysis and EV packaging as a mechanism by which melanoma cells lower intracellular EMILIN-1 to evade its anti-tumor properties.\",\n      \"evidence\": \"Small EV proteomics, overexpression/knockdown, migration/viability assays, and mouse tumor/metastasis model\",\n      \"pmids\": [\"34299025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease responsible for EV-associated cleavage not identified\", \"Mechanism of EV sorting unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Unified elastogenesis with collagen biology, showing EMILIN-1 loss impairs fibulin-4 deposition and LOX activity, reducing collagen crosslinking and causing bone phenotypes in humans and mice.\",\n      \"evidence\": \"Human bi-allelic variants, Emilin1-/- mice, EFEMP2 deposition, LOX activity, crosslinking biochemistry, electron microscopy, and bone histomorphometry\",\n      \"pmids\": [\"36351433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EMILIN-1 directly modulates LOX or acts via fibulin-4 not separated\", \"Tissue specificity of bone phenotype not fully explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected EMILIN-1 loss to inflammatory skin disease, showing both EMI and gC1q domains shape macrophage recruitment and non-canonical TGF-β signaling in psoriasis.\",\n      \"evidence\": \"IMQ psoriasis in Emilin1-/- and E933A mice, flow cytometry, TGF-β immunoblotting, and human lesion immunostaining\",\n      \"pmids\": [\"35764213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Separate contributions of EMI vs gC1q domains not cleanly resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed EMILIN-1 promotes proliferation and osteo/odontogenic differentiation of dental pulp stem cells.\",\n      \"evidence\": \"siRNA knockdown and recombinant EMILIN-1 addition with proliferation, mineralization, and differentiation marker assays\",\n      \"pmids\": [\"37024847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor and signaling pathway in hDPSCs not identified\", \"Apparent pro-proliferative role contrasts with anti-proliferative integrin signaling and is unreconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated tumor-suppressive activity in HNSCC and cancer-associated fibroblasts through downregulation of cell cycle and aurora kinase signaling.\",\n      \"evidence\": \"Overexpression/knockdown, co-culture, RNA-seq, immunoblotting, and in ovo CAM tumor model with Ki-67/cleaved caspase-3 staining\",\n      \"pmids\": [\"39892781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the aurora kinase axis links to the gC1q-integrin pathway unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed extravillous trophoblast-secreted EMILIN-1 acts as a TGF-β antagonist that reverses decidual myofibroblast activation and resistance to invasion.\",\n      \"evidence\": \"EVT conditioned medium assays, TGF-β signaling readouts, collagen production, and invasion assays\",\n      \"pmids\": [\"39756583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of TGF-β antagonism by secreted EMILIN-1 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EMILIN-1 mechanistically inhibits pro-TGF-β proteolysis, and how the same gC1q-integrin interaction yields opposite (anti-proliferative vs pro-survival) outcomes across cell contexts, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical mechanism for pro-TGF-β proteolysis inhibition\", \"Context-dependent signaling switch unexplained\", \"No experimental high-resolution structure of the gC1q-integrin complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 7, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 9, 18]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 7, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 4, 15, 19, 30]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 14, 37]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 4, 15, 19, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 18, 21]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 14, 26, 36]}\n    ],\n    \"complexes\": [\"fibrillin microfibril network\", \"elastic fiber\"],\n    \"partners\": [\"ITGA4\", \"ITGA9\", \"EFEMP2\", \"FBN1\", \"EMILIN2\", \"TSPAN9\", \"CNGA3\", \"HRAS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}