{"gene":"EGFL7","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2004,"finding":"EGFL7 (Egfl7) is an endothelial cell-derived secreted factor required for vascular tubulogenesis; loss of Egfl7 function in zebrafish embryos specifically blocks vascular tube formation by preventing proper spatial arrangement and separation of angioblasts during vascular cord assembly.","method":"Zebrafish morpholino knockdown; in vivo imaging of vascular development","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function in vivo with specific cellular phenotype (angioblast arrangement defect), replicated across multiple labs in subsequent work","pmids":["15085134"],"is_preprint":false},{"year":2004,"finding":"EGFL7 protein contains an N-terminal signal peptide and is localized to the endoplasmic reticulum and Golgi apparatus within cells, and is secreted into conditioned medium by transfected HEK293 cells, confirming it is a bona fide secreted protein.","method":"Subcellular fractionation, immunofluorescence localization in transfected cells, detection in conditioned media","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization experiment with functional implication (secretion), single lab with two orthogonal methods","pmids":["15162510"],"is_preprint":false},{"year":2005,"finding":"EGFL7 protein acts as a chemoattractant for embryonic endothelial cells and fibroblasts, and is upregulated in regenerating endothelium after arterial injury but not in the neointima, implicating it in endothelial integrity and vascular reorganization.","method":"In vitro cell migration (chemotaxis) assay with recombinant EGFL7; RNA in situ hybridization in injury models","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay with recombinant protein plus in vivo expression analysis, single lab","pmids":["15972971"],"is_preprint":false},{"year":2007,"finding":"EGFL7 is tightly associated with the extracellular matrix and supports endothelial cell migration either alone or in combination with other ECM molecules; in Egfl7 knockdown zebrafish, malformation of axial vessels results from accumulation of angioblasts and aberrant connections among themselves rather than abnormal EC–non-EC interactions.","method":"Ultrastructural analysis of knockdown zebrafish; in vitro biochemical ECM-binding and EC migration assays","journal":"Novartis Foundation symposium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biochemical assays plus in vivo ultrastructural phenotyping, single lab","pmids":["18300411"],"is_preprint":false},{"year":2008,"finding":"EGFL7 (VE-statin) is the first identified natural negative regulator of vascular elastogenesis: it interacts with the catalytic domain of lysyl oxidase (LOX) family enzymes, thereby inhibiting the crosslinking of tropoelastin into insoluble mature elastin. Endogenous EGFL7 colocalizes with LoxL2 in endothelial cells and prevents elastic fibre deposition.","method":"Transgenic mouse overexpression; in vitro fibroblast culture with recombinant EGFL7; biochemical interaction assays between EGFL7 and LOX catalytic domain; colocalization by immunofluorescence","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of biochemical interaction with identified domain, in vivo transgenic validation, colocalization, multiple orthogonal methods in one study","pmids":["18497746"],"is_preprint":false},{"year":2008,"finding":"Previously described vascular phenotypes attributed to Egfl7 mouse knockouts are actually caused by co-deleted miR-126 (located in Egfl7 intron 7), not by loss of EGFL7 protein itself; selective deletion of Egfl7 alone (Egfl7Δ/Δ) produces no detectable vascular phenotype in mice.","method":"Conditional/selective allele mouse knockouts (Egfl7Δ and miR-126Δ); cornea micropocket angiogenesis assay; VEGF signaling pathway analysis (Akt, Erk)","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous genetic dissection with selective alleles, multiple in vivo assays, clear negative result for Egfl7 protein function in mouse angiogenesis","pmids":["18987025"],"is_preprint":false},{"year":2008,"finding":"Egfl7-knockdown zebrafish endothelial cells fail to expand into the vascular area, leading to reduced or split lumens and open EC sheets; ectopic cell junctions form across obstructed lumens on luminal surfaces, suggesting EGFL7 provides ECs with cues for extension and establishing EC polarity.","method":"Quantitative ultrastructural analysis (electron microscopy) of Egfl7-knockdown zebrafish embryos","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — detailed ultrastructural phenotyping of loss-of-function, single lab","pmids":["18224713"],"is_preprint":false},{"year":2009,"finding":"EGFL7 binds directly to Notch receptors at a region involved in ligand-mediated activation, acting as a Notch antagonist; EGFL7 expression in neural stem cells (NSCs) decreases Notch signaling, reduces NSC proliferation and self-renewal, and shifts differentiation toward neurons and oligodendrocytes. Neurons are identified as a brain source of EGFL7.","method":"Biochemical binding assays; Notch reporter assays; NSC culture loss-of-function and gain-of-function; in vitro differentiation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding identified, Notch reporter activity, in vitro mechanistic dissection with multiple orthogonal methods in one study","pmids":["19503073"],"is_preprint":false},{"year":2010,"finding":"Endothelial overexpression of EGFL7 in transgenic mice causes impaired angiogenesis, hemorrhaging, and altered cardiac morphogenesis; EGFL7 physically interacts with endothelial-specific NOTCH in vivo, inhibits Notch reporter activity, and downregulates Notch target genes, confirming EGFL7 acts as a Notch antagonist in vascular development.","method":"Transgenic mouse overexpression; co-immunoprecipitation of EGFL7 and NOTCH in vivo; Notch reporter assays; EGFL7 knockdown in primary human endothelial cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — reciprocal Co-IP in vivo, reporter assay, transgenic phenotype, KD in primary human cells; multiple orthogonal methods replicating Notch antagonism finding","pmids":["20947685"],"is_preprint":false},{"year":2010,"finding":"VE-statin/Egfl7 gene expression in endothelial cells is directly controlled by transcription factors Erg and GATA-2 acting through a proximal promoter region (-252/+38) containing essential GATA and ETS binding sites, and a distal enhancer (-8409/-7563); Fli-1 exerts indirect control.","method":"Luciferase reporter gene assays; linker-scanning and site-directed mutagenesis; RNA interference knockdown of transcription factors; chromatin immunoprecipitation","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (reporter assays, mutagenesis, RNAi, ChIP) in single rigorous study establishing direct transcriptional regulation","pmids":["20808444"],"is_preprint":false},{"year":2010,"finding":"Egfl7 knockdown in mouse embryonic stem cells impairs vascular cord formation, resulting in abnormal CD31+ sheet-like structures due to increased proliferation of CD31+ cells, establishing a role for Egfl7 in mammalian vasculogenesis and angiogenesis independent of miR-126.","method":"siRNA knockdown targeting Egfl7 but not miR-126; embryoid body model; flow cytometry; collagen gel sprouting assay","journal":"Journal of angiogenesis research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA specifically sparing miR-126, in vitro vascular model with defined phenotypic readout, single lab","pmids":["20298530"],"is_preprint":false},{"year":2011,"finding":"Egfl7 promotes tumor immune escape by inhibiting expression of leukocyte adhesion molecules (ICAM-1, VCAM-1) on endothelial cells, thereby preventing lymphocyte adhesion and reducing immune cell infiltration into tumors. This was shown to accelerate tumor growth and metastasis in immunocompetent but not immunodeficient mice.","method":"In vitro endothelial cell treatment with Egfl7; lymphocyte adhesion assays; tumor implantation in immunocompetent vs. immunodeficient mice; cytokine and adhesion molecule expression analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean mechanistic experiment linking Egfl7 to adhesion molecule suppression, validated in vivo with immunocompetent vs. immunodeficient comparison, multiple methods","pmids":["22037871"],"is_preprint":false},{"year":2013,"finding":"EGFL7 is a direct transcriptional target of the zinc-finger transcription factor CASZ1; CASZ1 depletion reduces Egfl7 expression, and defects in CASZ1- or EGFL7-depleted endothelial cells include diminished RhoA expression and impaired focal adhesion localization; restoration of Egfl7 rescues CASZ1-depletion phenotypes, defining a CASZ1→EGFL7→RhoA signaling axis for vascular morphogenesis.","method":"Xenopus embryo depletion; human endothelial cell KD; epistasis rescue experiments; ChIP assay for CASZ1 binding to Egfl7 locus; RhoA activity assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — epistasis rescue, ChIP demonstrating direct binding, in vivo and in vitro validation, multiple orthogonal methods","pmids":["23639441","24150064"],"is_preprint":false},{"year":2013,"finding":"EGFL7 is a specific ligand of integrin αVβ3; EGFL7 attaches to the extracellular matrix and, through interaction with integrin αVβ3, increases endothelial cell motility to allow movement on the ECM during vessel remodeling. In zebrafish, deregulation of EGFL7 leads to integrin-dependent malformation of the caudal venous plexus.","method":"Biochemical binding assays between EGFL7 and integrin αVβ3; EC migration assays; integrin-blocking experiments; zebrafish in vivo validation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct ligand-receptor binding identified, functional assays with blocking, in vivo zebrafish phenotype, multiple orthogonal methods","pmids":["23386126"],"is_preprint":false},{"year":2013,"finding":"Recombinant EGFL7 protein supports endothelial cell adhesion and protects ECs from stress-induced apoptosis; anti-EGFL7 antibodies inhibit both EC adhesion and protection from apoptosis, and augment anti-VEGF-mediated vascular damage in tumor models.","method":"EC adhesion assay with recombinant EGFL7; apoptosis assay; anti-EGFL7 antibody blocking in vitro and in murine tumor models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein functional assay plus antibody blockade, validated in vivo, single lab","pmids":["23945239"],"is_preprint":false},{"year":2014,"finding":"EGFL7 promotes epithelial-mesenchymal transition (EMT) and metastasis in gastric cancer cells through activation of the EGFR-AKT-Snail signaling pathway; EGFL7 overexpression induces EGFR and AKT phosphorylation, upregulates Snail and vimentin, and downregulates E-cadherin; EGFR inhibition reverses EGFL7-induced invasion.","method":"EGFL7 overexpression/shRNA knockdown in gastric cancer lines; scratch wound and transwell migration assays; Western blot for EGFR, p-AKT, Snail, vimentin, E-cadherin; EGFR inhibitor AG1478 treatment; xenograft mouse model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with pharmacological pathway dissection, in vitro and in vivo, single lab","pmids":["24945379"],"is_preprint":false},{"year":2015,"finding":"EGFL7 is a downstream target of BMP9-ALK1-SMAD1/5 signaling in endothelial cells; BMP9 drives sprouting angiogenesis through EGFL7, which in turn promotes endothelium expansion via interference with NOTCH signaling, ERK activation, and ECM remodeling; CRISPR/Cas9 deletion of EGFL7 impairs BMP9-induced sprouting.","method":"hESC-derived EC differentiation; siRNA and CRISPR/Cas9 KO of EGFL7; SMAD1/5 phosphorylation assays; Notch reporter assays; ERK phosphorylation assays","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO plus pathway analysis, single lab with multiple readouts","pmids":["31155507"],"is_preprint":false},{"year":2015,"finding":"Endothelial cells act through secretion of EGFL7 to maintain pancreatic progenitor (PP) self-renewal and impair further differentiation into hormone-expressing cells; endothelial overexpression of EGFL7 in transgenic mice increases PP proliferation and decreases endocrine differentiation, establishing EGFL7 as the molecular handle in endothelium-to-pancreatic epithelium crosstalk.","method":"hESC-EC coculture system; recombinant EGFL7 treatment; Egfl7 transgenic mouse model; BrdU proliferation assay; endocrine differentiation markers","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — coculture mechanistic dissection, in vivo transgenic confirmation, single lab","pmids":["25601205"],"is_preprint":false},{"year":2015,"finding":"EGFL7 promotes angiogenesis in the bone microenvironment by inducing phosphorylation of ERK1/2, STAT3, and focal adhesion kinase (FAK) in endothelial cells; EGFL7 contains a conserved RGD/QGD motif and its pro-migratory effects are blocked by RGD peptides, implicating integrin-mediated signaling.","method":"Recombinant EGFL7 treatment of SVEC cells; kinase inhibitor experiments; ex vivo fetal mouse metatarsal angiogenesis assay; RGD peptide competition; Western blot for phospho-ERK, phospho-STAT3, phospho-FAK","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein functional assays with pathway inhibitors, ex vivo validation, single lab","pmids":["24909139"],"is_preprint":false},{"year":2015,"finding":"In Xenopus, EGFL7 depletion prevents vascular lumen formation by blocking endothelial cell shape changes and preventing clearance of cell-cell junctions from the cord center, while Claudin-5 still localizes appropriately; this demonstrates EGFL7 modulates cell shape and junctions to drive lumen morphogenesis.","method":"Morpholino depletion of EGFL7 in Xenopus; confocal imaging of tight junction markers (ZO-1, Claudin-5); cell morphology analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined cellular phenotype and junction marker analysis, single lab","pmids":["25705891"],"is_preprint":false},{"year":2016,"finding":"Egfl7 is a constitutive repressor of endothelial cell activation; TNFα strongly represses Egfl7 expression via an NF-κB-dependent mechanism acting on the egfl7 promoter (-7585 to -5550 bp); conversely, Egfl7 restrains TNFα-induced ICAM-1, VCAM-1, and E-selectin expression by preventing proteasome-mediated IκBα degradation, acting through both NF-κB and MEK/Erk pathways.","method":"In vivo LPS/TNFα mouse models; promoter deletion/reporter assays; NF-κB pathway analysis; IκBα protein stability assays; EGFL7 knockdown/overexpression in ECs; leukocyte adhesion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — promoter dissection, pathway mechanism (IκBα stabilization), in vitro and in vivo validation, multiple orthogonal methods in one study","pmids":["27650497"],"is_preprint":false},{"year":2016,"finding":"EGFL7 acts as an intercellular EGFR signal messenger: EGFRvIII-positive glioblastoma cells secrete EGFL7 protein to activate β-catenin/TCF4 transcription in EGFRwt cells, which in turn promotes EGFL7 expression in those cells, establishing an autocrine/paracrine loop maintaining oncogenic EGFR activation.","method":"Conditioned medium transfer experiments; β-catenin/TCF4 reporter assays; EGFL7 protein secretion analysis; EGFL7 knockdown/overexpression in glioma lines","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — conditioned medium and reporter assay evidence, single lab, mechanism partially characterized","pmids":["27725228"],"is_preprint":false},{"year":2017,"finding":"EGFL7 loss-of-function in the murine subventricular zone (SVZ) causes accumulation of activated neural stem cells (NSCs) with enhanced cell cycle re-entry; EGFL7 promotes Dll4-induced Notch signaling at the blood vessel–stem cell interface to push activated NSCs toward quiescence, and EGFL7-KO mice display impaired olfactory perception due to fewer inhibitory neurons in the olfactory bulb.","method":"EGFL7-KO mouse model; BrdU/EdU labeling of NSCs; Dll4-Notch signaling reporter assays; olfactory behavioral tests; immunofluorescence of SVZ niche","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined cellular and behavioral phenotype, mechanistic link to Dll4-Notch signaling, multiple orthogonal in vivo methods","pmids":["28656980"],"is_preprint":false},{"year":2017,"finding":"Egfl7 knockout mice show defects in chorioallantoic branching morphogenesis and placental vascular patterning with fetal growth restriction; placental endothelial cells are deficient in migration, cord formation, and sprouting. Importantly, Egfl7 knockout did not affect expression of the embedded miR-126, demonstrating these placental phenotypes are attributable to loss of EGFL7 protein.","method":"Novel Egfl7 KO mouse; microangiography and 3D imaging; placental endothelial cell functional assays (migration, cord formation, sprouting); miR-126 expression analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with miR-126 control, in vivo phenotype validated by multiple methods, establishes protein-specific function","pmids":["28526753"],"is_preprint":false},{"year":2018,"finding":"EGFL7 deposition into endothelial ECM is controlled by MAGP-1 and fibronectin, which drive EGFL7 into fibers and aggregates respectively; ECM accumulation of EGFL7 is required for its regulation of LOX activity and HEY2 (Notch target) expression, but NOT for regulation of endothelial adhesion molecule expression; interaction of EGFL7 with MAGP-1 is specifically required for LOX activity repression.","method":"Co-immunoprecipitation; ECM fractionation; LOX activity assays; Notch reporter (HEY2) assays; adhesion molecule expression; EGFL7 variant constructs","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays dissecting context-dependent EGFL7 function, single lab","pmids":["30338930"],"is_preprint":false},{"year":2018,"finding":"EGFL7 enhances surface expression of integrin α5β1 on endothelial cells, which in turn promotes fibronectin-induced angiogenic sprouting and produces more mature, less leaky glioma blood vessels; EGFL7-inhibiting antibody reduces experimental glioma vascularization and extends animal survival.","method":"EGFL7 KD/overexpression in vivo glioma models; flow cytometry for surface integrin α5β1; fibronectin sprouting assay; MRI vascular permeability; antibody blockade in experimental glioma","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — integrin surface expression mechanism, in vivo validation with antibody, single lab","pmids":["30065025"],"is_preprint":false},{"year":2018,"finding":"EGFL7 promotes hepatocellular carcinoma cell proliferation and inhibits apoptosis through activation of Wnt/β-catenin signaling, leading to increased CKS2 (cyclin-dependent kinase regulatory subunit 2) expression; CKS2 silencing blocks EGFL7-induced HCC proliferation.","method":"EGFL7 overexpression/shRNA in HCC lines; Wnt/β-catenin inhibitor (IWR-1-endo); CKS2 siRNA rescue; Western blot; xenograft model","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue with siRNA and pathway inhibitor, in vitro and in vivo, single lab","pmids":["30129142"],"is_preprint":false},{"year":2018,"finding":"EGFL7 activates the Flt3/Flt3 ligand pathway in thymic endothelial cells and early thymic precursors (ETPs), expanding ETPs and thymic ECs; selective Flt3 blockade prevents Egfl7-driven ETP and EC expansion in vivo.","method":"Egfl7 overexpression mouse model; flow cytometry for ETP populations; Flt3 ligand ELISA; anti-Flt3 blocking antibody in vivo","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with receptor blockade epistasis, single lab","pmids":["28601636"],"is_preprint":false},{"year":2018,"finding":"EGFL7 knockdown in growth hormone-producing pituitary adenoma cells inhibits EGFR signaling cascades (p-EGFR, p-AKT, p-ERK), and EGFR inhibitor AG1478 suppresses EGFL7-driven migration and invasion, establishing EGFL7 as a regulator of EGFR signaling pathway activity in these cells.","method":"EGFL7 siRNA knockdown; Western blot for EGFR signaling components; EGFR inhibitor pharmacological treatment; cell migration/invasion assays","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD plus pharmacological dissection in vitro, single lab","pmids":["29951953"],"is_preprint":false},{"year":2019,"finding":"EGFL7 directly binds NOTCH receptors on AML blasts to antagonize canonical Notch ligand (DLL4) binding; rEGFL7 stimulation reduces Notch intracellular domain and target gene expression; anti-EGFL7 blocking antibody reactivates Notch signaling, increases blast differentiation and apoptosis, and prolongs survival in three independent AML mouse models.","method":"Antibody interaction array (~400 proteins); competitive ligand-binding assays; Notch reporter assays; primary AML blast stimulation; three in vivo AML mouse models with antibody treatment","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding shown by interaction array and competitive ligand assay, functional validation in primary patient samples and three independent in vivo models","pmids":["31672772"],"is_preprint":false},{"year":2019,"finding":"EGFL7 knockdown impairs VEGF-A-induced sprouting angiogenesis, causes overproduction of endothelial filopodia, reduces collagen IV deposition, impairs barrier function, and disturbs VE-cadherin junction formation and phosphorylation in a 3D microvessel model.","method":"EGFL7 siRNA knockdown in 3D in vitro microvessel model; sprouting assay; filopodia imaging; immunofluorescence for collagen IV and VE-cadherin; barrier permeability assay; VE-cadherin phosphorylation by Western blot","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD in 3D physiological model with multiple orthogonal readouts, single lab","pmids":["30684886"],"is_preprint":false},{"year":2019,"finding":"EGFL7 establishes an EGFL7-ITGB3 (integrin β3)-KLF2 amplification loop in multiple myeloma cells: EGFL7 binds its receptor ITGB3 causing phosphorylation and focal adhesion kinase activation; ITGB3 overexpression upregulates the transcription factor KLF2 which further enhances EGFL7 transcription, supporting MM cell survival and proliferation.","method":"ITGB3 and EGFL7 overexpression in MM lines; Co-IP; FAK phosphorylation assays; KLF2 reporter assays; EGFL7 KD with neutralizing antibodies; in vivo xenograft (NOD-SCID mice)","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation assays, KD with antibody in vitro and in vivo, single lab","pmids":["32191808"],"is_preprint":false},{"year":2019,"finding":"The lncRNA lncEGFL7OS (located on the antisense strand of the EGFL7/miR-126 locus) regulates EGFL7/miR-126 expression by recruiting MAX protein to mediate histone acetylation at the EGFL7/miR-126 promoter/enhancer; lncEGFL7OS is required for MAPK and AKT pathway activation in endothelial cells.","method":"lncEGFL7OS KD/OE; MAX protein identification by pulldown and MS; ChIP for histone acetylation; CRISPR targeting of locus; in vitro/in vivo/ex vivo sprouting assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MAX pulldown with ChIP validation, CRISPR confirmation, though this primarily concerns the lncRNA regulating EGFL7 rather than EGFL7 mechanism per se; included as it defines upstream epigenetic regulation of EGFL7","pmids":["30741632"],"is_preprint":false},{"year":2023,"finding":"HCC cells secrete Egfl7 to recruit and activate liver fibroblasts into cancer-associated fibroblasts (CAFs) via the αvβ3 integrin signaling pathway, inducing phosphorylation of FAK and AKT in fibroblasts; CAFs activated by Egfl7 deposit fibrils/collagen and promote HCC cell proliferation, invasion, and metastasis.","method":"Transwell coculture; recombinant EGFL7 treatment of fibroblasts; αvβ3 integrin blocking; Western blot for FAK and AKT phosphorylation; in vivo orthotopic mouse transplantation model; ELISA","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identification with blocking experiment, in vitro and in vivo validation, single lab","pmids":["37480091"],"is_preprint":false},{"year":2022,"finding":"EGFL7 drives resistance to EGFR kinase inhibitors in lung cancer by activating NOTCH signaling; adaptive EGFL7 upregulation during EGFR inhibition is controlled by depression of the nonsense-mediated mRNA decay (NMD) pathway; EGFL7-activated Notch slows c-Myc decrease caused by EGFR inhibition, supporting cancer cell survival.","method":"EGFL7 expression analysis during EGFR inhibitor treatment; NMD pathway manipulation; Notch reporter assays; c-Myc Western blot; cell survival assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with NMD, Notch, and c-Myc analysis, single lab","pmids":["36309484"],"is_preprint":false},{"year":2022,"finding":"SMYD2 methyltransferase physically interacts with HNRNPK and mediates K422 monomethylation of HNRNPK, which increases its RNA-binding activity; methylated HNRNPK stabilizes EGFL7 mRNA, promoting CRC angiogenesis; targeting SMYD2 blocks EGFL7-dependent angiogenesis in tumors.","method":"Co-IP between SMYD2 and HNRNPK; in vitro methylation assay; HNRNPK RNA-binding assay; EGFL7 mRNA stability assay; xenograft model; SMYD2 inhibitor BAY-598","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution of methylation and RNA binding, single lab; this defines an upstream post-translational regulatory mechanism for EGFL7 mRNA","pmids":["35503397"],"is_preprint":false},{"year":2018,"finding":"EGFL7 reduces CNS inflammation by binding αvβ3 integrin on activated T lymphocytes; EGFL7-KO mice show earlier EAE onset and increased T lymphocyte brain infiltration; EC-restricted EGFL7-KO produces similar worsening; recombinant EGFL7 treatment improves EAE, reduces MCAM expression, and tightens the BBB.","method":"EGFL7-KO and EC-restricted KO mice; EAE model; T cell αvβ3 integrin upregulation analysis; adhesion assays; recombinant EGFL7 treatment; BBB permeability assay; MCAM expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — EC-restricted KO epistasis, recombinant protein rescue, integrin-mediated adhesion mechanism, multiple in vivo models","pmids":["29483510"],"is_preprint":false},{"year":2023,"finding":"EGFL7 loss in hippocampal neural stem cells (Nestin-CreERT2 KO) upregulates neurogenesis in the subgranular zone and correlates with increased VEGF-D expression; intraventricular infusion of VEGF-D upregulates neurogenesis in vivo, and VEGF-D KO downregulates neurogenesis; EGFL7-KO mice show improved spatial memory and memory consolidation.","method":"Nestin-CreERT2 conditional KO; RNA sequencing; intraventricular VEGF-D infusion; VEGF-D KO; BrdU/EdU neurogenesis labeling; behavioral (Morris water maze, pattern separation) assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with RNA-seq, VEGF-D gain/loss-of-function epistasis, behavioral readout, single lab","pmids":["36715759"],"is_preprint":false},{"year":2023,"finding":"EGFL7 secreted by human bone marrow mesenchymal stem cells promotes osteoblast differentiation partly by downregulating Notch1/NICD/Hes1 signaling; EGFL7 knockdown impairs hBMSC osteogenesis and activates Notch1 signaling, which is rescued by Notch1 inhibition; recombinant EGFL7 enhances bone healing in a femoral defect mouse model.","method":"EGFL7 siRNA KD; recombinant hEGFL7 treatment; Notch1 signaling inhibitor (γ-secretase inhibitor) rescue; osteogenic differentiation assays; femoral defect in vivo model","journal":"Stem cell reviews and reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue with Notch inhibitor, in vitro and in vivo validation, single lab","pmids":["36609902"],"is_preprint":false}],"current_model":"EGFL7 is an endothelial cell-derived secreted ECM-associated protein that promotes vascular tubulogenesis and angiogenesis primarily by (1) acting as a Notch receptor antagonist—binding directly to Notch at its ligand-interaction domain to inhibit signaling, thereby regulating endothelial sprouting, neural stem cell quiescence, and differentiation; (2) ligating integrin αVβ3 to enhance endothelial cell motility on ECM; (3) enhancing integrin α5β1 surface expression to promote fibronectin-driven sprouting; (4) inhibiting lysyl oxidase (LOX) family enzymes to suppress vascular elastogenesis; (5) repressing endothelial activation by stabilizing IκBα to reduce NF-κB-dependent adhesion molecule expression and limit immune cell infiltration; and (6) acting downstream of the CASZ1 transcription factor (itself directly regulated by Erg/GATA-2) to maintain RhoA expression and endothelial cell adhesion/cytoskeletal dynamics, with its ECM-localized functions further modulated by MAGP-1 and fibronectin."},"narrative":{"mechanistic_narrative":"EGFL7 is an endothelial-derived, secreted extracellular matrix-associated protein that orchestrates vascular tubulogenesis and angiogenesis by providing spatial cues that govern endothelial cell arrangement, polarity, and lumen formation [PMID:15085134, PMID:18224713, PMID:25705891]. It is a bona fide secreted protein routed through the ER and Golgi [PMID:15162510] that becomes tightly deposited into the endothelial ECM, where MAGP-1 and fibronectin direct it into distinct fibers and aggregates required for a subset of its functions [PMID:18300411, PMID:30338930]. A central molecular activity of EGFL7 is direct antagonism of Notch: it binds Notch receptors at the ligand-interaction region to block ligand-mediated (including Dll4/DLL4) activation, downregulating Notch target genes to control endothelial sprouting, neural stem cell quiescence and differentiation, and osteoblast differentiation [PMID:19503073, PMID:20947685, PMID:28656980, PMID:31672772, PMID:36609902]. EGFL7 also signals through integrins—ligating αVβ3 to enhance endothelial motility on ECM [PMID:23386126] and increasing surface integrin α5β1 to promote fibronectin-driven sprouting [PMID:30065025]—and represses vascular elastogenesis by binding the catalytic domain of lysyl oxidase family enzymes to inhibit tropoelastin crosslinking, an activity dependent on its MAGP-1-mediated ECM deposition [PMID:18497746, PMID:30338930]. In the vascular wall it acts as a constitutive repressor of endothelial activation, stabilizing IκBα to limit NF-κB-dependent ICAM-1/VCAM-1/E-selectin expression and leukocyte adhesion, thereby restraining immune cell infiltration [PMID:22037871, PMID:27650497, PMID:29483510]. Its endothelial expression is driven transcriptionally by Erg and GATA-2 and by a CASZ1→EGFL7→RhoA axis that maintains focal adhesion and cytoskeletal dynamics [PMID:20808444, PMID:23639441, PMID:24150064]. Across multiple cancers EGFL7 promotes proliferation, EMT, metastasis, immune escape, and tumor vascularization through EGFR/AKT, Wnt/β-catenin, Notch, and integrin signaling, marking it as a therapeutic target amenable to blocking antibodies [PMID:22037871, PMID:24945379, PMID:30065025, PMID:31672772].","teleology":[{"year":2004,"claim":"Established EGFL7 as an endothelial-secreted factor with a non-redundant in vivo role in vascular tube assembly, answering whether it acts cell-autonomously on angioblast organization.","evidence":"Zebrafish morpholino knockdown with in vivo vascular imaging; subcellular localization and secretion in transfected HEK293 cells","pmids":["15085134","15162510"],"confidence":"High","gaps":["Molecular receptor/partner mediating angioblast arrangement not yet identified","Did not distinguish protein function from the embedded miR-126"]},{"year":2008,"claim":"Resolved a major confound by showing earlier mouse 'Egfl7' vascular phenotypes were due to co-deleted intronic miR-126, forcing the field to use protein-selective alleles.","evidence":"Selective Egfl7Δ versus miR-126Δ mouse alleles with cornea angiogenesis and VEGF signaling analysis","pmids":["18987025"],"confidence":"High","gaps":["Left open whether EGFL7 protein has any mouse angiogenic function at all","Did not address non-vascular or context-specific roles"]},{"year":2008,"claim":"Identified the first biochemical activity of EGFL7—inhibition of lysyl oxidase family enzymes—defining it as a negative regulator of vascular elastogenesis.","evidence":"Transgenic mouse overexpression, fibroblast culture, EGFL7-LOX catalytic domain interaction assays, and LoxL2 colocalization","pmids":["18497746"],"confidence":"High","gaps":["Structural basis of the LOX catalytic-domain interaction not resolved","Physiological elastogenesis phenotype in loss-of-function not established here"]},{"year":2009,"claim":"Defined EGFL7 as a direct Notch antagonist binding the receptor ligand-interaction region, extending its role beyond vasculature into neural stem cell self-renewal and differentiation.","evidence":"Biochemical binding assays, Notch reporter assays, NSC gain/loss-of-function and differentiation assays","pmids":["19503073"],"confidence":"High","gaps":["Precise binding interface and stoichiometry not mapped","Whether antagonism is competitive with all canonical ligands unresolved"]},{"year":2010,"claim":"Confirmed Notch antagonism in vivo and in human endothelial cells, and mapped transcriptional control of EGFL7 to Erg/GATA-2, anchoring it within endothelial gene-regulatory networks.","evidence":"Transgenic mouse overexpression with in vivo Co-IP of EGFL7-NOTCH; reporter, mutagenesis, RNAi and ChIP for Erg/GATA-2","pmids":["20947685","20808444","20298530"],"confidence":"High","gaps":["How secreted EGFL7 accesses Notch on neighboring cells mechanistically","Relative contribution of Notch antagonism versus other activities to phenotypes"]},{"year":2013,"claim":"Placed EGFL7 in a CASZ1→EGFL7→RhoA axis and identified integrin αVβ3 as a direct receptor, connecting it to focal adhesion and cytoskeletal control of endothelial motility.","evidence":"Xenopus/EC depletion, epistasis rescue, CASZ1 ChIP, RhoA assays; EGFL7-integrin αVβ3 binding, blocking, and zebrafish validation; EC adhesion/anti-apoptosis with antibody blockade","pmids":["23639441","24150064","23386126","23945239"],"confidence":"High","gaps":["How a single secreted protein engages both Notch and integrins is not reconciled","Signaling downstream of αVβ3 ligation incompletely defined"]},{"year":2016,"claim":"Mechanistically linked EGFL7 to suppression of endothelial activation through IκBα stabilization, and showed reciprocal NF-κB repression of EGFL7 transcription.","evidence":"LPS/TNFα mouse models, promoter deletion/reporter assays, IκBα stability assays, leukocyte adhesion assays; preceding tumor immune-escape study","pmids":["27650497","22037871"],"confidence":"High","gaps":["Molecular target through which secreted EGFL7 stabilizes intracellular IκBα unknown","Receptor transducing the anti-inflammatory signal not identified"]},{"year":2017,"claim":"Demonstrated protein-specific (miR-126-independent) functions in placental vascular branching and in Notch-dependent neural stem cell quiescence, validating loss-of-function roles for EGFL7 protein itself.","evidence":"Egfl7 KO mice with miR-126 controls; SVZ NSC KO with Dll4-Notch reporters and olfactory behavior","pmids":["28526753","28656980"],"confidence":"High","gaps":["Tissue-specific receptor usage across vascular versus neural niches unresolved","Quantitative contribution to mouse developmental angiogenesis still limited"]},{"year":2018,"claim":"Dissected ECM-deposition-dependent versus -independent functions and added integrin α5β1 surface modulation, clarifying which EGFL7 activities require matrix incorporation.","evidence":"Co-IP, ECM fractionation, LOX/HEY2/adhesion-molecule assays with variant constructs (MAGP-1/fibronectin); integrin α5β1 surface expression and antibody blockade in glioma; αvβ3-mediated CNS T-cell adhesion in EAE","pmids":["30338930","30065025","29483510"],"confidence":"Medium","gaps":["Structural determinants of MAGP-1 versus fibronectin-driven deposition not resolved","EAE/glioma findings from single labs each"]},{"year":2019,"claim":"Extended Notch antagonism to malignant hematopoiesis and defined integrin-based amplification loops, establishing EGFL7 as a druggable target for blocking antibodies.","evidence":"Interaction array and competitive ligand assays in AML with antibody therapy in three mouse models; ITGB3-KLF2 loop Co-IP and FAK assays in myeloma; 3D microvessel KD","pmids":["31672772","32191808","30684886"],"confidence":"High","gaps":["Generality of EGFL7-Notch antagonism across tumor types not fully mapped","Integrin-KLF2 loop characterized in a single tumor context"]},{"year":2023,"claim":"Broadened the functional repertoire to fibroblast activation, hepatocellular and other cancer signaling, and adult neurogenesis/memory, showing EGFL7 acts through integrin-FAK-AKT, Wnt/β-catenin, EGFR, and VEGF-D-linked pathways across contexts.","evidence":"Recombinant EGFL7 with αvβ3 blocking in HCC-fibroblast coculture and orthotopic models; Wnt/β-catenin-CKS2 and EGFR pathway dissection in tumors; Nestin-CreERT2 KO with RNA-seq and VEGF-D epistasis","pmids":["37480091","30129142","24945379","36715759"],"confidence":"Medium","gaps":["Whether these diverse downstream pathways converge on a common receptor set unclear","Most cancer/neurogenesis mechanisms from single labs"]},{"year":null,"claim":"How EGFL7 integrates simultaneous engagement of Notch receptors, multiple integrins, and LOX enzymes into context-specific outputs—and the structural basis distinguishing these interactions—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of EGFL7 bound to any partner","Mechanism by which ECM deposition state selects among functions only partially defined","Receptor mediating the intracellular IκBα-stabilizing anti-inflammatory effect unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,7,8,29]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[13,31]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[13,25]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[3,4,24]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,6,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,13,29]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4,24]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,20,36]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,25,29,31]}],"complexes":[],"partners":["NOTCH1","LOX","ITGAV","ITGB3","ITGA5","ITGB1","MAGP1","FN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHF1","full_name":"Epidermal growth factor-like protein 7","aliases":["Multiple epidermal growth factor-like domains protein 7","Multiple EGF-like domains protein 7","NOTCH4-like protein","Vascular endothelial statin","VE-statin","Zneu1"],"length_aa":273,"mass_kda":29.6,"function":"Regulates vascular tubulogenesis in vivo. Inhibits platelet-derived growth factor (PDGF)-BB-induced smooth muscle cell migration and promotes endothelial cell adhesion to the extracellular matrix and angiogenesis","subcellular_location":"Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/Q9UHF1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EGFL7","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EGFL7","total_profiled":1310},"omim":[{"mim_id":"611767","title":"MICRO RNA 126; MIR126","url":"https://www.omim.org/entry/611767"},{"mim_id":"609897","title":"EPIDERMAL GROWTH FACTOR-LIKE 8; EGFL8","url":"https://www.omim.org/entry/609897"},{"mim_id":"608582","title":"EPIDERMAL GROWTH FACTOR-LIKE 7; EGFL7","url":"https://www.omim.org/entry/608582"},{"mim_id":"607929","title":"CCM2 SCAFFOLD PROTEIN; CCM2","url":"https://www.omim.org/entry/607929"},{"mim_id":"602016","title":"KLF TRANSCRIPTION FACTOR 2; KLF2","url":"https://www.omim.org/entry/602016"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EGFL7"},"hgnc":{"alias_symbol":["ZNEU1"],"prev_symbol":[]},"alphafold":{"accession":"Q9UHF1","domains":[{"cath_id":"-","chopping":"22-85","consensus_level":"medium","plddt":79.0919,"start":22,"end":85},{"cath_id":"2.10.25.10","chopping":"139-181","consensus_level":"medium","plddt":84.4835,"start":139,"end":181}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHF1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHF1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHF1-F1-predicted_aligned_error_v6.png","plddt_mean":75.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EGFL7","jax_strain_url":"https://www.jax.org/strain/search?query=EGFL7"},"sequence":{"accession":"Q9UHF1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHF1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHF1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHF1"}},"corpus_meta":[{"pmid":"15085134","id":"PMC_15085134","title":"The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation.","date":"2004","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15085134","citation_count":310,"is_preprint":false},{"pmid":"18987025","id":"PMC_18987025","title":"Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126.","date":"2008","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18987025","citation_count":305,"is_preprint":false},{"pmid":"19116145","id":"PMC_19116145","title":"Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19116145","citation_count":199,"is_preprint":false},{"pmid":"20034472","id":"PMC_20034472","title":"miR-126 inhibits non-small cell lung cancer cells proliferation by targeting EGFL7.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20034472","citation_count":158,"is_preprint":false},{"pmid":"15162510","id":"PMC_15162510","title":"Egfl7, a novel epidermal growth factor-domain gene expressed in endothelial cells.","date":"2004","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/15162510","citation_count":148,"is_preprint":false},{"pmid":"22160377","id":"PMC_22160377","title":"EGFL7: a unique angiogenic signaling factor in vascular development and disease.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22160377","citation_count":131,"is_preprint":false},{"pmid":"19503073","id":"PMC_19503073","title":"Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal.","date":"2009","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19503073","citation_count":120,"is_preprint":false},{"pmid":"15972971","id":"PMC_15972971","title":"EGFL7 is a chemoattractant for endothelial cells and is up-regulated in angiogenesis and arterial injury.","date":"2005","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15972971","citation_count":117,"is_preprint":false},{"pmid":"20529320","id":"PMC_20529320","title":"EGFL7 meets miRNA-126: an angiogenesis alliance.","date":"2010","source":"Journal of angiogenesis research","url":"https://pubmed.ncbi.nlm.nih.gov/20529320","citation_count":86,"is_preprint":false},{"pmid":"20947685","id":"PMC_20947685","title":"Impaired angiogenesis and altered Notch signaling in mice overexpressing endothelial Egfl7.","date":"2010","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20947685","citation_count":85,"is_preprint":false},{"pmid":"22037871","id":"PMC_22037871","title":"Egfl7 promotes tumor escape from immunity by repressing endothelial cell activation.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22037871","citation_count":84,"is_preprint":false},{"pmid":"30953521","id":"PMC_30953521","title":"A positive feed-forward loop between LncRNA-URRCC and EGFL7/P-AKT/FOXO3 signaling promotes proliferation and metastasis of clear cell renal cell carcinoma.","date":"2019","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30953521","citation_count":79,"is_preprint":false},{"pmid":"23639441","id":"PMC_23639441","title":"CASZ1 promotes vascular assembly and morphogenesis through the direct regulation of an EGFL7/RhoA-mediated pathway.","date":"2013","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/23639441","citation_count":64,"is_preprint":false},{"pmid":"23386126","id":"PMC_23386126","title":"EGFL7 ligates αvβ3 integrin to enhance vessel formation.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23386126","citation_count":63,"is_preprint":false},{"pmid":"28983240","id":"PMC_28983240","title":"Transcription Factor NFAT5 Promotes Glioblastoma Cell-driven Angiogenesis via SBF2-AS1/miR-338-3p-Mediated EGFL7 Expression Change.","date":"2017","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28983240","citation_count":60,"is_preprint":false},{"pmid":"24945379","id":"PMC_24945379","title":"Epidermal growth factor-like domain-containing protein 7 (EGFL7) enhances EGF receptor-AKT signaling, epithelial-mesenchymal transition, and metastasis of gastric cancer cells.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24945379","citation_count":59,"is_preprint":false},{"pmid":"27259812","id":"PMC_27259812","title":"Overexpressed MALAT1 promotes invasion and metastasis of gastric cancer cells via increasing EGFL7 expression.","date":"2016","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27259812","citation_count":56,"is_preprint":false},{"pmid":"18497746","id":"PMC_18497746","title":"VE-statin/egfl7 regulates vascular elastogenesis by interacting with lysyl oxidases.","date":"2008","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/18497746","citation_count":52,"is_preprint":false},{"pmid":"20213100","id":"PMC_20213100","title":"Expression and clinical significance of EGFL7 in malignant glioma.","date":"2010","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20213100","citation_count":50,"is_preprint":false},{"pmid":"24909139","id":"PMC_24909139","title":"EGFL7 is expressed in bone microenvironment and promotes angiogenesis via ERK, STAT3, and integrin signaling cascades.","date":"2015","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24909139","citation_count":49,"is_preprint":false},{"pmid":"29923200","id":"PMC_29923200","title":"EGFL7: Master regulator of cancer pathogenesis, angiogenesis and an emerging mediator of bone homeostasis.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29923200","citation_count":48,"is_preprint":false},{"pmid":"30065025","id":"PMC_30065025","title":"EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors.","date":"2018","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30065025","citation_count":43,"is_preprint":false},{"pmid":"23558933","id":"PMC_23558933","title":"The expression of Egfl7 in human normal tissues and epithelial tumors.","date":"2013","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/23558933","citation_count":42,"is_preprint":false},{"pmid":"28526753","id":"PMC_28526753","title":"Altered feto-placental vascularization, feto-placental malperfusion and fetal growth restriction in mice with Egfl7 loss of function.","date":"2017","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28526753","citation_count":41,"is_preprint":false},{"pmid":"29483510","id":"PMC_29483510","title":"EGFL7 reduces CNS inflammation in mouse.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29483510","citation_count":40,"is_preprint":false},{"pmid":"27725228","id":"PMC_27725228","title":"EGFL7 is an intercellular EGFR signal messenger that plays an oncogenic role in glioma.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27725228","citation_count":40,"is_preprint":false},{"pmid":"28881749","id":"PMC_28881749","title":"Effects of microRNA-126 on cell proliferation, apoptosis and tumor angiogenesis via the down-regulating ERK signaling pathway by targeting EGFL7 in hepatocellular carcinoma.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28881749","citation_count":37,"is_preprint":false},{"pmid":"25601205","id":"PMC_25601205","title":"Endothelial cells control pancreatic cell fate at defined stages through EGFL7 signaling.","date":"2015","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25601205","citation_count":37,"is_preprint":false},{"pmid":"26504055","id":"PMC_26504055","title":"Methylation-associated Silencing of microRNA-126 and its Host Gene EGFL7 in Malignant Pleural Mesothelioma.","date":"2015","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26504055","citation_count":34,"is_preprint":false},{"pmid":"24751645","id":"PMC_24751645","title":"Novel expression of EGFL7 in placental trophoblast and endothelial cells and its implication in preeclampsia.","date":"2014","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/24751645","citation_count":32,"is_preprint":false},{"pmid":"30684886","id":"PMC_30684886","title":"EGFL7 regulates sprouting angiogenesis and endothelial integrity in a human blood vessel model.","date":"2019","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/30684886","citation_count":32,"is_preprint":false},{"pmid":"28656980","id":"PMC_28656980","title":"Neurovascular EGFL7 regulates adult neurogenesis in the subventricular zone and thereby affects olfactory perception.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28656980","citation_count":32,"is_preprint":false},{"pmid":"31155507","id":"PMC_31155507","title":"EGFL7 Mediates BMP9-Induced Sprouting Angiogenesis of Endothelial Cells Derived from Human Embryonic Stem Cells.","date":"2019","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31155507","citation_count":31,"is_preprint":false},{"pmid":"27611944","id":"PMC_27611944","title":"MicroRNA-126 inhibits tumor proliferation and angiogenesis of hepatocellular carcinoma by down-regulating EGFL7 expression.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27611944","citation_count":29,"is_preprint":false},{"pmid":"22018271","id":"PMC_22018271","title":"Heterogeneity and degree of TIMP4, GATA4, SOX18, and EGFL7 gene promoter methylation in non-small cell lung cancer and surrounding tissues.","date":"2011","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22018271","citation_count":29,"is_preprint":false},{"pmid":"23945239","id":"PMC_23945239","title":"Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/23945239","citation_count":28,"is_preprint":false},{"pmid":"18224713","id":"PMC_18224713","title":"Egfl7 knockdown causes defects in the extension and junctional arrangements of endothelial cells during zebrafish vasculogenesis.","date":"2008","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/18224713","citation_count":28,"is_preprint":false},{"pmid":"27650497","id":"PMC_27650497","title":"Endothelial Cell Activation Is Regulated by Epidermal Growth Factor-like Domain 7 (Egfl7) during Inflammation.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27650497","citation_count":27,"is_preprint":false},{"pmid":"20298530","id":"PMC_20298530","title":"A role for Egfl7 during endothelial organization in the embryoid body model system.","date":"2010","source":"Journal of angiogenesis research","url":"https://pubmed.ncbi.nlm.nih.gov/20298530","citation_count":26,"is_preprint":false},{"pmid":"28705113","id":"PMC_28705113","title":"EGFL7 participates in regulating biological behavior of growth hormone-secreting pituitary adenomas via Notch2/DLL3 signaling pathway.","date":"2017","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28705113","citation_count":25,"is_preprint":false},{"pmid":"35695550","id":"PMC_35695550","title":"Single-cell RNA sequencing reveals differential expression of EGFL7 and VEGF in giant-cell tumor of bone and osteosarcoma.","date":"2022","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/35695550","citation_count":24,"is_preprint":false},{"pmid":"32191808","id":"PMC_32191808","title":"The EGFL7-ITGB3-KLF2 axis enhances survival of multiple myeloma in preclinical models.","date":"2020","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/32191808","citation_count":23,"is_preprint":false},{"pmid":"31672772","id":"PMC_31672772","title":"EGFL7 Antagonizes NOTCH Signaling and Represents a Novel Therapeutic Target in Acute Myeloid Leukemia.","date":"2019","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/31672772","citation_count":23,"is_preprint":false},{"pmid":"31170663","id":"PMC_31170663","title":"microRNA-126 inhibits tube formation of HUVECs by interacting with EGFL7 and down-regulating PI3K/AKT signaling pathway.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/31170663","citation_count":23,"is_preprint":false},{"pmid":"28980146","id":"PMC_28980146","title":"Egfl7 Represses the Vasculogenic Potential of Human Endothelial Progenitor Cells.","date":"2018","source":"Stem cell reviews and reports","url":"https://pubmed.ncbi.nlm.nih.gov/28980146","citation_count":22,"is_preprint":false},{"pmid":"30129142","id":"PMC_30129142","title":"EGFL7 promotes hepatocellular carcinoma cell proliferation and inhibits cell apoptosis through increasing CKS2 expression by activating Wnt/β-catenin signaling.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30129142","citation_count":22,"is_preprint":false},{"pmid":"33502949","id":"PMC_33502949","title":"Suppression of lncRNA HOTAIR alleviates RCC angiogenesis through regulating miR-126/EGFL7 axis.","date":"2021","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33502949","citation_count":22,"is_preprint":false},{"pmid":"23404186","id":"PMC_23404186","title":"Expression of Egfl7 correlates with low-grade invasive lesions in human breast cancer.","date":"2013","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23404186","citation_count":21,"is_preprint":false},{"pmid":"20808444","id":"PMC_20808444","title":"VE-statin/egfl7 expression in endothelial cells is regulated by a distal enhancer and a proximal promoter under the direct control of Erg and GATA-2.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20808444","citation_count":21,"is_preprint":false},{"pmid":"28275117","id":"PMC_28275117","title":"Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First-Line Metastatic Colorectal Cancer.","date":"2017","source":"The oncologist","url":"https://pubmed.ncbi.nlm.nih.gov/28275117","citation_count":21,"is_preprint":false},{"pmid":"30741632","id":"PMC_30741632","title":"LncEGFL7OS regulates human angiogenesis by interacting with MAX at the EGFL7/miR-126 locus.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30741632","citation_count":20,"is_preprint":false},{"pmid":"18300411","id":"PMC_18300411","title":"The role of Egfl7 in vascular morphogenesis.","date":"2007","source":"Novartis Foundation symposium","url":"https://pubmed.ncbi.nlm.nih.gov/18300411","citation_count":20,"is_preprint":false},{"pmid":"35503397","id":"PMC_35503397","title":"Targeting SMYD2 inhibits angiogenesis and increases the efficiency of apatinib by suppressing EGFL7 in colorectal cancer.","date":"2022","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/35503397","citation_count":20,"is_preprint":false},{"pmid":"29438092","id":"PMC_29438092","title":"Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with Carboplatin, Paclitaxel, and Bevacizumab for First-Line Nonsquamous Non-Small Cell Lung Cancer.","date":"2018","source":"The oncologist","url":"https://pubmed.ncbi.nlm.nih.gov/29438092","citation_count":20,"is_preprint":false},{"pmid":"33804387","id":"PMC_33804387","title":"The Multifaceted Roles of EGFL7 in Cancer and Drug Resistance.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33804387","citation_count":19,"is_preprint":false},{"pmid":"24815445","id":"PMC_24815445","title":"Targeting EGFL7 expression through RNA interference suppresses renal cell carcinoma growth by inhibiting angiogenesis.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24815445","citation_count":19,"is_preprint":false},{"pmid":"18556249","id":"PMC_18556249","title":"Expression of EGFL7 in primordial germ cells and in adult ovaries and testes.","date":"2008","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/18556249","citation_count":19,"is_preprint":false},{"pmid":"29951953","id":"PMC_29951953","title":"Role of EGFL7/EGFR-signaling pathway in migration and invasion of growth hormone-producing pituitary adenomas.","date":"2018","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29951953","citation_count":19,"is_preprint":false},{"pmid":"24286167","id":"PMC_24286167","title":"Decreased expression of the endothelial cell-derived factor EGFL7 in systemic sclerosis: potential contribution to impaired angiogenesis and vasculogenesis.","date":"2013","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/24286167","citation_count":19,"is_preprint":false},{"pmid":"28799610","id":"PMC_28799610","title":"Viral nanoparticles decorated with novel EGFL7 ligands enable intravital imaging of tumor neovasculature.","date":"2017","source":"Nanoscale","url":"https://pubmed.ncbi.nlm.nih.gov/28799610","citation_count":19,"is_preprint":false},{"pmid":"30338930","id":"PMC_30338930","title":"MAGP-1 and fibronectin control EGFL7 functions by driving its deposition into distinct endothelial extracellular matrix locations.","date":"2018","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/30338930","citation_count":18,"is_preprint":false},{"pmid":"37480091","id":"PMC_37480091","title":"Hepatocellular carcinoma cells remodel the pro-metastatic tumour microenvironment through recruitment and activation of fibroblasts via paracrine Egfl7 signaling.","date":"2023","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/37480091","citation_count":16,"is_preprint":false},{"pmid":"32724375","id":"PMC_32724375","title":"MicroRNA-126 exerts antitumor functions in ovarian cancer by targeting EGFL7 and affecting epithelial-to-mesenchymal transition and ERK/MAPK signaling pathway.","date":"2020","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/32724375","citation_count":16,"is_preprint":false},{"pmid":"26542361","id":"PMC_26542361","title":"Different expression of VEGF and EGFL7 in human hepatocellular carcinoma.","date":"2015","source":"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/26542361","citation_count":15,"is_preprint":false},{"pmid":"20372059","id":"PMC_20372059","title":"EGFL7: a new player in homeostasis of the nervous system.","date":"2010","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/20372059","citation_count":15,"is_preprint":false},{"pmid":"27766530","id":"PMC_27766530","title":"EGFL7-overexpressing epidermal stem cells promotes fibroblast proliferation and migration via mediating cell adhesion and strengthening cytoskeleton.","date":"2016","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27766530","citation_count":15,"is_preprint":false},{"pmid":"36072982","id":"PMC_36072982","title":"Paeoniflorin Inhibits the Proliferation and Metastasis of Ulcerative Colitis-Associated Colon Cancer by Targeting EGFL7.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36072982","citation_count":15,"is_preprint":false},{"pmid":"36309484","id":"PMC_36309484","title":"EGFL7 drives the evolution of resistance to EGFR inhibitors in lung cancer by activating NOTCH signaling.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36309484","citation_count":15,"is_preprint":false},{"pmid":"24696719","id":"PMC_24696719","title":"VE-statin/Egfl7 expression in malignant glioma and its relevant molecular network.","date":"2014","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24696719","citation_count":14,"is_preprint":false},{"pmid":"30569717","id":"PMC_30569717","title":"EGFL7 silencing inactivates the Notch signaling pathway; enhancing cell apoptosis and suppressing cell proliferation in human cutaneous melanoma.","date":"2018","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/30569717","citation_count":13,"is_preprint":false},{"pmid":"26722408","id":"PMC_26722408","title":"In-vitro inhibitory effect of EGFL7-RNAi on endothelial angiogenesis in glioma.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26722408","citation_count":13,"is_preprint":false},{"pmid":"33635474","id":"PMC_33635474","title":"EGFL7 as a novel therapeutic candidate regulates cell invasion and anoikis in colorectal cancer through PI3K/AKT signaling pathway.","date":"2021","source":"International journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33635474","citation_count":13,"is_preprint":false},{"pmid":"24696724","id":"PMC_24696724","title":"VE-statin/Egfl7 siRNA inhibits angiogenesis in malignant glioma in vitro.","date":"2014","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24696724","citation_count":13,"is_preprint":false},{"pmid":"24150064","id":"PMC_24150064","title":"The CASZ1/Egfl7 transcriptional pathway is required for RhoA expression in vascular endothelial cells.","date":"2013","source":"Small GTPases","url":"https://pubmed.ncbi.nlm.nih.gov/24150064","citation_count":13,"is_preprint":false},{"pmid":"35494025","id":"PMC_35494025","title":"The Polymorphism and Expression of EGFL7 and miR-126 Are Associated With NSCLC Susceptibility.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35494025","citation_count":12,"is_preprint":false},{"pmid":"23280513","id":"PMC_23280513","title":"Circulating mRNA for epidermal growth factor-like domain 7 (EGFL7) in maternal blood and early intrauterine growth restriction. A preliminary analysis.","date":"2012","source":"Prenatal diagnosis","url":"https://pubmed.ncbi.nlm.nih.gov/23280513","citation_count":12,"is_preprint":false},{"pmid":"32117731","id":"PMC_32117731","title":"Novel Expression of EGFL7 in Osteosarcoma and Sensitivity to Cisplatin.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32117731","citation_count":11,"is_preprint":false},{"pmid":"26064204","id":"PMC_26064204","title":"Attenuation of EGFL7 inhibits human laryngocarcinoma cells growth and invasion.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26064204","citation_count":11,"is_preprint":false},{"pmid":"29778234","id":"PMC_29778234","title":"EGFL7 and RASSF1 promoter hypermethylation in epithelial ovarian cancer.","date":"2018","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29778234","citation_count":10,"is_preprint":false},{"pmid":"22737620","id":"PMC_22737620","title":"Egfl7 promotes tumor escape from immunity.","date":"2012","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/22737620","citation_count":10,"is_preprint":false},{"pmid":"25270395","id":"PMC_25270395","title":"Astragalus polysaccharides exert protective effects in newborn rats with bronchopulmonary dysplasia by upregulating the expression of EGFL7 in lung tissue.","date":"2014","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25270395","citation_count":10,"is_preprint":false},{"pmid":"36715759","id":"PMC_36715759","title":"EGFL7 loss correlates with increased VEGF-D expression, upregulating hippocampal adult neurogenesis and improving spatial learning and memory.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/36715759","citation_count":9,"is_preprint":false},{"pmid":"25705891","id":"PMC_25705891","title":"A distinct mechanism of vascular lumen formation in Xenopus requires EGFL7.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25705891","citation_count":9,"is_preprint":false},{"pmid":"29466872","id":"PMC_29466872","title":"Attenuation of EGFL7 Expression Inhibits Growth Hormone-Producing Pituitary Adenomas Growth and Invasion.","date":"2018","source":"Human gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29466872","citation_count":8,"is_preprint":false},{"pmid":"24595089","id":"PMC_24595089","title":"Egfl7 is differentially expressed in arteries and veins during retinal vascular development.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24595089","citation_count":8,"is_preprint":false},{"pmid":"38307238","id":"PMC_38307238","title":"The mechanism of EGFL7 regulating neovascularization in diabetic retinopathy through the PI3K/AKT/VEGFA pathway.","date":"2024","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38307238","citation_count":8,"is_preprint":false},{"pmid":"31245291","id":"PMC_31245291","title":"microRNA-126 Is a Tumor Suppressor of Granulosa Cell Tumor Mediated by Its Host Gene EGFL7.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31245291","citation_count":8,"is_preprint":false},{"pmid":"23981988","id":"PMC_23981988","title":"[DNA methylation status of miR-126 and its host gene EGFL7 in CD4+ T cells from patients with systemic lupus erythematosus].","date":"2013","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23981988","citation_count":8,"is_preprint":false},{"pmid":"28601636","id":"PMC_28601636","title":"The angiogenic factor Egfl7 alters thymogenesis by activating Flt3 signaling.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28601636","citation_count":7,"is_preprint":false},{"pmid":"30811740","id":"PMC_30811740","title":"Effect of benzo[a]pyrene on the expression of miR-126, miR-190a and their target genes EGFL7, TP53INP1 and PHLPP1 in primary endometrial cells.","date":"2019","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/30811740","citation_count":7,"is_preprint":false},{"pmid":"36609902","id":"PMC_36609902","title":"EGFL7 Secreted By Human Bone Mesenchymal Stem Cells Promotes Osteoblast Differentiation Partly Via Downregulation Of Notch1-Hes1 Signaling Pathway.","date":"2023","source":"Stem cell reviews and reports","url":"https://pubmed.ncbi.nlm.nih.gov/36609902","citation_count":6,"is_preprint":false},{"pmid":"36530156","id":"PMC_36530156","title":"EGFL7 affects the migration of epidermal stem cells in refractory diabetic wounds by regulating Notch signaling pathway.","date":"2022","source":"Regenerative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36530156","citation_count":6,"is_preprint":false},{"pmid":"37490307","id":"PMC_37490307","title":"Role of EGFL7 in human cancers: A review.","date":"2023","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37490307","citation_count":5,"is_preprint":false},{"pmid":"35234000","id":"PMC_35234000","title":"EGFL7 and HIF-1a Expression on Human Trophoblast Placental by Rhodomyrtus tomentosa and Zanthoxylum acanthopodium.","date":"2022","source":"Pakistan journal of biological sciences : PJBS","url":"https://pubmed.ncbi.nlm.nih.gov/35234000","citation_count":5,"is_preprint":false},{"pmid":"34635968","id":"PMC_34635968","title":"Relation among EGFL7, ITGB3, and KLF2 and their clinical implication in multiple myeloma patients: a prospective study.","date":"2021","source":"Irish journal of medical science","url":"https://pubmed.ncbi.nlm.nih.gov/34635968","citation_count":5,"is_preprint":false},{"pmid":"22297616","id":"PMC_22297616","title":"Human anti-EGFL7 recombinant full-length antibodies selected from a mammalian cell-based antibody display library.","date":"2012","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22297616","citation_count":5,"is_preprint":false},{"pmid":"30504933","id":"PMC_30504933","title":"Epidermal growth factor-like domain multiple 7 (EGFL7): Expression and possible effect on biliary epithelium growth in cholangiocarcinoma.","date":"2018","source":"European journal of histochemistry : EJH","url":"https://pubmed.ncbi.nlm.nih.gov/30504933","citation_count":5,"is_preprint":false},{"pmid":"39080995","id":"PMC_39080995","title":"Overexpression of EGFL7 promotes angiogenesis and nerve regeneration in peripheral nerve injury.","date":"2024","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/39080995","citation_count":4,"is_preprint":false},{"pmid":"26799121","id":"PMC_26799121","title":"Expression of Egfl7 and miRNA-126-5p in Symptomatic Carotid Artery Disease.","date":"2016","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/26799121","citation_count":4,"is_preprint":false},{"pmid":"37957249","id":"PMC_37957249","title":"Low EGFL7 expression is associated with high lymph node spread and invasion of lymphatic vessels in colorectal cancer.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37957249","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49056,"output_tokens":10128,"usd":0.149544,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20646,"output_tokens":4457,"usd":0.107328,"stage2_stop_reason":"end_turn"},"total_usd":0.256872,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"EGFL7 (Egfl7) is an endothelial cell-derived secreted factor required for vascular tubulogenesis; loss of Egfl7 function in zebrafish embryos specifically blocks vascular tube formation by preventing proper spatial arrangement and separation of angioblasts during vascular cord assembly.\",\n      \"method\": \"Zebrafish morpholino knockdown; in vivo imaging of vascular development\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function in vivo with specific cellular phenotype (angioblast arrangement defect), replicated across multiple labs in subsequent work\",\n      \"pmids\": [\"15085134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EGFL7 protein contains an N-terminal signal peptide and is localized to the endoplasmic reticulum and Golgi apparatus within cells, and is secreted into conditioned medium by transfected HEK293 cells, confirming it is a bona fide secreted protein.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence localization in transfected cells, detection in conditioned media\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization experiment with functional implication (secretion), single lab with two orthogonal methods\",\n      \"pmids\": [\"15162510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EGFL7 protein acts as a chemoattractant for embryonic endothelial cells and fibroblasts, and is upregulated in regenerating endothelium after arterial injury but not in the neointima, implicating it in endothelial integrity and vascular reorganization.\",\n      \"method\": \"In vitro cell migration (chemotaxis) assay with recombinant EGFL7; RNA in situ hybridization in injury models\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay with recombinant protein plus in vivo expression analysis, single lab\",\n      \"pmids\": [\"15972971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EGFL7 is tightly associated with the extracellular matrix and supports endothelial cell migration either alone or in combination with other ECM molecules; in Egfl7 knockdown zebrafish, malformation of axial vessels results from accumulation of angioblasts and aberrant connections among themselves rather than abnormal EC–non-EC interactions.\",\n      \"method\": \"Ultrastructural analysis of knockdown zebrafish; in vitro biochemical ECM-binding and EC migration assays\",\n      \"journal\": \"Novartis Foundation symposium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biochemical assays plus in vivo ultrastructural phenotyping, single lab\",\n      \"pmids\": [\"18300411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EGFL7 (VE-statin) is the first identified natural negative regulator of vascular elastogenesis: it interacts with the catalytic domain of lysyl oxidase (LOX) family enzymes, thereby inhibiting the crosslinking of tropoelastin into insoluble mature elastin. Endogenous EGFL7 colocalizes with LoxL2 in endothelial cells and prevents elastic fibre deposition.\",\n      \"method\": \"Transgenic mouse overexpression; in vitro fibroblast culture with recombinant EGFL7; biochemical interaction assays between EGFL7 and LOX catalytic domain; colocalization by immunofluorescence\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of biochemical interaction with identified domain, in vivo transgenic validation, colocalization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"18497746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Previously described vascular phenotypes attributed to Egfl7 mouse knockouts are actually caused by co-deleted miR-126 (located in Egfl7 intron 7), not by loss of EGFL7 protein itself; selective deletion of Egfl7 alone (Egfl7Δ/Δ) produces no detectable vascular phenotype in mice.\",\n      \"method\": \"Conditional/selective allele mouse knockouts (Egfl7Δ and miR-126Δ); cornea micropocket angiogenesis assay; VEGF signaling pathway analysis (Akt, Erk)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous genetic dissection with selective alleles, multiple in vivo assays, clear negative result for Egfl7 protein function in mouse angiogenesis\",\n      \"pmids\": [\"18987025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Egfl7-knockdown zebrafish endothelial cells fail to expand into the vascular area, leading to reduced or split lumens and open EC sheets; ectopic cell junctions form across obstructed lumens on luminal surfaces, suggesting EGFL7 provides ECs with cues for extension and establishing EC polarity.\",\n      \"method\": \"Quantitative ultrastructural analysis (electron microscopy) of Egfl7-knockdown zebrafish embryos\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — detailed ultrastructural phenotyping of loss-of-function, single lab\",\n      \"pmids\": [\"18224713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EGFL7 binds directly to Notch receptors at a region involved in ligand-mediated activation, acting as a Notch antagonist; EGFL7 expression in neural stem cells (NSCs) decreases Notch signaling, reduces NSC proliferation and self-renewal, and shifts differentiation toward neurons and oligodendrocytes. Neurons are identified as a brain source of EGFL7.\",\n      \"method\": \"Biochemical binding assays; Notch reporter assays; NSC culture loss-of-function and gain-of-function; in vitro differentiation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding identified, Notch reporter activity, in vitro mechanistic dissection with multiple orthogonal methods in one study\",\n      \"pmids\": [\"19503073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Endothelial overexpression of EGFL7 in transgenic mice causes impaired angiogenesis, hemorrhaging, and altered cardiac morphogenesis; EGFL7 physically interacts with endothelial-specific NOTCH in vivo, inhibits Notch reporter activity, and downregulates Notch target genes, confirming EGFL7 acts as a Notch antagonist in vascular development.\",\n      \"method\": \"Transgenic mouse overexpression; co-immunoprecipitation of EGFL7 and NOTCH in vivo; Notch reporter assays; EGFL7 knockdown in primary human endothelial cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reciprocal Co-IP in vivo, reporter assay, transgenic phenotype, KD in primary human cells; multiple orthogonal methods replicating Notch antagonism finding\",\n      \"pmids\": [\"20947685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"VE-statin/Egfl7 gene expression in endothelial cells is directly controlled by transcription factors Erg and GATA-2 acting through a proximal promoter region (-252/+38) containing essential GATA and ETS binding sites, and a distal enhancer (-8409/-7563); Fli-1 exerts indirect control.\",\n      \"method\": \"Luciferase reporter gene assays; linker-scanning and site-directed mutagenesis; RNA interference knockdown of transcription factors; chromatin immunoprecipitation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (reporter assays, mutagenesis, RNAi, ChIP) in single rigorous study establishing direct transcriptional regulation\",\n      \"pmids\": [\"20808444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Egfl7 knockdown in mouse embryonic stem cells impairs vascular cord formation, resulting in abnormal CD31+ sheet-like structures due to increased proliferation of CD31+ cells, establishing a role for Egfl7 in mammalian vasculogenesis and angiogenesis independent of miR-126.\",\n      \"method\": \"siRNA knockdown targeting Egfl7 but not miR-126; embryoid body model; flow cytometry; collagen gel sprouting assay\",\n      \"journal\": \"Journal of angiogenesis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA specifically sparing miR-126, in vitro vascular model with defined phenotypic readout, single lab\",\n      \"pmids\": [\"20298530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Egfl7 promotes tumor immune escape by inhibiting expression of leukocyte adhesion molecules (ICAM-1, VCAM-1) on endothelial cells, thereby preventing lymphocyte adhesion and reducing immune cell infiltration into tumors. This was shown to accelerate tumor growth and metastasis in immunocompetent but not immunodeficient mice.\",\n      \"method\": \"In vitro endothelial cell treatment with Egfl7; lymphocyte adhesion assays; tumor implantation in immunocompetent vs. immunodeficient mice; cytokine and adhesion molecule expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean mechanistic experiment linking Egfl7 to adhesion molecule suppression, validated in vivo with immunocompetent vs. immunodeficient comparison, multiple methods\",\n      \"pmids\": [\"22037871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EGFL7 is a direct transcriptional target of the zinc-finger transcription factor CASZ1; CASZ1 depletion reduces Egfl7 expression, and defects in CASZ1- or EGFL7-depleted endothelial cells include diminished RhoA expression and impaired focal adhesion localization; restoration of Egfl7 rescues CASZ1-depletion phenotypes, defining a CASZ1→EGFL7→RhoA signaling axis for vascular morphogenesis.\",\n      \"method\": \"Xenopus embryo depletion; human endothelial cell KD; epistasis rescue experiments; ChIP assay for CASZ1 binding to Egfl7 locus; RhoA activity assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — epistasis rescue, ChIP demonstrating direct binding, in vivo and in vitro validation, multiple orthogonal methods\",\n      \"pmids\": [\"23639441\", \"24150064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EGFL7 is a specific ligand of integrin αVβ3; EGFL7 attaches to the extracellular matrix and, through interaction with integrin αVβ3, increases endothelial cell motility to allow movement on the ECM during vessel remodeling. In zebrafish, deregulation of EGFL7 leads to integrin-dependent malformation of the caudal venous plexus.\",\n      \"method\": \"Biochemical binding assays between EGFL7 and integrin αVβ3; EC migration assays; integrin-blocking experiments; zebrafish in vivo validation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct ligand-receptor binding identified, functional assays with blocking, in vivo zebrafish phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"23386126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Recombinant EGFL7 protein supports endothelial cell adhesion and protects ECs from stress-induced apoptosis; anti-EGFL7 antibodies inhibit both EC adhesion and protection from apoptosis, and augment anti-VEGF-mediated vascular damage in tumor models.\",\n      \"method\": \"EC adhesion assay with recombinant EGFL7; apoptosis assay; anti-EGFL7 antibody blocking in vitro and in murine tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein functional assay plus antibody blockade, validated in vivo, single lab\",\n      \"pmids\": [\"23945239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EGFL7 promotes epithelial-mesenchymal transition (EMT) and metastasis in gastric cancer cells through activation of the EGFR-AKT-Snail signaling pathway; EGFL7 overexpression induces EGFR and AKT phosphorylation, upregulates Snail and vimentin, and downregulates E-cadherin; EGFR inhibition reverses EGFL7-induced invasion.\",\n      \"method\": \"EGFL7 overexpression/shRNA knockdown in gastric cancer lines; scratch wound and transwell migration assays; Western blot for EGFR, p-AKT, Snail, vimentin, E-cadherin; EGFR inhibitor AG1478 treatment; xenograft mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with pharmacological pathway dissection, in vitro and in vivo, single lab\",\n      \"pmids\": [\"24945379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EGFL7 is a downstream target of BMP9-ALK1-SMAD1/5 signaling in endothelial cells; BMP9 drives sprouting angiogenesis through EGFL7, which in turn promotes endothelium expansion via interference with NOTCH signaling, ERK activation, and ECM remodeling; CRISPR/Cas9 deletion of EGFL7 impairs BMP9-induced sprouting.\",\n      \"method\": \"hESC-derived EC differentiation; siRNA and CRISPR/Cas9 KO of EGFL7; SMAD1/5 phosphorylation assays; Notch reporter assays; ERK phosphorylation assays\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO plus pathway analysis, single lab with multiple readouts\",\n      \"pmids\": [\"31155507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Endothelial cells act through secretion of EGFL7 to maintain pancreatic progenitor (PP) self-renewal and impair further differentiation into hormone-expressing cells; endothelial overexpression of EGFL7 in transgenic mice increases PP proliferation and decreases endocrine differentiation, establishing EGFL7 as the molecular handle in endothelium-to-pancreatic epithelium crosstalk.\",\n      \"method\": \"hESC-EC coculture system; recombinant EGFL7 treatment; Egfl7 transgenic mouse model; BrdU proliferation assay; endocrine differentiation markers\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — coculture mechanistic dissection, in vivo transgenic confirmation, single lab\",\n      \"pmids\": [\"25601205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EGFL7 promotes angiogenesis in the bone microenvironment by inducing phosphorylation of ERK1/2, STAT3, and focal adhesion kinase (FAK) in endothelial cells; EGFL7 contains a conserved RGD/QGD motif and its pro-migratory effects are blocked by RGD peptides, implicating integrin-mediated signaling.\",\n      \"method\": \"Recombinant EGFL7 treatment of SVEC cells; kinase inhibitor experiments; ex vivo fetal mouse metatarsal angiogenesis assay; RGD peptide competition; Western blot for phospho-ERK, phospho-STAT3, phospho-FAK\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein functional assays with pathway inhibitors, ex vivo validation, single lab\",\n      \"pmids\": [\"24909139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In Xenopus, EGFL7 depletion prevents vascular lumen formation by blocking endothelial cell shape changes and preventing clearance of cell-cell junctions from the cord center, while Claudin-5 still localizes appropriately; this demonstrates EGFL7 modulates cell shape and junctions to drive lumen morphogenesis.\",\n      \"method\": \"Morpholino depletion of EGFL7 in Xenopus; confocal imaging of tight junction markers (ZO-1, Claudin-5); cell morphology analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined cellular phenotype and junction marker analysis, single lab\",\n      \"pmids\": [\"25705891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Egfl7 is a constitutive repressor of endothelial cell activation; TNFα strongly represses Egfl7 expression via an NF-κB-dependent mechanism acting on the egfl7 promoter (-7585 to -5550 bp); conversely, Egfl7 restrains TNFα-induced ICAM-1, VCAM-1, and E-selectin expression by preventing proteasome-mediated IκBα degradation, acting through both NF-κB and MEK/Erk pathways.\",\n      \"method\": \"In vivo LPS/TNFα mouse models; promoter deletion/reporter assays; NF-κB pathway analysis; IκBα protein stability assays; EGFL7 knockdown/overexpression in ECs; leukocyte adhesion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — promoter dissection, pathway mechanism (IκBα stabilization), in vitro and in vivo validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27650497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EGFL7 acts as an intercellular EGFR signal messenger: EGFRvIII-positive glioblastoma cells secrete EGFL7 protein to activate β-catenin/TCF4 transcription in EGFRwt cells, which in turn promotes EGFL7 expression in those cells, establishing an autocrine/paracrine loop maintaining oncogenic EGFR activation.\",\n      \"method\": \"Conditioned medium transfer experiments; β-catenin/TCF4 reporter assays; EGFL7 protein secretion analysis; EGFL7 knockdown/overexpression in glioma lines\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — conditioned medium and reporter assay evidence, single lab, mechanism partially characterized\",\n      \"pmids\": [\"27725228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EGFL7 loss-of-function in the murine subventricular zone (SVZ) causes accumulation of activated neural stem cells (NSCs) with enhanced cell cycle re-entry; EGFL7 promotes Dll4-induced Notch signaling at the blood vessel–stem cell interface to push activated NSCs toward quiescence, and EGFL7-KO mice display impaired olfactory perception due to fewer inhibitory neurons in the olfactory bulb.\",\n      \"method\": \"EGFL7-KO mouse model; BrdU/EdU labeling of NSCs; Dll4-Notch signaling reporter assays; olfactory behavioral tests; immunofluorescence of SVZ niche\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined cellular and behavioral phenotype, mechanistic link to Dll4-Notch signaling, multiple orthogonal in vivo methods\",\n      \"pmids\": [\"28656980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Egfl7 knockout mice show defects in chorioallantoic branching morphogenesis and placental vascular patterning with fetal growth restriction; placental endothelial cells are deficient in migration, cord formation, and sprouting. Importantly, Egfl7 knockout did not affect expression of the embedded miR-126, demonstrating these placental phenotypes are attributable to loss of EGFL7 protein.\",\n      \"method\": \"Novel Egfl7 KO mouse; microangiography and 3D imaging; placental endothelial cell functional assays (migration, cord formation, sprouting); miR-126 expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with miR-126 control, in vivo phenotype validated by multiple methods, establishes protein-specific function\",\n      \"pmids\": [\"28526753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EGFL7 deposition into endothelial ECM is controlled by MAGP-1 and fibronectin, which drive EGFL7 into fibers and aggregates respectively; ECM accumulation of EGFL7 is required for its regulation of LOX activity and HEY2 (Notch target) expression, but NOT for regulation of endothelial adhesion molecule expression; interaction of EGFL7 with MAGP-1 is specifically required for LOX activity repression.\",\n      \"method\": \"Co-immunoprecipitation; ECM fractionation; LOX activity assays; Notch reporter (HEY2) assays; adhesion molecule expression; EGFL7 variant constructs\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays dissecting context-dependent EGFL7 function, single lab\",\n      \"pmids\": [\"30338930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EGFL7 enhances surface expression of integrin α5β1 on endothelial cells, which in turn promotes fibronectin-induced angiogenic sprouting and produces more mature, less leaky glioma blood vessels; EGFL7-inhibiting antibody reduces experimental glioma vascularization and extends animal survival.\",\n      \"method\": \"EGFL7 KD/overexpression in vivo glioma models; flow cytometry for surface integrin α5β1; fibronectin sprouting assay; MRI vascular permeability; antibody blockade in experimental glioma\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — integrin surface expression mechanism, in vivo validation with antibody, single lab\",\n      \"pmids\": [\"30065025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EGFL7 promotes hepatocellular carcinoma cell proliferation and inhibits apoptosis through activation of Wnt/β-catenin signaling, leading to increased CKS2 (cyclin-dependent kinase regulatory subunit 2) expression; CKS2 silencing blocks EGFL7-induced HCC proliferation.\",\n      \"method\": \"EGFL7 overexpression/shRNA in HCC lines; Wnt/β-catenin inhibitor (IWR-1-endo); CKS2 siRNA rescue; Western blot; xenograft model\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue with siRNA and pathway inhibitor, in vitro and in vivo, single lab\",\n      \"pmids\": [\"30129142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EGFL7 activates the Flt3/Flt3 ligand pathway in thymic endothelial cells and early thymic precursors (ETPs), expanding ETPs and thymic ECs; selective Flt3 blockade prevents Egfl7-driven ETP and EC expansion in vivo.\",\n      \"method\": \"Egfl7 overexpression mouse model; flow cytometry for ETP populations; Flt3 ligand ELISA; anti-Flt3 blocking antibody in vivo\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with receptor blockade epistasis, single lab\",\n      \"pmids\": [\"28601636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EGFL7 knockdown in growth hormone-producing pituitary adenoma cells inhibits EGFR signaling cascades (p-EGFR, p-AKT, p-ERK), and EGFR inhibitor AG1478 suppresses EGFL7-driven migration and invasion, establishing EGFL7 as a regulator of EGFR signaling pathway activity in these cells.\",\n      \"method\": \"EGFL7 siRNA knockdown; Western blot for EGFR signaling components; EGFR inhibitor pharmacological treatment; cell migration/invasion assays\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD plus pharmacological dissection in vitro, single lab\",\n      \"pmids\": [\"29951953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGFL7 directly binds NOTCH receptors on AML blasts to antagonize canonical Notch ligand (DLL4) binding; rEGFL7 stimulation reduces Notch intracellular domain and target gene expression; anti-EGFL7 blocking antibody reactivates Notch signaling, increases blast differentiation and apoptosis, and prolongs survival in three independent AML mouse models.\",\n      \"method\": \"Antibody interaction array (~400 proteins); competitive ligand-binding assays; Notch reporter assays; primary AML blast stimulation; three in vivo AML mouse models with antibody treatment\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding shown by interaction array and competitive ligand assay, functional validation in primary patient samples and three independent in vivo models\",\n      \"pmids\": [\"31672772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGFL7 knockdown impairs VEGF-A-induced sprouting angiogenesis, causes overproduction of endothelial filopodia, reduces collagen IV deposition, impairs barrier function, and disturbs VE-cadherin junction formation and phosphorylation in a 3D microvessel model.\",\n      \"method\": \"EGFL7 siRNA knockdown in 3D in vitro microvessel model; sprouting assay; filopodia imaging; immunofluorescence for collagen IV and VE-cadherin; barrier permeability assay; VE-cadherin phosphorylation by Western blot\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD in 3D physiological model with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"30684886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGFL7 establishes an EGFL7-ITGB3 (integrin β3)-KLF2 amplification loop in multiple myeloma cells: EGFL7 binds its receptor ITGB3 causing phosphorylation and focal adhesion kinase activation; ITGB3 overexpression upregulates the transcription factor KLF2 which further enhances EGFL7 transcription, supporting MM cell survival and proliferation.\",\n      \"method\": \"ITGB3 and EGFL7 overexpression in MM lines; Co-IP; FAK phosphorylation assays; KLF2 reporter assays; EGFL7 KD with neutralizing antibodies; in vivo xenograft (NOD-SCID mice)\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation assays, KD with antibody in vitro and in vivo, single lab\",\n      \"pmids\": [\"32191808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The lncRNA lncEGFL7OS (located on the antisense strand of the EGFL7/miR-126 locus) regulates EGFL7/miR-126 expression by recruiting MAX protein to mediate histone acetylation at the EGFL7/miR-126 promoter/enhancer; lncEGFL7OS is required for MAPK and AKT pathway activation in endothelial cells.\",\n      \"method\": \"lncEGFL7OS KD/OE; MAX protein identification by pulldown and MS; ChIP for histone acetylation; CRISPR targeting of locus; in vitro/in vivo/ex vivo sprouting assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MAX pulldown with ChIP validation, CRISPR confirmation, though this primarily concerns the lncRNA regulating EGFL7 rather than EGFL7 mechanism per se; included as it defines upstream epigenetic regulation of EGFL7\",\n      \"pmids\": [\"30741632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HCC cells secrete Egfl7 to recruit and activate liver fibroblasts into cancer-associated fibroblasts (CAFs) via the αvβ3 integrin signaling pathway, inducing phosphorylation of FAK and AKT in fibroblasts; CAFs activated by Egfl7 deposit fibrils/collagen and promote HCC cell proliferation, invasion, and metastasis.\",\n      \"method\": \"Transwell coculture; recombinant EGFL7 treatment of fibroblasts; αvβ3 integrin blocking; Western blot for FAK and AKT phosphorylation; in vivo orthotopic mouse transplantation model; ELISA\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identification with blocking experiment, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"37480091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EGFL7 drives resistance to EGFR kinase inhibitors in lung cancer by activating NOTCH signaling; adaptive EGFL7 upregulation during EGFR inhibition is controlled by depression of the nonsense-mediated mRNA decay (NMD) pathway; EGFL7-activated Notch slows c-Myc decrease caused by EGFR inhibition, supporting cancer cell survival.\",\n      \"method\": \"EGFL7 expression analysis during EGFR inhibitor treatment; NMD pathway manipulation; Notch reporter assays; c-Myc Western blot; cell survival assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with NMD, Notch, and c-Myc analysis, single lab\",\n      \"pmids\": [\"36309484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMYD2 methyltransferase physically interacts with HNRNPK and mediates K422 monomethylation of HNRNPK, which increases its RNA-binding activity; methylated HNRNPK stabilizes EGFL7 mRNA, promoting CRC angiogenesis; targeting SMYD2 blocks EGFL7-dependent angiogenesis in tumors.\",\n      \"method\": \"Co-IP between SMYD2 and HNRNPK; in vitro methylation assay; HNRNPK RNA-binding assay; EGFL7 mRNA stability assay; xenograft model; SMYD2 inhibitor BAY-598\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution of methylation and RNA binding, single lab; this defines an upstream post-translational regulatory mechanism for EGFL7 mRNA\",\n      \"pmids\": [\"35503397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EGFL7 reduces CNS inflammation by binding αvβ3 integrin on activated T lymphocytes; EGFL7-KO mice show earlier EAE onset and increased T lymphocyte brain infiltration; EC-restricted EGFL7-KO produces similar worsening; recombinant EGFL7 treatment improves EAE, reduces MCAM expression, and tightens the BBB.\",\n      \"method\": \"EGFL7-KO and EC-restricted KO mice; EAE model; T cell αvβ3 integrin upregulation analysis; adhesion assays; recombinant EGFL7 treatment; BBB permeability assay; MCAM expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EC-restricted KO epistasis, recombinant protein rescue, integrin-mediated adhesion mechanism, multiple in vivo models\",\n      \"pmids\": [\"29483510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EGFL7 loss in hippocampal neural stem cells (Nestin-CreERT2 KO) upregulates neurogenesis in the subgranular zone and correlates with increased VEGF-D expression; intraventricular infusion of VEGF-D upregulates neurogenesis in vivo, and VEGF-D KO downregulates neurogenesis; EGFL7-KO mice show improved spatial memory and memory consolidation.\",\n      \"method\": \"Nestin-CreERT2 conditional KO; RNA sequencing; intraventricular VEGF-D infusion; VEGF-D KO; BrdU/EdU neurogenesis labeling; behavioral (Morris water maze, pattern separation) assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with RNA-seq, VEGF-D gain/loss-of-function epistasis, behavioral readout, single lab\",\n      \"pmids\": [\"36715759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EGFL7 secreted by human bone marrow mesenchymal stem cells promotes osteoblast differentiation partly by downregulating Notch1/NICD/Hes1 signaling; EGFL7 knockdown impairs hBMSC osteogenesis and activates Notch1 signaling, which is rescued by Notch1 inhibition; recombinant EGFL7 enhances bone healing in a femoral defect mouse model.\",\n      \"method\": \"EGFL7 siRNA KD; recombinant hEGFL7 treatment; Notch1 signaling inhibitor (γ-secretase inhibitor) rescue; osteogenic differentiation assays; femoral defect in vivo model\",\n      \"journal\": \"Stem cell reviews and reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue with Notch inhibitor, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"36609902\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EGFL7 is an endothelial cell-derived secreted ECM-associated protein that promotes vascular tubulogenesis and angiogenesis primarily by (1) acting as a Notch receptor antagonist—binding directly to Notch at its ligand-interaction domain to inhibit signaling, thereby regulating endothelial sprouting, neural stem cell quiescence, and differentiation; (2) ligating integrin αVβ3 to enhance endothelial cell motility on ECM; (3) enhancing integrin α5β1 surface expression to promote fibronectin-driven sprouting; (4) inhibiting lysyl oxidase (LOX) family enzymes to suppress vascular elastogenesis; (5) repressing endothelial activation by stabilizing IκBα to reduce NF-κB-dependent adhesion molecule expression and limit immune cell infiltration; and (6) acting downstream of the CASZ1 transcription factor (itself directly regulated by Erg/GATA-2) to maintain RhoA expression and endothelial cell adhesion/cytoskeletal dynamics, with its ECM-localized functions further modulated by MAGP-1 and fibronectin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EGFL7 is an endothelial-derived, secreted extracellular matrix-associated protein that orchestrates vascular tubulogenesis and angiogenesis by providing spatial cues that govern endothelial cell arrangement, polarity, and lumen formation [#0, #6, #19]. It is a bona fide secreted protein routed through the ER and Golgi [#1] that becomes tightly deposited into the endothelial ECM, where MAGP-1 and fibronectin direct it into distinct fibers and aggregates required for a subset of its functions [#3, #24]. A central molecular activity of EGFL7 is direct antagonism of Notch: it binds Notch receptors at the ligand-interaction region to block ligand-mediated (including Dll4/DLL4) activation, downregulating Notch target genes to control endothelial sprouting, neural stem cell quiescence and differentiation, and osteoblast differentiation [#7, #8, #22, #29, #38]. EGFL7 also signals through integrins—ligating αVβ3 to enhance endothelial motility on ECM [#13] and increasing surface integrin α5β1 to promote fibronectin-driven sprouting [#25]—and represses vascular elastogenesis by binding the catalytic domain of lysyl oxidase family enzymes to inhibit tropoelastin crosslinking, an activity dependent on its MAGP-1-mediated ECM deposition [#4, #24]. In the vascular wall it acts as a constitutive repressor of endothelial activation, stabilizing IκBα to limit NF-κB-dependent ICAM-1/VCAM-1/E-selectin expression and leukocyte adhesion, thereby restraining immune cell infiltration [#11, #20, #36]. Its endothelial expression is driven transcriptionally by Erg and GATA-2 and by a CASZ1→EGFL7→RhoA axis that maintains focal adhesion and cytoskeletal dynamics [#9, #12]. Across multiple cancers EGFL7 promotes proliferation, EMT, metastasis, immune escape, and tumor vascularization through EGFR/AKT, Wnt/β-catenin, Notch, and integrin signaling, marking it as a therapeutic target amenable to blocking antibodies [#11, #15, #25, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established EGFL7 as an endothelial-secreted factor with a non-redundant in vivo role in vascular tube assembly, answering whether it acts cell-autonomously on angioblast organization.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with in vivo vascular imaging; subcellular localization and secretion in transfected HEK293 cells\",\n      \"pmids\": [\"15085134\", \"15162510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular receptor/partner mediating angioblast arrangement not yet identified\", \"Did not distinguish protein function from the embedded miR-126\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved a major confound by showing earlier mouse 'Egfl7' vascular phenotypes were due to co-deleted intronic miR-126, forcing the field to use protein-selective alleles.\",\n      \"evidence\": \"Selective Egfl7Δ versus miR-126Δ mouse alleles with cornea angiogenesis and VEGF signaling analysis\",\n      \"pmids\": [\"18987025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Left open whether EGFL7 protein has any mouse angiogenic function at all\", \"Did not address non-vascular or context-specific roles\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the first biochemical activity of EGFL7—inhibition of lysyl oxidase family enzymes—defining it as a negative regulator of vascular elastogenesis.\",\n      \"evidence\": \"Transgenic mouse overexpression, fibroblast culture, EGFL7-LOX catalytic domain interaction assays, and LoxL2 colocalization\",\n      \"pmids\": [\"18497746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the LOX catalytic-domain interaction not resolved\", \"Physiological elastogenesis phenotype in loss-of-function not established here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined EGFL7 as a direct Notch antagonist binding the receptor ligand-interaction region, extending its role beyond vasculature into neural stem cell self-renewal and differentiation.\",\n      \"evidence\": \"Biochemical binding assays, Notch reporter assays, NSC gain/loss-of-function and differentiation assays\",\n      \"pmids\": [\"19503073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise binding interface and stoichiometry not mapped\", \"Whether antagonism is competitive with all canonical ligands unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Confirmed Notch antagonism in vivo and in human endothelial cells, and mapped transcriptional control of EGFL7 to Erg/GATA-2, anchoring it within endothelial gene-regulatory networks.\",\n      \"evidence\": \"Transgenic mouse overexpression with in vivo Co-IP of EGFL7-NOTCH; reporter, mutagenesis, RNAi and ChIP for Erg/GATA-2\",\n      \"pmids\": [\"20947685\", \"20808444\", \"20298530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How secreted EGFL7 accesses Notch on neighboring cells mechanistically\", \"Relative contribution of Notch antagonism versus other activities to phenotypes\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed EGFL7 in a CASZ1→EGFL7→RhoA axis and identified integrin αVβ3 as a direct receptor, connecting it to focal adhesion and cytoskeletal control of endothelial motility.\",\n      \"evidence\": \"Xenopus/EC depletion, epistasis rescue, CASZ1 ChIP, RhoA assays; EGFL7-integrin αVβ3 binding, blocking, and zebrafish validation; EC adhesion/anti-apoptosis with antibody blockade\",\n      \"pmids\": [\"23639441\", \"24150064\", \"23386126\", \"23945239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single secreted protein engages both Notch and integrins is not reconciled\", \"Signaling downstream of αVβ3 ligation incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mechanistically linked EGFL7 to suppression of endothelial activation through IκBα stabilization, and showed reciprocal NF-κB repression of EGFL7 transcription.\",\n      \"evidence\": \"LPS/TNFα mouse models, promoter deletion/reporter assays, IκBα stability assays, leukocyte adhesion assays; preceding tumor immune-escape study\",\n      \"pmids\": [\"27650497\", \"22037871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target through which secreted EGFL7 stabilizes intracellular IκBα unknown\", \"Receptor transducing the anti-inflammatory signal not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated protein-specific (miR-126-independent) functions in placental vascular branching and in Notch-dependent neural stem cell quiescence, validating loss-of-function roles for EGFL7 protein itself.\",\n      \"evidence\": \"Egfl7 KO mice with miR-126 controls; SVZ NSC KO with Dll4-Notch reporters and olfactory behavior\",\n      \"pmids\": [\"28526753\", \"28656980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific receptor usage across vascular versus neural niches unresolved\", \"Quantitative contribution to mouse developmental angiogenesis still limited\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Dissected ECM-deposition-dependent versus -independent functions and added integrin α5β1 surface modulation, clarifying which EGFL7 activities require matrix incorporation.\",\n      \"evidence\": \"Co-IP, ECM fractionation, LOX/HEY2/adhesion-molecule assays with variant constructs (MAGP-1/fibronectin); integrin α5β1 surface expression and antibody blockade in glioma; αvβ3-mediated CNS T-cell adhesion in EAE\",\n      \"pmids\": [\"30338930\", \"30065025\", \"29483510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural determinants of MAGP-1 versus fibronectin-driven deposition not resolved\", \"EAE/glioma findings from single labs each\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended Notch antagonism to malignant hematopoiesis and defined integrin-based amplification loops, establishing EGFL7 as a druggable target for blocking antibodies.\",\n      \"evidence\": \"Interaction array and competitive ligand assays in AML with antibody therapy in three mouse models; ITGB3-KLF2 loop Co-IP and FAK assays in myeloma; 3D microvessel KD\",\n      \"pmids\": [\"31672772\", \"32191808\", \"30684886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of EGFL7-Notch antagonism across tumor types not fully mapped\", \"Integrin-KLF2 loop characterized in a single tumor context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened the functional repertoire to fibroblast activation, hepatocellular and other cancer signaling, and adult neurogenesis/memory, showing EGFL7 acts through integrin-FAK-AKT, Wnt/β-catenin, EGFR, and VEGF-D-linked pathways across contexts.\",\n      \"evidence\": \"Recombinant EGFL7 with αvβ3 blocking in HCC-fibroblast coculture and orthotopic models; Wnt/β-catenin-CKS2 and EGFR pathway dissection in tumors; Nestin-CreERT2 KO with RNA-seq and VEGF-D epistasis\",\n      \"pmids\": [\"37480091\", \"30129142\", \"24945379\", \"36715759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these diverse downstream pathways converge on a common receptor set unclear\", \"Most cancer/neurogenesis mechanisms from single labs\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EGFL7 integrates simultaneous engagement of Notch receptors, multiple integrins, and LOX enzymes into context-specific outputs—and the structural basis distinguishing these interactions—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of EGFL7 bound to any partner\", \"Mechanism by which ECM deposition state selects among functions only partially defined\", \"Receptor mediating the intracellular IκBα-stabilizing anti-inflammatory effect unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 7, 8, 29]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [13, 31]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [13, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [3, 4, 24]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 6, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 13, 29]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4, 24]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 20, 36]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 25, 29, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NOTCH1\", \"LOX\", \"ITGAV\", \"ITGB3\", \"ITGA5\", \"ITGB1\", \"MAGP1\", \"FN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}