Affinage

EGFL7

Epidermal growth factor-like protein 7 · UniProt Q9UHF1

Length
273 aa
Mass
29.6 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2004 High

    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

    PMID:15085134 PMID:15162510

    Open questions at the time
    • Molecular receptor/partner mediating angioblast arrangement not yet identified
    • Did not distinguish protein function from the embedded miR-126
  2. 2008 High

    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

    PMID:18987025

    Open questions at the time
    • Left open whether EGFL7 protein has any mouse angiogenic function at all
    • Did not address non-vascular or context-specific roles
  3. 2008 High

    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

    PMID:18497746

    Open questions at the time
    • Structural basis of the LOX catalytic-domain interaction not resolved
    • Physiological elastogenesis phenotype in loss-of-function not established here
  4. 2009 High

    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

    PMID:19503073

    Open questions at the time
    • Precise binding interface and stoichiometry not mapped
    • Whether antagonism is competitive with all canonical ligands unresolved
  5. 2010 High

    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

    PMID:20298530 PMID:20808444 PMID:20947685

    Open questions at the time
    • How secreted EGFL7 accesses Notch on neighboring cells mechanistically
    • Relative contribution of Notch antagonism versus other activities to phenotypes
  6. 2013 High

    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

    PMID:23386126 PMID:23639441 PMID:23945239 PMID:24150064

    Open questions at the time
    • How a single secreted protein engages both Notch and integrins is not reconciled
    • Signaling downstream of αVβ3 ligation incompletely defined
  7. 2016 High

    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

    PMID:22037871 PMID:27650497

    Open questions at the time
    • Molecular target through which secreted EGFL7 stabilizes intracellular IκBα unknown
    • Receptor transducing the anti-inflammatory signal not identified
  8. 2017 High

    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

    PMID:28526753 PMID:28656980

    Open questions at the time
    • Tissue-specific receptor usage across vascular versus neural niches unresolved
    • Quantitative contribution to mouse developmental angiogenesis still limited
  9. 2018 Medium

    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

    PMID:29483510 PMID:30065025 PMID:30338930

    Open questions at the time
    • Structural determinants of MAGP-1 versus fibronectin-driven deposition not resolved
    • EAE/glioma findings from single labs each
  10. 2019 High

    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

    PMID:30684886 PMID:31672772 PMID:32191808

    Open questions at the time
    • Generality of EGFL7-Notch antagonism across tumor types not fully mapped
    • Integrin-KLF2 loop characterized in a single tumor context
  11. 2023 Medium

    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

    PMID:24945379 PMID:30129142 PMID:36715759 PMID:37480091

    Open questions at the time
    • Whether these diverse downstream pathways converge on a common receptor set unclear
    • Most cancer/neurogenesis mechanisms from single labs

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0048018 receptor ligand activity 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 3 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
FN1ITGA5ITGAVITGB1ITGB3LOXMAGP1NOTCH1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 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. Zebrafish morpholino knockdown; in vivo imaging of vascular development Nature High 15085134
2004 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. Subcellular fractionation, immunofluorescence localization in transfected cells, detection in conditioned media Developmental dynamics Medium 15162510
2005 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. In vitro cell migration (chemotaxis) assay with recombinant EGFL7; RNA in situ hybridization in injury models The American journal of pathology Medium 15972971
2007 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. Ultrastructural analysis of knockdown zebrafish; in vitro biochemical ECM-binding and EC migration assays Novartis Foundation symposium Medium 18300411
2008 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. Transgenic mouse overexpression; in vitro fibroblast culture with recombinant EGFL7; biochemical interaction assays between EGFL7 and LOX catalytic domain; colocalization by immunofluorescence The EMBO journal High 18497746
2008 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. Conditional/selective allele mouse knockouts (Egfl7Δ and miR-126Δ); cornea micropocket angiogenesis assay; VEGF signaling pathway analysis (Akt, Erk) Development (Cambridge, England) High 18987025
2008 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. Quantitative ultrastructural analysis (electron microscopy) of Egfl7-knockdown zebrafish embryos Developmental dynamics Medium 18224713
2009 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. Biochemical binding assays; Notch reporter assays; NSC culture loss-of-function and gain-of-function; in vitro differentiation assays Nature cell biology High 19503073
2010 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. Transgenic mouse overexpression; co-immunoprecipitation of EGFL7 and NOTCH in vivo; Notch reporter assays; EGFL7 knockdown in primary human endothelial cells Blood High 20947685
2010 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. Luciferase reporter gene assays; linker-scanning and site-directed mutagenesis; RNA interference knockdown of transcription factors; chromatin immunoprecipitation PloS one High 20808444
2010 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. siRNA knockdown targeting Egfl7 but not miR-126; embryoid body model; flow cytometry; collagen gel sprouting assay Journal of angiogenesis research Medium 20298530
2011 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. In vitro endothelial cell treatment with Egfl7; lymphocyte adhesion assays; tumor implantation in immunocompetent vs. immunodeficient mice; cytokine and adhesion molecule expression analysis Cancer research High 22037871
2013 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. Xenopus embryo depletion; human endothelial cell KD; epistasis rescue experiments; ChIP assay for CASZ1 binding to Egfl7 locus; RhoA activity assays Developmental cell High 23639441 24150064
2013 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. Biochemical binding assays between EGFL7 and integrin αVβ3; EC migration assays; integrin-blocking experiments; zebrafish in vivo validation Blood High 23386126
2013 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. EC adhesion assay with recombinant EGFL7; apoptosis assay; anti-EGFL7 antibody blocking in vitro and in murine tumor models The Journal of clinical investigation Medium 23945239
2014 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. 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 PloS one Medium 24945379
2015 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. hESC-derived EC differentiation; siRNA and CRISPR/Cas9 KO of EGFL7; SMAD1/5 phosphorylation assays; Notch reporter assays; ERK phosphorylation assays Stem cell reports Medium 31155507
2015 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. hESC-EC coculture system; recombinant EGFL7 treatment; Egfl7 transgenic mouse model; BrdU proliferation assay; endocrine differentiation markers Stem cell reports Medium 25601205
2015 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. 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 of cellular physiology Medium 24909139
2015 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. Morpholino depletion of EGFL7 in Xenopus; confocal imaging of tight junction markers (ZO-1, Claudin-5); cell morphology analysis PloS one Medium 25705891
2016 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. 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 The Journal of biological chemistry High 27650497
2016 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. Conditioned medium transfer experiments; β-catenin/TCF4 reporter assays; EGFL7 protein secretion analysis; EGFL7 knockdown/overexpression in glioma lines Cancer letters Medium 27725228
2017 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. EGFL7-KO mouse model; BrdU/EdU labeling of NSCs; Dll4-Notch signaling reporter assays; olfactory behavioral tests; immunofluorescence of SVZ niche Nature communications High 28656980
2017 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. Novel Egfl7 KO mouse; microangiography and 3D imaging; placental endothelial cell functional assays (migration, cord formation, sprouting); miR-126 expression analysis Development (Cambridge, England) High 28526753
2018 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. Co-immunoprecipitation; ECM fractionation; LOX activity assays; Notch reporter (HEY2) assays; adhesion molecule expression; EGFL7 variant constructs The FEBS journal Medium 30338930
2018 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. EGFL7 KD/overexpression in vivo glioma models; flow cytometry for surface integrin α5β1; fibronectin sprouting assay; MRI vascular permeability; antibody blockade in experimental glioma EMBO molecular medicine Medium 30065025
2018 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. EGFL7 overexpression/shRNA in HCC lines; Wnt/β-catenin inhibitor (IWR-1-endo); CKS2 siRNA rescue; Western blot; xenograft model Journal of cellular biochemistry Medium 30129142
2018 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. Egfl7 overexpression mouse model; flow cytometry for ETP populations; Flt3 ligand ELISA; anti-Flt3 blocking antibody in vivo Biochemical and biophysical research communications Medium 28601636
2018 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. EGFL7 siRNA knockdown; Western blot for EGFR signaling components; EGFR inhibitor pharmacological treatment; cell migration/invasion assays Science China. Life sciences Medium 29951953
2019 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. 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 Clinical cancer research High 31672772
2019 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. 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 Biomaterials Medium 30684886
2019 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. 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) Blood advances Medium 32191808
2019 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. 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 eLife Medium 30741632
2023 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. Transwell coculture; recombinant EGFL7 treatment of fibroblasts; αvβ3 integrin blocking; Western blot for FAK and AKT phosphorylation; in vivo orthotopic mouse transplantation model; ELISA Cell communication and signaling Medium 37480091
2022 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. EGFL7 expression analysis during EGFR inhibitor treatment; NMD pathway manipulation; Notch reporter assays; c-Myc Western blot; cell survival assays Cell death & disease Medium 36309484
2022 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. Co-IP between SMYD2 and HNRNPK; in vitro methylation assay; HNRNPK RNA-binding assay; EGFL7 mRNA stability assay; xenograft model; SMYD2 inhibitor BAY-598 Angiogenesis Medium 35503397
2018 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. 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 Nature communications High 29483510
2023 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. Nestin-CreERT2 conditional KO; RNA sequencing; intraventricular VEGF-D infusion; VEGF-D KO; BrdU/EdU neurogenesis labeling; behavioral (Morris water maze, pattern separation) assays Cellular and molecular life sciences Medium 36715759
2023 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. EGFL7 siRNA KD; recombinant hEGFL7 treatment; Notch1 signaling inhibitor (γ-secretase inhibitor) rescue; osteogenic differentiation assays; femoral defect in vivo model Stem cell reviews and reports Medium 36609902

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation. Nature 310 15085134
2008 Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126. Development (Cambridge, England) 305 18987025
2008 Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells. Biochemical and biophysical research communications 199 19116145
2009 miR-126 inhibits non-small cell lung cancer cells proliferation by targeting EGFL7. Biochemical and biophysical research communications 158 20034472
2004 Egfl7, a novel epidermal growth factor-domain gene expressed in endothelial cells. Developmental dynamics : an official publication of the American Association of Anatomists 148 15162510
2011 EGFL7: a unique angiogenic signaling factor in vascular development and disease. Blood 131 22160377
2009 Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal. Nature cell biology 120 19503073
2005 EGFL7 is a chemoattractant for endothelial cells and is up-regulated in angiogenesis and arterial injury. The American journal of pathology 117 15972971
2010 EGFL7 meets miRNA-126: an angiogenesis alliance. Journal of angiogenesis research 86 20529320
2010 Impaired angiogenesis and altered Notch signaling in mice overexpressing endothelial Egfl7. Blood 85 20947685
2011 Egfl7 promotes tumor escape from immunity by repressing endothelial cell activation. Cancer research 84 22037871
2019 A positive feed-forward loop between LncRNA-URRCC and EGFL7/P-AKT/FOXO3 signaling promotes proliferation and metastasis of clear cell renal cell carcinoma. Molecular cancer 79 30953521
2013 CASZ1 promotes vascular assembly and morphogenesis through the direct regulation of an EGFL7/RhoA-mediated pathway. Developmental cell 64 23639441
2013 EGFL7 ligates αvβ3 integrin to enhance vessel formation. Blood 63 23386126
2017 Transcription Factor NFAT5 Promotes Glioblastoma Cell-driven Angiogenesis via SBF2-AS1/miR-338-3p-Mediated EGFL7 Expression Change. Frontiers in molecular neuroscience 60 28983240
2014 Epidermal growth factor-like domain-containing protein 7 (EGFL7) enhances EGF receptor-AKT signaling, epithelial-mesenchymal transition, and metastasis of gastric cancer cells. PloS one 59 24945379
2016 Overexpressed MALAT1 promotes invasion and metastasis of gastric cancer cells via increasing EGFL7 expression. Life sciences 56 27259812
2008 VE-statin/egfl7 regulates vascular elastogenesis by interacting with lysyl oxidases. The EMBO journal 52 18497746
2010 Expression and clinical significance of EGFL7 in malignant glioma. Journal of cancer research and clinical oncology 50 20213100
2015 EGFL7 is expressed in bone microenvironment and promotes angiogenesis via ERK, STAT3, and integrin signaling cascades. Journal of cellular physiology 49 24909139
2018 EGFL7: Master regulator of cancer pathogenesis, angiogenesis and an emerging mediator of bone homeostasis. Journal of cellular physiology 48 29923200
2018 EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors. EMBO molecular medicine 43 30065025
2013 The expression of Egfl7 in human normal tissues and epithelial tumors. The International journal of biological markers 42 23558933
2017 Altered feto-placental vascularization, feto-placental malperfusion and fetal growth restriction in mice with Egfl7 loss of function. Development (Cambridge, England) 41 28526753
2018 EGFL7 reduces CNS inflammation in mouse. Nature communications 40 29483510
2016 EGFL7 is an intercellular EGFR signal messenger that plays an oncogenic role in glioma. Cancer letters 40 27725228
2017 Effects of microRNA-126 on cell proliferation, apoptosis and tumor angiogenesis via the down-regulating ERK signaling pathway by targeting EGFL7 in hepatocellular carcinoma. Oncotarget 37 28881749
2015 Endothelial cells control pancreatic cell fate at defined stages through EGFL7 signaling. Stem cell reports 37 25601205
2015 Methylation-associated Silencing of microRNA-126 and its Host Gene EGFL7 in Malignant Pleural Mesothelioma. Anticancer research 34 26504055
2019 EGFL7 regulates sprouting angiogenesis and endothelial integrity in a human blood vessel model. Biomaterials 32 30684886
2017 Neurovascular EGFL7 regulates adult neurogenesis in the subventricular zone and thereby affects olfactory perception. Nature communications 32 28656980
2014 Novel expression of EGFL7 in placental trophoblast and endothelial cells and its implication in preeclampsia. Mechanisms of development 32 24751645
2019 EGFL7 Mediates BMP9-Induced Sprouting Angiogenesis of Endothelial Cells Derived from Human Embryonic Stem Cells. Stem cell reports 31 31155507
2016 MicroRNA-126 inhibits tumor proliferation and angiogenesis of hepatocellular carcinoma by down-regulating EGFL7 expression. Oncotarget 29 27611944
2011 Heterogeneity and degree of TIMP4, GATA4, SOX18, and EGFL7 gene promoter methylation in non-small cell lung cancer and surrounding tissues. Cancer genetics 29 22018271
2013 Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy. The Journal of clinical investigation 28 23945239
2008 Egfl7 knockdown causes defects in the extension and junctional arrangements of endothelial cells during zebrafish vasculogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 28 18224713
2016 Endothelial Cell Activation Is Regulated by Epidermal Growth Factor-like Domain 7 (Egfl7) during Inflammation. The Journal of biological chemistry 27 27650497
2010 A role for Egfl7 during endothelial organization in the embryoid body model system. Journal of angiogenesis research 26 20298530
2017 EGFL7 participates in regulating biological behavior of growth hormone-secreting pituitary adenomas via Notch2/DLL3 signaling pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 25 28705113
2022 Single-cell RNA sequencing reveals differential expression of EGFL7 and VEGF in giant-cell tumor of bone and osteosarcoma. Experimental biology and medicine (Maywood, N.J.) 24 35695550
2020 The EGFL7-ITGB3-KLF2 axis enhances survival of multiple myeloma in preclinical models. Blood advances 23 32191808
2019 microRNA-126 inhibits tube formation of HUVECs by interacting with EGFL7 and down-regulating PI3K/AKT signaling pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 31170663
2019 EGFL7 Antagonizes NOTCH Signaling and Represents a Novel Therapeutic Target in Acute Myeloid Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 23 31672772
2021 Suppression of lncRNA HOTAIR alleviates RCC angiogenesis through regulating miR-126/EGFL7 axis. American journal of physiology. Cell physiology 22 33502949
2018 Egfl7 Represses the Vasculogenic Potential of Human Endothelial Progenitor Cells. Stem cell reviews and reports 22 28980146
2018 EGFL7 promotes hepatocellular carcinoma cell proliferation and inhibits cell apoptosis through increasing CKS2 expression by activating Wnt/β-catenin signaling. Journal of cellular biochemistry 22 30129142
2017 Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First-Line Metastatic Colorectal Cancer. The oncologist 21 28275117
2013 Expression of Egfl7 correlates with low-grade invasive lesions in human breast cancer. International journal of oncology 21 23404186
2010 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. PloS one 21 20808444
2022 Targeting SMYD2 inhibits angiogenesis and increases the efficiency of apatinib by suppressing EGFL7 in colorectal cancer. Angiogenesis 20 35503397
2019 LncEGFL7OS regulates human angiogenesis by interacting with MAX at the EGFL7/miR-126 locus. eLife 20 30741632
2018 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. The oncologist 20 29438092
2007 The role of Egfl7 in vascular morphogenesis. Novartis Foundation symposium 20 18300411
2021 The Multifaceted Roles of EGFL7 in Cancer and Drug Resistance. Cancers 19 33804387
2018 Role of EGFL7/EGFR-signaling pathway in migration and invasion of growth hormone-producing pituitary adenomas. Science China. Life sciences 19 29951953
2017 Viral nanoparticles decorated with novel EGFL7 ligands enable intravital imaging of tumor neovasculature. Nanoscale 19 28799610
2014 Targeting EGFL7 expression through RNA interference suppresses renal cell carcinoma growth by inhibiting angiogenesis. Asian Pacific journal of cancer prevention : APJCP 19 24815445
2013 Decreased expression of the endothelial cell-derived factor EGFL7 in systemic sclerosis: potential contribution to impaired angiogenesis and vasculogenesis. Arthritis research & therapy 19 24286167
2008 Expression of EGFL7 in primordial germ cells and in adult ovaries and testes. Gene expression patterns : GEP 19 18556249
2018 MAGP-1 and fibronectin control EGFL7 functions by driving its deposition into distinct endothelial extracellular matrix locations. The FEBS journal 18 30338930
2023 Hepatocellular carcinoma cells remodel the pro-metastatic tumour microenvironment through recruitment and activation of fibroblasts via paracrine Egfl7 signaling. Cell communication and signaling : CCS 16 37480091
2020 MicroRNA-126 exerts antitumor functions in ovarian cancer by targeting EGFL7 and affecting epithelial-to-mesenchymal transition and ERK/MAPK signaling pathway. Oncology letters 16 32724375
2022 Paeoniflorin Inhibits the Proliferation and Metastasis of Ulcerative Colitis-Associated Colon Cancer by Targeting EGFL7. Journal of oncology 15 36072982
2022 EGFL7 drives the evolution of resistance to EGFR inhibitors in lung cancer by activating NOTCH signaling. Cell death & disease 15 36309484
2016 EGFL7-overexpressing epidermal stem cells promotes fibroblast proliferation and migration via mediating cell adhesion and strengthening cytoskeleton. Molecular and cellular biochemistry 15 27766530
2015 Different expression of VEGF and EGFL7 in human hepatocellular carcinoma. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 15 26542361
2010 EGFL7: a new player in homeostasis of the nervous system. Cell cycle (Georgetown, Tex.) 15 20372059
2014 VE-statin/Egfl7 expression in malignant glioma and its relevant molecular network. International journal of clinical and experimental pathology 14 24696719
2021 EGFL7 as a novel therapeutic candidate regulates cell invasion and anoikis in colorectal cancer through PI3K/AKT signaling pathway. International journal of clinical oncology 13 33635474
2018 EGFL7 silencing inactivates the Notch signaling pathway; enhancing cell apoptosis and suppressing cell proliferation in human cutaneous melanoma. Neoplasma 13 30569717
2015 In-vitro inhibitory effect of EGFL7-RNAi on endothelial angiogenesis in glioma. International journal of clinical and experimental pathology 13 26722408
2014 VE-statin/Egfl7 siRNA inhibits angiogenesis in malignant glioma in vitro. International journal of clinical and experimental pathology 13 24696724
2013 The CASZ1/Egfl7 transcriptional pathway is required for RhoA expression in vascular endothelial cells. Small GTPases 13 24150064
2022 The Polymorphism and Expression of EGFL7 and miR-126 Are Associated With NSCLC Susceptibility. Frontiers in oncology 12 35494025
2012 Circulating mRNA for epidermal growth factor-like domain 7 (EGFL7) in maternal blood and early intrauterine growth restriction. A preliminary analysis. Prenatal diagnosis 12 23280513
2020 Novel Expression of EGFL7 in Osteosarcoma and Sensitivity to Cisplatin. Frontiers in oncology 11 32117731
2015 Attenuation of EGFL7 inhibits human laryngocarcinoma cells growth and invasion. International journal of clinical and experimental medicine 11 26064204
2018 EGFL7 and RASSF1 promoter hypermethylation in epithelial ovarian cancer. Cancer genetics 10 29778234
2014 Astragalus polysaccharides exert protective effects in newborn rats with bronchopulmonary dysplasia by upregulating the expression of EGFL7 in lung tissue. International journal of molecular medicine 10 25270395
2012 Egfl7 promotes tumor escape from immunity. Oncoimmunology 10 22737620
2023 EGFL7 loss correlates with increased VEGF-D expression, upregulating hippocampal adult neurogenesis and improving spatial learning and memory. Cellular and molecular life sciences : CMLS 9 36715759
2015 A distinct mechanism of vascular lumen formation in Xenopus requires EGFL7. PloS one 9 25705891
2024 The mechanism of EGFL7 regulating neovascularization in diabetic retinopathy through the PI3K/AKT/VEGFA pathway. Life sciences 8 38307238
2019 microRNA-126 Is a Tumor Suppressor of Granulosa Cell Tumor Mediated by Its Host Gene EGFL7. Frontiers in oncology 8 31245291
2018 Attenuation of EGFL7 Expression Inhibits Growth Hormone-Producing Pituitary Adenomas Growth and Invasion. Human gene therapy 8 29466872
2014 Egfl7 is differentially expressed in arteries and veins during retinal vascular development. PloS one 8 24595089
2013 [DNA methylation status of miR-126 and its host gene EGFL7 in CD4+ T cells from patients with systemic lupus erythematosus]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 8 23981988
2019 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. Journal of biochemical and molecular toxicology 7 30811740
2017 The angiogenic factor Egfl7 alters thymogenesis by activating Flt3 signaling. Biochemical and biophysical research communications 7 28601636
2023 EGFL7 Secreted By Human Bone Mesenchymal Stem Cells Promotes Osteoblast Differentiation Partly Via Downregulation Of Notch1-Hes1 Signaling Pathway. Stem cell reviews and reports 6 36609902
2022 EGFL7 affects the migration of epidermal stem cells in refractory diabetic wounds by regulating Notch signaling pathway. Regenerative medicine 6 36530156
2023 Role of EGFL7 in human cancers: A review. Journal of cellular physiology 5 37490307
2022 EGFL7 and HIF-1a Expression on Human Trophoblast Placental by Rhodomyrtus tomentosa and Zanthoxylum acanthopodium. Pakistan journal of biological sciences : PJBS 5 35234000
2021 Relation among EGFL7, ITGB3, and KLF2 and their clinical implication in multiple myeloma patients: a prospective study. Irish journal of medical science 5 34635968
2018 Epidermal growth factor-like domain multiple 7 (EGFL7): Expression and possible effect on biliary epithelium growth in cholangiocarcinoma. European journal of histochemistry : EJH 5 30504933
2012 Human anti-EGFL7 recombinant full-length antibodies selected from a mammalian cell-based antibody display library. Molecular and cellular biochemistry 5 22297616
2024 Overexpression of EGFL7 promotes angiogenesis and nerve regeneration in peripheral nerve injury. Cell biology international 4 39080995
2016 Expression of Egfl7 and miRNA-126-5p in Symptomatic Carotid Artery Disease. Genetic testing and molecular biomarkers 4 26799121
2023 Low EGFL7 expression is associated with high lymph node spread and invasion of lymphatic vessels in colorectal cancer. Scientific reports 3 37957249

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