Affinage

EFEMP1

EGF-containing fibulin-like extracellular matrix protein 1 · UniProt Q12805

Length
493 aa
Mass
54.6 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 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

EFEMP1 (fibulin-3) is a secreted extracellular matrix glycoprotein that organizes ECM architecture and modulates multiple signaling pathways governing cell migration, invasion, angiogenesis, and apoptosis in a cell-context-dependent manner (PMID:21955618, PMID:35998264, PMID:39717503). Wild-type fibulin-3 is efficiently secreted, where it binds the macular-degeneration protein TIMP-3 through TIMP-3's COOH-terminus (PMID:15123717) and supports ECM functions including MMP-2 production and collagen VI filament assembly (PMID:35998264) and elastic-fiber organization in tissues such as the extrahepatic bile duct (PMID:39717503). In the extracellular compartment EFEMP1 engages EGFR competitively with EGF, triggering EGFR autophosphorylation and downstream AKT and p44/p42 MAPK activation (PMID:19804359), and across cancer contexts it bidirectionally tunes MMP expression, Wnt/β-catenin and TGF-β/Smad signaling (in part through binding STEAP1), ERK1/2, PI3K/AKT/VEGF, and Notch/γ-secretase pathways to either suppress or promote tumor behavior depending on cell type (PMID:21955618, PMID:25987128, PMID:27015552, PMID:36388640). EFEMP1 also restrains Rho/ROCK-dependent actin stress-fiber and fibronectin remodeling and regulates focal-adhesion dynamics and FAK phosphorylation (PMID:38467175, PMID:40171970). The single missense mutation Arg345Trp causes the inherited maculopathies Malattia Leventinese and Doyne honeycomb retinal dystrophy (PMID:10369267); this and other pathogenic substitutions disrupt native disulfide bonding in EGF-like domain 6, impair secretion, and cause intracellular retention and aggregation (PMID:12242346, PMID:22031286, PMID:34923728, PMID:38083999). In R345W knockin mice the misfolded protein and TIMP-3 accumulate in sub-RPE basal deposits, and deposit formation depends critically on complement C3 (but not C5) and on NLRP3 inflammasome/caspase-1 activation (PMID:17666404, PMID:17664227, PMID:23943789, PMID:41198612). Distinct loss-of-function cysteine mutations instead drive aberrant extracellular disulfide-linked homodimers with loss of ECM function (PMID:35998264).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1999 High

    Establishing EFEMP1 as a disease gene answered whether a single locus underlies inherited macular drusen dystrophies, linking the protein to sub-RPE deposit disease.

    Evidence Positional cloning and candidate sequencing in families, mutation absent in controls

    PMID:10369267

    Open questions at the time
    • Did not establish the cellular mechanism by which R345W causes drusen
    • Did not address the protein's normal function
  2. 2002 High

    Showing that R345W is misfolded and poorly secreted while accumulating in RPE cells reframed the disease as a protein-trafficking defect rather than simple loss of an ECM component.

    Evidence Secretion assays in transfected cells and immunolocalization in human ML/AMD eye sections

    PMID:12242346

    Open questions at the time
    • Did not define the structural basis of misfolding
    • Did not show how retained protein triggers deposit formation
  3. 2003 Medium

    Mapping the FBLN3 promoter and showing retinal expression and estrogen responsiveness established how EFEMP1 transcription is controlled and where the protein is normally made.

    Evidence Reporter deletion assays, in situ hybridization, RT-PCR, estrogen treatment of ARPE-19/COS-7 cells

    PMID:14578376

    Open questions at the time
    • Promoter dissection from a single lab
    • Functional consequence of estrogen regulation in vivo unresolved
  4. 2004 High

    Identifying TIMP-3 as a fibulin-3 binding partner connected two macular-degeneration proteins and gave EFEMP1 a defined extracellular interaction in the subretinal space.

    Evidence In vivo binding screen, co-IP/pulldown, co-localization, TIMP-3 C-terminus domain mapping

    PMID:15123717

    Open questions at the time
    • Functional consequence of the interaction not defined
    • Whether interaction is altered by R345W not tested
  5. 2007 High

    R345W knockin mice answered whether the mutation is sufficient to cause disease in vivo, recapitulating sub-RPE deposits containing fibulin-3 and TIMP-3 with complement activation.

    Evidence Knockin mouse histopathology, EM, immunofluorescence, complement assays (two concurrent studies)

    PMID:17664227 PMID:17666404

    Open questions at the time
    • Did not establish causality of complement in deposit formation
    • Mechanism linking retained protein to deposits unresolved
  6. 2009 High

    Demonstrating that EFEMP1 binds EGFR competitively with EGF and activates AKT/MAPK gave the protein a defined extracellular signaling activity beyond a structural ECM role.

    Evidence Competitive binding assay, site-specific phospho-Western blots, EGFR kinase inhibitor in pancreatic carcinoma cells

    PMID:19804359

    Open questions at the time
    • Whether EGFR engagement is direct or via co-receptor not resolved
    • Relevance to retinal disease untested
  7. 2011 High

    Pinpointing reduced native disulfide bonding in EGF-like domain 6 and rescue by proteostasis manipulation defined the biochemical basis of the secretion defect.

    Evidence Luciferase secretion assays, position-345 mutant panel, disulfide analysis, temperature/translation attenuation rescue

    PMID:22031286

    Open questions at the time
    • Did not resolve full folded structure of domain 6
    • Did not link disulfide defect to in vivo deposit formation
  8. 2011 High

    Glioblastoma experiments showed EFEMP1 acts extracellularly to lower EGFR, attenuate AKT, and suppress VEGFA/angiogenesis, establishing a tumor-suppressive, anti-angiogenic role in this context.

    Evidence Overexpression/knockdown, xenografts, exogenous protein treatment, VEGFA rescue, Western blot

    PMID:21955618

    Open questions at the time
    • Apparently opposite EGFR effect versus pancreatic carcinoma not reconciled
    • Receptor-level mechanism of EGFR downregulation unresolved
  9. 2013 High

    Genetic ablation of C3 (but not C5) in R345W mice answered whether complement is causal, showing C3 is required for basal deposit formation.

    Evidence Double-mutant mouse genetics, Bruch's membrane proteomics, histopathology

    PMID:23943789

    Open questions at the time
    • How retained fibulin-3 triggers complement activation unresolved
    • Upstream initiator of C3 activation not defined
  10. 2014 Medium

    Linking EFEMP1 to γ-secretase/Notch-mediated temozolomide resistance placed it within a druggable survival pathway in glioblastoma.

    Evidence TMZ-resistant cell engineering, siRNA/overexpression, γ-secretase inhibitor, survival assays in vitro and in vivo

    PMID:24495907

    Open questions at the time
    • Direct biochemical link between EFEMP1 and Notch activation not shown
    • Single lab
  11. 2016 Medium

    Defining context-dependent MMP regulation showed EFEMP1 can promote (osteosarcoma, MMP-2 via AEG-1/NF-κB) or suppress (HCC, MMP-2/9 via ERK1/2) invasion depending on cell type, and that ERα directly represses EFEMP1 to relieve Wnt/β-catenin-driven EMT in endometrial carcinoma.

    Evidence siRNA/overexpression, exogenous protein, pathway inhibitors (PDTC, U0126, XAV93920/LiCl), ChIP and luciferase reporter, EMT/MMP readouts

    PMID:25987128 PMID:27015552 PMID:27108677

    Open questions at the time
    • Determinants of context-dependent opposite effects unresolved
    • Direct receptor mediating each effect not defined
  12. 2018 Medium

    Identifying EFEMP1 as an HTRA1 cleavage substrate connected the protein to the high-risk 10q26 AMD locus through increased proteolytic processing.

    Evidence Proteomic comparison of RPE cells with/without high-risk HTRA1 allele

    PMID:29730901

    Open questions at the time
    • No in vitro reconstitution of cleavage reported
    • Functional consequence of cleavage fragments unresolved
  13. 2021 High

    NLRP3/caspase-1 epistasis in R345W mice established inflammasome signaling as a second critical mediator of basal laminar deposit formation alongside complement.

    Evidence R345W:Nlrp3-/- and R345W:Casp1-/- double mutants, histopathology, immunofluorescence, RT-qPCR in RPE/choroid

    PMID:41198612

    Open questions at the time
    • Trigger of inflammasome activation by retained fibulin-3 unknown
    • Relationship between C3 and NLRP3 pathways unresolved
  14. 2021 Medium

    Showing that JOAG-causing variants all aggregate intracellularly, with retention correlating with severity, extended the misfolding/retention mechanism beyond retinal disease to glaucoma.

    Evidence Transient transfection of variants in COS7 cells, fluorescence microscopy

    PMID:34923728

    Open questions at the time
    • No structural or biochemical follow-up
    • How retention causes raised IOP unresolved
  15. 2022 High

    Distinguishing loss-of-function cysteine mutations that form aberrant extracellular disulfide-linked homodimers, plus KO-cell rescue, defined fibulin-3's normal ECM role in MMP-2 and collagen VI assembly and a distinct dimerization mechanism of dysfunction.

    Evidence Dual cysteine mutagenesis, non-reducing SDS-PAGE, CRISPR KO RPE cells, MMP-2/collagen VI readouts, WT vs C55R rescue

    PMID:35998264

    Open questions at the time
    • In vivo consequence of homodimerization untested
    • Single lab
  16. 2022 Medium

    Identifying STEAP1 as an EFEMP1 binding partner required for Wnt/β-catenin and TGF-β/Smad-driven EMT provided a receptor-level handle on EFEMP1 pro-tumor signaling in osteosarcoma.

    Evidence Overexpression/knockdown, STEAP1 knockdown epistasis, pathway/EMT Western blots, rescue

    PMID:36388640

    Open questions at the time
    • Direct EFEMP1-STEAP1 binding not biochemically mapped
    • Single lab
  17. 2022 Medium

    Showing FBLN1 binds and stabilizes EFEMP1 to suppress ferroptosis in endometrial stromal cells added a protein-stability partnership and a redox-survival role.

    Evidence Co-IP, EFEMP1 siRNA rescue in FBLN1-overexpressing cells, ferroptosis markers, viability assays

    PMID:35127942

    Open questions at the time
    • Mechanism of stabilization unresolved
    • Single lab, reciprocal validation limited
  18. 2023 Medium

    Comparing multiple missense mutants showed they share intracellular aggregation but differentially activate ER-stress and downstream kinase signaling, indicating mutation-specific gain-of-function consequences.

    Evidence IP/Western for aggregation, ER-stress markers, phospho-antibodies in HEK293T; intravitreal Ad5-EFEMP1 in rat eyes

    PMID:38083999

    Open questions at the time
    • Causal link between specific ER-stress signature and disease phenotype unresolved
    • Single lab
  19. 2023 Medium

    Demonstrating EFEMP1 regulation of scleral remodeling via PI3K/AKT/MMP2, with AAV knockdown delaying myopia, broadened its role to ocular ECM remodeling beyond the RPE.

    Evidence Lentiviral OE/shRNA in scleral fibroblasts, transcriptomics, PI3K inhibitor, AAV in guinea pig myopia model, histology

    PMID:38101653

    Open questions at the time
    • Receptor mediating EFEMP1 signaling in sclera not defined
    • Single lab
  20. 2024 High

    Defining fibulin-3 control of Rho/ROCK-dependent stress fibers and fibronectin in trabecular meshwork, and its requirement for elastic-fiber organization in the bile duct, established core cytoskeletal/ECM-remodeling functions of the wild-type protein.

    Evidence WT/mutant OE in TM cells and rat eyes with IOP/fibronectin readouts; Efemp1+/- mouse bile-duct histology and pressure myography

    PMID:38467175 PMID:39717503

    Open questions at the time
    • Molecular link between fibulin-3 and Rho/ROCK not defined
    • Whether bile-duct elastin role applies to other tissues unresolved
  21. 2025 Medium

    Loss-of-function in hepatic stellate cells and transcriptional control by the HIPK4-TAp63 and miR-9 axes refined how EFEMP1 abundance is set and how it controls focal-adhesion dynamics, migration, and tumor progression.

    Evidence EFEMP1 knockdown with FAK/focal-adhesion/fibronectin readouts (stellate cells); HIPK4-TAp63 pulldown, ChIP/reporter, phospho-mutagenesis, knockdown rescue and tumor models; miR-9 luciferase target validation

    PMID:32972039 PMID:40171970 PMID:40316017

    Open questions at the time
    • Direct downstream effector of focal-adhesion regulation unresolved
    • Integration of the multiple upstream regulators in vivo unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How intracellular retention of misfolded EFEMP1 mechanistically triggers complement C3 and NLRP3 inflammasome activation in the RPE, and what reconciles its opposite signaling outcomes across cell types, remain unresolved.
  • No defined molecular link between ER retention and complement/inflammasome activation
  • No unifying receptor model explaining context-dependent pro- vs anti-tumor effects
  • No high-resolution structure of EGF-like domain 6 explaining disulfide-dependent misfolding

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0005198 structural molecule activity 2 GO:0048018 receptor ligand activity 1
Localization
GO:0005576 extracellular region 3 GO:0005783 endoplasmic reticulum 3 GO:0031012 extracellular matrix 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-168256 Immune System 2
Partners
EGFRFBLN1HTRA1STEAP1TIMP3

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 A single non-conservative missense mutation (Arg345Trp) in EFEMP1 was identified as the cause of both Malattia Leventinese and Doyne honeycomb retinal dystrophy, establishing EFEMP1 as the disease gene for these inherited macular degenerations characterized by drusen accumulation beneath the RPE. Positional cloning combined with candidate gene sequencing in affected families; mutation absent in 477 controls and 494 AMD patients Nature genetics High 10369267
2002 Wild-type EFEMP1 is a secreted protein, whereas the R345W mutant is misfolded, secreted inefficiently, and retained intracellularly; in ML eyes mutant EFEMP1 accumulates within RPE cells and between RPE and drusen, suggesting aberrant intracellular retention drives drusen formation. Cell transfection secretion assays, immunolocalization in human ML and AMD eye sections, Western blot Proceedings of the National Academy of Sciences of the United States of America High 12242346
2004 TIMP-3 (tissue inhibitor of metalloproteinases-3) was identified as a binding partner of EFEMP1 in the subretinal space; the COOH-terminal end of TIMP-3 mediates the interaction, linking two macular degeneration disease proteins. In vivo subretinal binding partner screen, Co-immunoprecipitation/pulldown, expression overlap analysis in human ML and AMD eye sections The Journal of biological chemistry High 15123717
2007 The R345W mutation in EFEMP1 is pathogenic: Efemp1-R345W knockin mice develop sub-RPE basal deposits containing Efemp1 and Timp3, and show evidence of complement activation in RPE/Bruch's membrane, recapitulating AMD-like pathology. Efemp1-R345W knockin mouse generation, histopathology, immunofluorescence for Efemp1 and Timp3 in deposits, complement activation assays Human molecular genetics High 17664227 17666404
2007 Efemp1 R345W knockin mice develop small isolated sub-RPE deposits as early as 4 months, progressing to continuous sheets with membranous debris, RPE vacuolation, choroidal atrophy, and Bruch's membrane thickening; fibulin-3 accumulates in sub-RPE deposits. Knock-in mouse model histopathology, electron microscopy, immunofluorescence for fibulin-3 in deposits Human molecular genetics High 17664227
2009 EFEMP1 binds the EGF receptor (EGFR) competitively relative to EGF, and treatment of pancreatic carcinoma cells with purified EFEMP1 activates EGFR autophosphorylation at Tyr-992 and Tyr-1068, followed by downstream phosphorylation of Akt (Thr-308) and p44/p42 MAPK (Thr-202/Tyr-204); these effects are blocked by the EGFR kinase inhibitor PD 153035. Competitive binding assay (EFEMP1 vs EGF for EGFR), phospho-Western blot for EGFR, Akt, and MAPK phosphorylation sites, kinase inhibitor treatment Biological chemistry High 19804359
2011 Secretion deficiency of R345W EFEMP1 is caused, in part, by reduced native disulfide bonding in the sixth EGF-like domain harboring position 345; aromatic residue substitutions (Trp, Tyr, Phe) at position 345 cause significant secretion deficiencies; mutant secretion and proper disulfide formation are enhanced by reduced growth temperature or translational attenuation. Cell-based Gaussia luciferase secretion assay, panel of position-345 mutants, disulfide bond analysis, pharmacological proteostasis manipulation Molecular biology of the cell High 22031286
2013 Genetic ablation of complement component C3 (but not C5) in Efemp1-R345W knockin mice inhibits formation of sub-RPE basal deposits; proteomic analysis of Bruch's membrane showed basal deposits contain normal ECM components in abnormal amounts and significant increases in complement proteins, demonstrating a critical role for complement (via C3) in basal deposit formation. Double-mutant mouse genetics (Efemp1(R345W/R345W):C3(-/-)), proteomics of Bruch's membrane/choroid, histopathology Human molecular genetics High 23943789
2018 HTRA1 serine protease cleaves EFEMP1 as a novel substrate; HTRA1 protein level is increased in high-risk (10q26) RPE cells, accompanied by increased EFEMP1 proteolytic processing. Proteomic comparison of RPE cells with/without high-risk HTRA1 allele, identification of EFEMP1 as HTRA1 cleavage target Aging cell Medium 29730901
2011 In glioblastoma, EFEMP1 overexpression reduces EGFR protein levels and attenuates AKT signaling, suppresses VEGFA expression and angiogenesis, and inhibits tumor formation when EFEMP1 protein is mixed with cells prior to implantation or injected around established xenografts, indicating it acts in the extracellular compartment; VEGFA re-expression partially restores tumor onset but not overall growth rate. EFEMP1 overexpression/knockdown in glioma cell lines, subcutaneous and intracranial xenograft models, exogenous recombinant protein treatment, ectopic VEGFA rescue experiment, Western blot for EGFR and p-AKT Molecular cancer High 21955618
2014 EFEMP1 promotes temozolomide resistance in glioblastoma via γ-secretase-mediated activation of the Notch pathway; silencing EFEMP1 sensitizes cells to TMZ while overexpression causes resistance; γ-secretase inhibitor RO4929097 partially sensitizes cells to TMZ in vitro and in vivo. TMZ-resistant glioblastoma cell line engineering, EFEMP1 siRNA/overexpression, γ-secretase inhibitor treatment, in vitro and in vivo survival assays Oncotarget Medium 24495907
2015 EFEMP1 promotes osteosarcoma migration and invasion by directly upregulating MMP-2 expression; EFEMP1 is induced by oncogenic AEG-1 via NF-κB signaling pathway, placing EFEMP1 as a mediator between AEG-1 and MMP-2. EFEMP1 siRNA, plasmid transfection, purified EFEMP1 protein treatment in osteosarcoma cells, NF-κB inhibitor (PDTC), Western blot for MMP-2, invasion assays Oncotarget Medium 25987128
2016 EFEMP1 inhibits migration of hepatocellular carcinoma cells by suppressing ERK1/2 phosphorylation, leading to decreased MMP-2 and MMP-9 expression; ERK1/2 inhibitor U0126 abrogates the increased migration caused by EFEMP1 siRNA knockdown. EFEMP1 siRNA, purified EFEMP1 protein treatment, ERK1/2 inhibitor U0126, Western blot for ERK1/2, MMP-2, MMP-9, migration assays Oncology reports Medium 27108677
2016 In endometrial carcinoma, estrogen/ERα signaling directly binds to an estrogen response element (ERE) in the EFEMP1 promoter and represses EFEMP1 expression; EFEMP1 in turn inhibits epithelial-mesenchymal transition (EMT) by suppressing Wnt/β-catenin signaling targets (Cyclin-D1, c-Myc, Vimentin, Snail). Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, EFEMP1 overexpression/knockdown, Wnt pathway inhibitor XAV93920 and activator LiCl, in vitro EMT marker analysis Oncotarget High 27015552
2003 The FBLN3 proximal promoter is contained within 425 bp upstream of exon 1; important regulatory elements include three Sp1-binding sites, a trans-activating Tant motif, and an estrogen response element (ERE) that acts as a trans-repressor; fibulin-3 is expressed in murine and human RPE and in the outer and inner nuclear layers of the retina; estrogen modifies EFEMP1 expression in ARPE-19 cells. Reporter deletion-mutation luciferase transfection assays, in situ hybridization, RT-PCR, estrogen treatment of COS-7 and ARPE-19 cells Investigative ophthalmology & visual science Medium 14578376
2021 Three novel EFEMP1 variants causing juvenile open-angle glaucoma (JOAG) all produce significant intracellular protein aggregation and retention in COS7 cells compared to wild-type; the degree of intracellular retention correlates with disease severity/phenotype across different EFEMP1 mutations. Transient transfection of COS7 cells with EFEMP1 variant constructs, fluorescence microscopy for intracellular accumulation Human mutation Medium 34923728
2022 A loss-of-function cysteine mutation C55R in EFEMP1 forms aberrant extracellular disulfide-linked homodimers, driven by new availability of Cys70 on adjacent monomers; single cysteine mutations near Cys55 (Cys29, Cys42, Cys48, Cys61, Cys70, Cys159, Cys171) also produce similar disulfide-linked dimers; F3 knockout RPE cells show reduced MMP-2 levels and reduced collagen VI ECM filament formation, both partially rescued by wild-type but not C55R F3 re-expression. Dual cysteine mutagenesis, non-reducing SDS-PAGE, F3 knockout RPE cells (CRISPR), Western blot for MMP-2, collagen VI immunostaining, rescue experiments with WT and C55R constructs Human mutation High 35998264
2021 NLRP3 inflammasome activation is a critical mediator of basal laminar deposit (BLamD) formation in R345W Efemp1 knockin mice; R345W+/+ mice show increased Muller gliosis, subretinal Iba-1+ cells, elevated Nlrp3 immunoreactivity, and transcriptional upregulation of complement C3, Nlrp3, pro-Il1b, and pro-caspase-1 in RPE/choroid; genetic elimination of Nlrp3 or Casp1 significantly reduces BLamD size and coverage. Double-mutant mouse genetics (R345W+/+:Nlrp3-/- and R345W+/+:Casp1-/-), histopathology, immunofluorescence, RT-qPCR for inflammasome components in RPE/choroid Cell death & disease High 41198612
2024 Wild-type fibulin-3 reduces intracellular actin stress fiber formation and extracellular fibronectin levels in human trabecular meshwork (TM) cells by inhibiting Rho/ROCK signaling; TGFβ1 upregulates fibulin-3 protein in TM cells via Rho/ROCK; overexpression of a stop-codon EFEMP1 mutant (p.X494Q) has opposite effects, increasing IOP and fibronectin in rat eyes. Overexpression of WT and mutant EFEMP1 in human TM cells and rat eyes, actin stress fiber staining, fibronectin Western blot, IOP measurement, Rho/ROCK pathway analysis Experimental eye research Medium 38467175
2024 Fibulin-3 is required for normal elastic fiber organization in the extrahepatic bile duct (EHBD); Efemp1+/- mouse ducts show approximately half the normal elastin fiber density and altered mechanical properties (increased stretch), similar to elastase-treated ducts and neonatal ducts. Histology/staining for elastic fibers in mouse, rat, and human EHBD; pressure myography of Efemp1+/- vs wild-type ducts; elastase treatment comparison JHEP reports : innovation in hepatology High 39717503
2025 In hepatic stellate cells, fibulin-3 (EFEMP1) depletion impairs focal adhesions, FAK phosphorylation, fibronectin network formation, and cell migration, establishing EFEMP1 as a regulator of focal adhesion dynamics and migration in these cells. Gene silencing (EFEMP1 knockdown) in hepatic stellate cells, Western blot for FAK phosphorylation, immunostaining for focal adhesions and fibronectin network, migration assays FASEB journal Medium 40171970
2023 EFEMP1 promotes scleral remodeling in form-deprivation myopia by regulating the PI3K/AKT/MMP2 axis in scleral fibroblasts; AAV-mediated shEFEMP1 injection under Tenon's capsule delays myopia progression and posterior scleral remodeling in guinea pigs, while EFEMP1 overexpression exacerbates myopia and collagen fiber thinning. Lentiviral EFEMP1 overexpression/shRNA in primary scleral fibroblasts, transcriptome sequencing, PI3K inhibitor LY294002, AAV injection in guinea pig form-deprivation myopia model, refraction/axial length measurement, histology Biochimica et biophysica acta. Molecular basis of disease Medium 38101653
2022 EFEMP1 binds to STEAP1 and enables Wnt/β-catenin and TGF-β/Smad2/3 signaling to promote EMT in osteosarcoma cells; exogenous EFEMP1 fails to activate these pathways or EMT when STEAP1 is knocked down. EFEMP1 overexpression/knockdown, STEAP1 knockdown, Western blot for Wnt/β-catenin and TGF-β/Smad2/3 pathway markers, EMT marker analysis, rescue experiments Journal of bone oncology Medium 36388640
2022 FBLN1 (fibulin-1) interacts with EFEMP1 protein and increases its protein stability; FBLN1-mediated suppression of ferroptosis in ectopic endometrial stromal cells requires EFEMP1, as EFEMP1 silencing reverses FBLN1-induced protection from ferroptosis, cell death, and migration. Co-immunoprecipitation (FBLN1-EFEMP1 interaction), EFEMP1 siRNA rescue in FBLN1-overexpressing cells, ferroptosis markers (Fe2+, lipid ROS, MDA, GPX4, GSH), cell viability assays BioMed research international Medium 35127942
2025 HIPK4 kinase phosphorylates the transcription factor TAp63 at Ser395, which decreases EFEMP1 expression; this HIPK4-TAp63-EFEMP1 axis promotes cutaneous squamous cell carcinoma progression, and HIPK4 knockdown tumor suppression is reversed by EFEMP1 knockdown. Co-IP and GST-pulldown (HIPK4-TAp63 interaction), ChIP and dual luciferase reporter assay (TAp63 binding to EFEMP1 promoter), phospho-mutagenesis (TAp63 Ser395), HIPK4/EFEMP1 knockdown rescue experiments, mouse tumor models The Journal of biological chemistry High 40316017
2020 miR-9 directly targets EFEMP1 in normal fibroblasts (confirmed by luciferase reporter assay); miR-9-induced EFEMP1 silencing recapitulates conversion of normal fibroblasts to cancer-associated fibroblast (CAF)-like cells with increased migration, invasion, and ability to induce cisplatin resistance in breast cancer cells. Luciferase reporter assay for miR-9 targeting of EFEMP1, siRNA knockdown of EFEMP1, migration/invasion assays, co-culture conditioned medium cisplatin resistance assay Cells Medium 32972039
2019 EFEMP1 suppresses hepatocellular carcinoma cell proliferation by promoting Semaphorin 3B (SEMA3B) expression via the Axon guidance pathway; EFEMP1 promotes HCC cell apoptosis mainly through the mitochondrial apoptosis pathway. Lentiviral EFEMP1 overexpression in HCC cells, gene chip expression profiling, GO/pathway analysis, SEMA3B siRNA rescue, apoptosis assays (Annexin V), in vivo xenograft Cancer medicine Low 30972979
2023 Different EFEMP1 missense mutants (p.Met59Leu, p.Arg140Trp, p.Arg345Trp) each increase intracellular protein aggregation but differentially activate ER stress markers (ATF4, GRP78/94, CHOP) and phosphorylation of CREB, AKT, p44/42, and STAT3, demonstrating mutation-dependent signaling consequences. Immunoprecipitation and Western blot for intracellular aggregation, ER stress marker Western blots, phospho-specific antibodies for downstream kinases in HEK293T cells; intravitreal Ad5-EFEMP1 injection in rat eyes for IOP and RGC measurement Journal of cellular biochemistry Medium 38083999

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nature genetics 382 10369267
2002 Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 185 12242346
2021 METTL1-m7 G-EGFR/EFEMP1 axis promotes the bladder cancer development. Clinical and translational medicine 159 34936728
2004 Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1). Implications for macular degenerations. The Journal of biological chemistry 136 15123717
2007 The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice. Human molecular genetics 116 17666404
2007 Formation and progression of sub-retinal pigment epithelium deposits in Efemp1 mutation knock-in mice: a model for the early pathogenic course of macular degeneration. Human molecular genetics 101 17664227
2018 HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1. Aging cell 85 29730901
2009 EFEMP1 expression promotes in vivo tumor growth in human pancreatic adenocarcinoma. Molecular cancer research : MCR 85 19208748
2009 Decreased expression of angiogenesis antagonist EFEMP1 in sporadic breast cancer is caused by aberrant promoter methylation and points to an impact of EFEMP1 as molecular biomarker. International journal of cancer 83 19115204
2009 EFEMP1 binds the EGF receptor and activates MAPK and Akt pathways in pancreatic carcinoma cells. Biological chemistry 74 19804359
2007 Frequent inactivation of RAMP2, EFEMP1 and Dutt1 in lung cancer by promoter hypermethylation. Clinical cancer research : an official journal of the American Association for Cancer Research 74 17671114
2010 EFEMP1 expression promotes angiogenesis and accelerates the growth of cervical cancer in vivo. Gynecologic oncology 70 21163514
2009 Epidermal growth factor-containing fibulin-like extracellular matrix protein 1, EFEMP1, a novel tumor-suppressor gene detected in hepatocellular carcinoma using double combination array analysis. Annals of surgical oncology 69 19898900
2011 EFEMP1 suppresses malignant glioma growth and exerts its action within the tumor extracellular compartment. Molecular cancer 63 21955618
1997 Human fibulin-1D: molecular cloning, expression and similarity with S1-5 protein, a new member of the fibulin gene family. Matrix biology : journal of the International Society for Matrix Biology 57 9106159
2011 EFEMP1 as a novel DNA methylation marker for prostate cancer: array-based DNA methylation and expression profiling. Clinical cancer research : an official journal of the American Association for Cancer Research 55 21571867
2015 EFEMP1 promotes the migration and invasion of osteosarcoma via MMP-2 with induction by AEG-1 via NF-κB signaling pathway. Oncotarget 52 25987128
2015 Exome Sequencing Identifies a Missense Variant in EFEMP1 Co-Segregating in a Family with Autosomal Dominant Primary Open-Angle Glaucoma. PloS one 52 26162006
1996 The gene responsible for autosomal dominant Doyne's honeycomb retinal dystrophy (DHRD) maps to chromosome 2p16. Human molecular genetics 48 8817347
2014 EFEMP1 induces γ-secretase/Notch-mediated temozolomide resistance in glioblastoma. Oncotarget 45 24495907
2013 Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration. Human molecular genetics 45 23943789
2017 MiR-338-5p suppresses proliferation, migration, invasion, and promote apoptosis of glioblastoma cells by directly targeting EFEMP1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 44 28292024
2016 EFEMP1 inhibits migration of hepatocellular carcinoma by regulating MMP2 and MMP9 via ERK1/2 activity. Oncology reports 41 27108677
2021 EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma. Human mutation 39 34923728
2004 Association of EFEMP1 with malattia leventinese and age-related macular degeneration: a mini-review. Ophthalmic genetics 39 15512998
2011 Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration. Molecular biology of the cell 37 22031286
2003 Cloning, expression and characterization of the murine Efemp1, a gene mutated in Doyne-Honeycomb retinal dystrophy. Gene expression patterns : GEP 37 12915309
2013 Epigenetic inactivation of EFEMP1 is associated with tumor suppressive function in endometrial carcinoma. PloS one 36 23840707
2013 Efemp1 and p27(Kip1) modulate responsiveness of pancreatic cancer cells towards a dual PI3K/mTOR inhibitor in preclinical models. Oncotarget 34 23470560
2009 A novel haplotype with the R345W mutation in the EFEMP1 gene associated with autosomal dominant drusen in a Japanese family. Investigative ophthalmology & visual science 34 19850834
1999 Virus and autoimmunity: induction of autoimmune disease in mice by mouse T lymphotropic virus (MTLV) destroying CD4+ T cells. Journal of immunology (Baltimore, Md. : 1950) 33 10228006
2003 Transcriptional regulation and expression of the dominant drusen gene FBLN3 (EFEMP1) in mammalian retina. Investigative ophthalmology & visual science 28 14578376
2016 EFEMP1 promotes ovarian cancer cell growth, invasion and metastasis via activated the AKT pathway. Oncotarget 27 27351229
2009 Aberrant promoter methylation of FBLN-3 gene and clinicopathological significance in non-small cell lung carcinoma. Lung cancer (Amsterdam, Netherlands) 26 19913326
2022 Upregulated Fibulin-1 Increased Endometrial Stromal Cell Viability and Migration by Repressing EFEMP1-Dependent Ferroptosis in Endometriosis. BioMed research international 25 35127942
2019 Epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) suppressed the growth of hepatocellular carcinoma cells by promoting Semaphorin 3B(SEMA3B). Cancer medicine 25 30972979
2016 EFEMP1 is repressed by estrogen and inhibits the epithelial-mesenchymal transition via Wnt/β-catenin signaling in endometrial carcinoma. Oncotarget 24 27015552
1996 Structure and chromosomal assignment of the human S1-5 gene (FBNL) that is highly homologous to fibrillin. Genomics 23 8812496
2021 EFEMP1 Overexpression Contributes to Neovascularization in Age-Related Macular Degeneration. Frontiers in pharmacology 22 33584252
2014 Epigenetic regulation of EFEMP1 in prostate cancer: biological relevance and clinical potential. Journal of cellular and molecular medicine 22 25211630
2005 Analysis of the EFEMP1 gene in individuals and families with early onset drusen. Eye (London, England) 21 15218514
2017 Epidermal Growth Factor-Containing Fibulin-Like Extracellular Matrix Protein 1 (EFEMP1) Acts as a Potential Diagnostic Biomarker for Prostate Cancer. Medical science monitor : international medical journal of experimental and clinical research 19 28085790
2002 Analysis of the Arg345Trp disease-associated allele of the EFEMP1 gene in individuals with early onset drusen or familial age-related macular degeneration. Clinical & experimental ophthalmology 19 12427233
1999 Radiation hybrid mapping of chromosomal region 2p15-p16: integration of expressed and polymorphic sequences maps at the Carney complex (CNC) and Doyne honeycomb retinal dystrophy (DHRD) loci. Genomics 19 10087203
2020 miR-9-Mediated Inhibition of EFEMP1 Contributes to the Acquisition of Pro-Tumoral Properties in Normal Fibroblasts. Cells 18 32972039
2022 A loss-of-function cysteine mutant in fibulin-3 (EFEMP1) forms aberrant extracellular disulfide-linked homodimers and alters extracellular matrix composition. Human mutation 15 35998264
2021 Utility of EFEMP1 in the Prediction of Oncologic Outcomes of Urothelial Carcinoma. Genes 15 34204134
2020 The novel form of amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) preferentially affects the lower gastrointestinal tract of elderly femalesa. Histopathology 15 33020971
2016 HIF2α/EFEMP1 cascade mediates hypoxic effects on breast cancer stem cell hierarchy. Oncotarget 15 27270657
2008 Retinal microstructure in patients with EFEMP1 retinal dystrophy evaluated by Fourier domain OCT. Eye (London, England) 15 18791549
2023 Targeting scleral remodeling and myopia development in form deprivation myopia through inhibition of EFEMP1 expression. Biochimica et biophysica acta. Molecular basis of disease 14 38101653
2022 Plasma EFEMP1 Is Associated with Brain Aging and Dementia: The Framingham Heart Study. Journal of Alzheimer's disease : JAD 14 34958018
2013 The EFEMP1 gene: a frequent target for epigenetic silencing in multiple human pituitary adenoma subtypes. Neuroendocrinology 14 24080855
2001 Dominant radial drusen and Arg345Trp EFEMP1 mutation. American journal of ophthalmology 14 11384588
2022 EFEMP1 binds to STEAP1 to promote osteosarcoma proliferation and invasion via the Wnt/β-catenin and TGF-β/Smad2/3 signal pathways. Journal of bone oncology 13 36388640
1999 Refined genetic and physical positioning of the gene for Doyne honeycomb retinal dystrophy (DHRD). Human genetics 12 10071196
2022 Association of EFEMP1 with juvenile-onset open angle glaucoma in a patient with concomitant COL11A1-related Stickler syndrome. Ophthalmic genetics 11 35946471
2021 Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice. Scientific reports 11 34001980
2022 The extracellular matrix protein fibulin-3/EFEMP1 promotes pleural mesothelioma growth by activation of PI3K/Akt signaling. Frontiers in oncology 10 36303838
2020 EFEMP1 in Direct Inguinal Hernia: correlation with TIMP3 and Regulation Toward Elastin Homoeostasis as Well as Fibroblast Mobility. Journal of investigative surgery : the official journal of the Academy of Surgical Research 10 33131351
2019 FBLN3 inhibited the invasion and metastasis of colorectal cancer through the AKT/mTOR pathway. Neoplasma 10 30784281
2018 Doyne honeycomb retinal dystrophy/malattia leventinese induced by EFEMP1 mutation in a Chinese family. BMC ophthalmology 10 30541486
1988 Mouse thymic virus (MTLV; murid herpesvirus 3) infection in athymic nude mice: evidence for a T lymphocyte requirement. Virology 10 2831663
2024 Exploring ocular fibulin-3 (EFEMP1): Anatomical, age-related, and species perspectives. Biochimica et biophysica acta. Molecular basis of disease 9 38750770
2023 EFEMP1 is a potential biomarker of choroid thickness change in myopia. Frontiers in neuroscience 9 36891459
2015 Association of EFEMP1 gene polymorphisms with the risk of glioma: A hospital-based case-control study in a Chinese Han population. Journal of the neurological sciences 9 25638659
2012 Laser clearance of drusen deposit in patients with autosomal dominant drusen (p.Arg345Trp in EFEMP1). American journal of ophthalmology 9 23036572
2021 Loss-of-Function Variants in EFEMP1 Cause a Recognizable Connective Tissue Disorder Characterized by Cutis Laxa and Multiple Herniations. Genes 8 33807164
2021 Systemic amyloidosis derived from EFEMP1 in a captive Tsushima leopard cat. Veterinary pathology 8 34763604
2016 Weaponizing human EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) for 21st century cancer therapeutics. Oncoscience 8 27713911
2014 Malattia leventinese/Doyne honeycomb retinal dystrophy in a chinese family with mutation of the EFEMP1 gene. Retina (Philadelphia, Pa.) 8 25111685
2023 Novel mutation in EFEMP1 identified from two Chinese POAG families differentially activated endoplasmic reticulum stress markers and induced glaucoma in mouse. Journal of cellular biochemistry 7 38083999
2017 Impact of interaction between the G870A and EFEMP1 gene polymorphism on glioma risk in Chinese Han population. Oncotarget 7 28380465
2015 [EFEMP1 suppresses growth and invasion of lung cancer cells 
by downregulating matrix metalloproteinase-7 expression]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 7 25676403
2015 Cell context-dependent dual effects of EFEMP1 stabilizes subpopulation equilibrium in responding to changes of in vivo growth environment. Oncotarget 7 26307682
2024 Stop codon variant in EFEMP1 is associated with primary open-angle glaucoma due to impaired regulation of aqueous humor outflow. Experimental eye research 6 38467175
2024 Biliary atresia susceptibility gene EFEMP1 regulates extrahepatic bile duct elastic fiber formation and mechanics. JHEP reports : innovation in hepatology 6 39717503
2023 PUM2 regulates the formation of thoracic aortic dissection through EFEMP1. Experimental cell research 6 37062520
2022 Impact of EFEMP1 on the survival outcome of biliary atresia in Thai infants. Scientific reports 6 36114336
2020 Hypermethylation of EFEMP1 in the Hippocampus May Be Related to the Deficit in Spatial Memory of Rat Neonates Triggered by Repeated Administration of Propofol. BioMed research international 6 33381589
2016 Expansion of epigenetic alterations in EFEMP1 promoter predicts malignant formation in pancreatobiliary intraductal papillary mucinous neoplasms. Journal of cancer research and clinical oncology 6 27095449
1990 Comparative sensitivity of infectivity assay and mouse antibody production (MAP) test for detection of mouse thymic virus (MTLV). Journal of virological methods 6 2161418
2024 EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder. American journal of medical genetics. Part A 5 38348595
2024 A New Ocular Phenotype Combining Juvenile Glaucoma and Doyne Honeycomb Retinal Dystrophy (Malattia Leventinese) due to a Novel EFEMP1 Pathogenic Variant. American journal of medical genetics. Part A 5 39264138
2023 A Zebrafish Mutant in the Extracellular Matrix Protein Gene efemp1 as a Model for Spinal Osteoarthritis. Animals : an open access journal from MDPI 5 38200805
2017 Evaluating EFEMP1 in Cerebrospinal Fluid and Serum as a Potential Diagnosis Biomarker for Meningiomas. Clinical laboratory 5 29035461
2025 Proteomic analysis of liver fibrosis reveals EFEMP1 as a new modulator of focal adhesion and migration of hepatic stellate cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 40171970
2016 Assessing the association between EFEMP1 rs3791679 polymorphism and risk of glioma in a Chinese Han population. Genetics and molecular research : GMR 4 27706619
2001 EFEMP1 is not associated with sporadic early onset drusen. Ophthalmic genetics 4 11262647
1990 Critical factors in an enzyme immunoassay (ELISA) for antibodies to mouse thymic virus (MTLV). Laboratory animals 4 2176703
2025 The GOLM1-ACLY pathway regulates macrophage-secreted EFEMP1 via H3K27ac modifications to drive tumor progression. Journal of advanced research 3 40619122
2024 Circulating exosomal protein EFEMP1 and SERPINC1 as diagnostic biomarkers for epithelial ovarian cancer. Translational oncology 3 39317065
2015 EFEMP1 rs3791679 polymorphism was associated with susceptibility to glioma. International journal of clinical and experimental pathology 3 26823870
2024 Biallelic and monoallelic variants in EFEMP1 can cause a severe and distinct subtype of heritable connective tissue disorder. European journal of human genetics : EJHG 2 39367272
2024 Single-cell transcriptomic analysis and luteolin treatment reveal three adipogenic genes, including Aspn, Htra1 and Efemp1. Biochimica et biophysica acta. Molecular and cell biology of lipids 2 39662603
1990 Detection of mouse thymic virus (MTLV) antigens in infected thymus by competition immunoassay. Laboratory animal science 2 2153856
2025 HIPK4 accelerates cutaneous squamous cell carcinoma progression by phosphorylating TAp63 and inhibiting EFEMP1 expression. The Journal of biological chemistry 1 40316017
2025 A review of the role of EFEMP1 in ophthalmic disease. Ophthalmic genetics 1 40640104
2025 Genetic removal of Nlrp3 protects against age-related and R345W Efemp1-induced basal laminar deposit formation. Cell death & disease 1 41198612
2024 EFEMP1 contributes to light-dependent ocular growth in zebrafish. Biology open 1 39607017

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