Affinage

EFEMP2

EGF-containing fibulin-like extracellular matrix protein 2 · UniProt O95967

Length
443 aa
Mass
49.4 kDa
Annotated
2026-06-09
29 papers in source corpus 13 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EFEMP2 (Fibulin-4) is a secreted extracellular matrix glycoprotein that acts as a scaffolding factor during collagen maturation by binding lysyl oxidase (LOX); smooth-muscle-specific loss in mice decreases LOX activity and collagen cross-linking and produces large, poorly organized fibrillar collagen (PMID:26220971). It also binds the procollagen-processing enhancer Pcolce, although this interaction does not measurably alter procollagen cleavage in vitro (PMID:26220971). In the vasculature, loss of EFEMP2 drives ascending aortic aneurysm through a thrombin/MMP-9→PAR1→Egr1 mechanosensing axis, and genetic deletion of Egr1 prevents aneurysm in a subset of Fbln4SMKO mice (PMID:32580633). Beyond the matrix, EFEMP2 modulates tumor-cell behavior with context-dependent directionality: it binds EGFR to activate ERK1/2/c-Jun signaling and upregulate PD-L1, promoting ovarian cancer invasion (PMID:37420173), and it suppresses or promotes EMT through Wnt/β-catenin signaling and MMP regulation depending on cancer type (PMID:31592144, PMID:32110039). Its protein stability is governed by GALNT14-mediated O-glycosylation, which is required for GALNT14-driven breast cancer invasion (PMID:29428518).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2012 Medium

    Established a physical link between EFEMP2 and a transcription factor, mapping a discrete interaction domain and raising the possibility of intracellular/nuclear partners beyond the matrix.

    Evidence Yeast two-hybrid of trabecular meshwork cDNA plus co-IP in COS-7 cells

    PMID:22919265

    Open questions at the time
    • Functional consequence of the PITX2 interaction not established
    • No demonstration this interaction occurs at endogenous levels in relevant tissue
  2. 2015 High

    Defined EFEMP2's core ECM function as a LOX-binding scaffold required for proper collagen cross-linking and fibril organization, explaining its role in matrix maturation.

    Evidence Smooth-muscle-specific Efemp2 knockout mice, proteomic partner screen, in vitro binding and collagen cross-linking assays

    PMID:26220971

    Open questions at the time
    • Mechanism by which scaffolding promotes LOX activity not resolved
    • Pcolce binding identified but functionally negative in vitro for procollagen cleavage
  3. 2020 High

    Connected EFEMP2 loss to a defined mechanosensing signaling cascade in the aorta, identifying PAR1→Egr1 as the effector axis of aneurysm initiation.

    Evidence Fbln4SMKO;Egr1-/- double knockout, pathway analysis, cyclic stretch of primary VSMCs, western blot

    PMID:32580633

    Open questions at the time
    • Egr1 deletion rescued only a subset of animals
    • Direct link from matrix defect to PAR1 upregulation not fully mapped
  4. 2018 Medium

    Identified post-translational control of EFEMP2: GALNT14-mediated O-glycosylation regulates EFEMP2 stability and is required for cancer cell invasion.

    Evidence Yeast two-hybrid, reciprocal co-IP, glycosylation and invasion assays with knockdown

    PMID:29428518

    Open questions at the time
    • Specific glycosylated residues not mapped
    • Single lab; effect on secreted vs intracellular pools unclear
  5. 2019 Medium

    Began establishing EFEMP2 as a context-dependent regulator of tumor EMT, here acting as a Wnt/β-catenin suppressor in bladder cancer.

    Evidence KD/OE with EMT marker panel and pharmacological Wnt rescue (LiCl/XAV939) in vitro and in vivo

    PMID:31592144

    Open questions at the time
    • No direct molecular link between EFEMP2 and Wnt pathway components
    • Directionality opposite to other cancer contexts
  6. 2020 Medium

    Extended the tumor-suppressive role to lung cancer and glioma, linking EFEMP2 to MMP-2/MMP-9 downregulation and reduced invasion.

    Evidence Reciprocal KD/OE, invasion assays, zymography, xenografts, flow cytometry

    PMID:26617746 PMID:32110039

    Open questions at the time
    • Mechanism of MMP regulation not defined
    • Contradicts pro-invasive roles seen elsewhere
  7. 2023 Medium

    Provided a direct receptor-binding mechanism for EFEMP2's pro-tumor activity, showing EGFR engagement drives ERK1/2/c-Jun signaling and PD-L1 induction.

    Evidence Co-IP, phospho-pathway profiling array, lentiviral OE/KD, in vitro and in vivo invasion assays in ovarian cancer

    PMID:37420173

    Open questions at the time
    • Whether EGFR binding is direct or matrix-mediated unclear
    • Single lab; reconciliation with tumor-suppressive contexts unresolved
  8. 2021 Medium

    Placed Efemp2 in a neuronal apoptosis pathway as a miR-211-5p target, linking its loss to Smad2/3-Bim-cytochrome C signaling.

    Evidence RISC enrichment RNA-IP, miRNA mimic/inhibitor, 3'-UTR reporter, in vivo mouse model

    PMID:34730432

    Open questions at the time
    • How EFEMP2 mechanistically restrains Smad2/3 signaling not defined
    • Single lab
  9. 2022 Low

    Further mapped context-dependent pro-tumor signaling axes (Raf/MEK/ERK, PI3K/AKT/mTOR via STEAP2) downstream of EFEMP2 in cervical cancer and osteosarcoma.

    Evidence OE/KD, western blot, invasion assays, double knockdown epistasis, xenografts

    PMID:36004647 PMID:36316642

    Open questions at the time
    • No direct binding between EFEMP2 and Raf or STEAP2 established
    • Low-confidence single-lab studies
  10. 2025 Low

    Positioned EFEMP2 as an intermediate node downstream of MFAP5 and upstream of Wnt/β-catenin in papillary thyroid cancer metabolism.

    Evidence Lentiviral OE/KD, proliferation and glycolysis assays, xenograft

    PMID:40020327

    Open questions at the time
    • No direct mechanistic link between EFEMP2 and β-catenin shown
    • Single lab, epistasis only

Open questions

Synthesis pass · forward-looking unresolved questions
  • The basis for EFEMP2's opposite (suppressive vs promoting) effects on EMT and invasion across cancer types, and whether these reflect distinct receptor/glycosylation states, remains unresolved.
  • No unifying mechanism reconciling tumor-suppressive and tumor-promoting reports
  • Structural basis of EGFR vs LOX vs PITX2 binding not compared
  • Role of O-glycosylation in dictating context-dependent signaling unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0005576 extracellular region 2 GO:0031012 extracellular matrix 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1474244 Extracellular matrix organization 1 R-HSA-1643685 Disease 1
Partners
EGFRGALNT14LOXPCOLCEPITX2

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Fibulin-4 (EFEMP2) binds lysyl oxidase (LOX) and serves as a scaffolding protein during collagen maturation in the extracellular space; loss of fibulin-4 in smooth muscle-specific knockout mice decreased LOX activity and collagen cross-linking (but not elastin cross-linking), and altered fibrillar collagen localization with larger, poorly organized fibrils. Smooth muscle-specific Efemp2 knockout mouse model, proteomic screening for binding partners, in vitro binding assays, collagen cross-linking analysis Human molecular genetics High 26220971
2015 Fibulin-4 (EFEMP2) binds procollagen C-endopeptidase enhancer 1 (Pcolce), a protein that enhances proteolytic cleavage of the procollagen C-terminal propeptide during procollagen processing; however, procollagen cleavage itself was not affected by the presence or absence of fibulin-4 in vitro. Proteomic screening, in vitro binding assay Human molecular genetics Medium 26220971
2020 In the Fbln4SMKO mouse model, loss of fibulin-4 leads to upregulation of PAR1 (protease-activated receptor 1) and Egr1 in the ascending aorta; thrombin and MMP-9 activate PAR1, which induces Egr1 expression, initiating ascending aortic aneurysm formation. Deletion of Egr1 in Fbln4SMKO mice prevented aneurysm in a subset of animals. Double knockout mouse model (Fbln4SMKO; Egr1-/-), Ingenuity Pathway Analysis, in vitro cyclic stretch assay of primary vascular smooth muscle cells, western blot Arteriosclerosis, thrombosis, and vascular biology High 32580633
2019 EFEMP2 suppresses epithelial-mesenchymal transition (EMT) in bladder cancer cells via the Wnt/β-catenin signaling pathway; knockdown of EFEMP2 reduced E-cadherin and increased N-cadherin, Vimentin, Snail, Slug, β-catenin, c-Myc and cyclin D1, while overexpression reversed these changes. EMT marker changes induced by EFEMP2 modulation were rescued by LiCl (Wnt activator) or XAV939 (Wnt inhibitor). RNA interference, overexpression transfection, western blot, in vitro and in vivo functional assays, pharmacological rescue with LiCl/XAV939 International journal of biological sciences Medium 31592144
2018 EFEMP2 interacts with GALNT14 (N-acetylgalactosaminyltransferase-14), which mediates O-glycosylation of EFEMP2; this GALNT14-dependent O-glycosylation regulates EFEMP2 protein stability and is required for GALNT14-mediated promotion of breast cancer cell invasion. Yeast two-hybrid, in vitro and in vivo binding assays (co-immunoprecipitation), glycosylation assay, knockdown experiments, invasion assays Translational oncology Medium 29428518
2023 EFEMP2 binds to EGFR and activates the EGFR/ERK1/2/c-Jun signaling pathway, leading to upregulation of PD-L1 expression, which promotes invasion and intraperitoneal dissemination of ovarian cancer cells. Immunoprecipitation, phosphorylation pathway profiling array, KEGG analysis, lentiviral overexpression/knockdown, in vitro and in vivo functional assays Cellular & molecular biology letters Medium 37420173
2021 miR-211-5p targets the 3'-UTR of Efemp2 mRNA, reducing Efemp2 expression and thereby promoting neuronal apoptosis via phosphorylation of Smad2/Smad3, upregulation of pro-apoptotic Bim, and mitochondrial release of cytochrome C; this pathway is downstream of sevoflurane exposure. RNA immunoprecipitation (RISC enrichment assay), miRNA mimic/inhibitor transfection, luciferase 3'-UTR reporter (implied), western blot, in vivo mouse model ASN neuro Medium 34730432
2012 EFEMP2 physically interacts with the transcription factor PITX2 (both isoforms A and C); the PITX2-interaction domain in EFEMP2 lies between the second EGF-like module and the C-terminal fibulin-like module. Yeast two-hybrid screening of human trabecular meshwork cDNA library, co-immunoprecipitation in COS-7 cells Molecular vision Medium 22919265
2020 EFEMP2 knockdown in glioma cells (U87, U373) inhibited cell proliferation and G1/S transition, induced apoptosis by increasing the Bax/Bcl-2 ratio, and inhibited invasion by downregulating MMP-2 and MMP-9 expression. RNA interference (siRNA), cell proliferation assay, flow cytometry (apoptosis/cell cycle), invasion assay, western blot International journal of clinical and experimental pathology Medium 26617746
2020 EFEMP2 overexpression in lung cancer cells inhibited invasion, blocked EMT, and decreased MMP2 and MMP9 expression and activity; knockdown had the opposite effects. RNA interference, overexpression transfection, invasion assay, western blot, gelatin zymography, in vivo xenograft OncoTargets and therapy Medium 32110039
2019 EFEMP2 knockdown in colon cancer cells attenuated ERK1/2 activation and decreased MMP-3 expression, suppressing cancer cell growth and invasion. RNA interference, western blot (ERK1/2 phosphorylation), invasion assay International journal of clinical and experimental pathology Low 31933893
2022 EFEMP2 overexpression in cervical cancer cells promoted EMT and invasion by activating the Raf/MEK/ERK signaling pathway and upregulating MMP-1, MMP-3, MMP-10, and MMP-13; knockdown had the opposite effects. Overexpression and knockdown transfection, western blot, invasion assay, in vivo xenograft Neoplasma Low 36004647
2022 In osteosarcoma cells, EFEMP2 overexpression activates the PI3K/AKT/mTOR pathway and promotes EMT partly by targeting STEAP2; this effect was abolished when STEAP2 or Akt was knocked down, placing STEAP2 downstream of EFEMP2 in this signaling axis. Overexpression and knockdown experiments, western blot, in vitro invasion/migration assays, in vivo xenograft Cancer biology & therapy Low 36316642
2025 MFAP5 overexpression activates EFEMP2 expression, which in turn suppresses the Wnt/β-catenin pathway; knockdown of EFEMP2 reversed the inhibition of PTC cell proliferation and aerobic glycolysis caused by MFAP5 overexpression, placing EFEMP2 downstream of MFAP5 and upstream of Wnt/β-catenin in this context. Overexpression and knockdown (lentiviral), western blot, CCK8 proliferation assay, glucose uptake/lactate production assays, in vivo xenograft Pathology, research and practice Low 40020327

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 EFEMP2 indicates assembly of M0 macrophage and more malignant phenotypes of glioma. Aging 53 32396873
2019 EFEMP2 suppresses epithelial-mesenchymal transition via Wnt/β-catenin signaling pathway in human bladder cancer. International journal of biological sciences 52 31592144
2015 Loss of fibulin-4 disrupts collagen synthesis and maturation: implications for pathology resulting from EFEMP2 mutations. Human molecular genetics 44 26220971
2012 Identification of EFEMP2 as a serum biomarker for the early detection of colorectal cancer with lectin affinity capture assisted secretome analysis of cultured fresh tissues. Journal of proteome research 43 22506683
2012 Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis. Orphanet journal of rare diseases 38 22943132
2015 EFEMP2 is upregulated in gliomas and promotes glioma cell proliferation and invasion. International journal of clinical and experimental pathology 31 26617746
2020 Role of PAR1-Egr1 in the Initiation of Thoracic Aortic Aneurysm in Fbln4-Deficient Mice. Arteriosclerosis, thrombosis, and vascular biology 20 32580633
2023 EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells. Cellular & molecular biology letters 19 37420173
2020 EFEMP2 Suppresses the Invasion of Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition (EMT) and Down-Regulating MMPs. OncoTargets and therapy 19 32110039
2013 Longer term survival of a child with autosomal recessive cutis laxa due to a mutation in FBLN4. American journal of medical genetics. Part A 19 23532871
2012 Recessively inherited severe aortic aneurysm caused by mutated EFEMP2. The American journal of cardiology 19 22440127
2022 STEAP2 promotes osteosarcoma progression by inducing epithelial-mesenchymal transition via the PI3K/AKT/mTOR signaling pathway and is regulated by EFEMP2. Cancer biology & therapy 18 36316642
2018 EFEMP2 Mediates GALNT14-Dependent Breast Cancer Cell Invasion. Translational oncology 16 29428518
2017 FBLN4 as candidate gene associated with long-term and short-term survival with primary glioblastoma. OncoTargets and therapy 16 28144153
2021 Sevoflurane-Induced miR-211-5p Promotes Neuronal Apoptosis by Inhibiting Efemp2. ASN neuro 15 34730432
2022 EFEMP2 increases the invasion ability of cervical cancer cells by promoting EMT via the Raf/MEK/ERK signaling pathway. Neoplasma 10 36004647
2019 EFEMP2 Inhibits Breast Cancer Invasion And Metastasis In Vitro And In Vivo. OncoTargets and therapy 8 31802903
2014 Imaging findings in a distinct lethal inherited arteriopathy syndrome associated with a novel mutation in the FBLN4 gene. European radiology 8 24838734
2019 EFEMP2 promotes colon cancer cell invasion and growth through the ERK1/2 signaling pathway. International journal of clinical and experimental pathology 7 31933893
2018 Severe Phenotype of Cutis Laxa Type 1B with Antenatal Signs due to a Novel Homozygous Nonsense Mutation in EFEMP2. Molecular syndromology 7 30140196
2012 Yeast two-hybrid analysis of a human trabecular meshwork cDNA library identified EFEMP2 as a novel PITX2 interacting protein. Molecular vision 5 22919265
2025 Overexpression of MFAP5 inhibits the progression of papillary thyroid cancer and aerobic glycolysis by regulating the EFEMP2/Wnt/β-catenin pathway. Pathology, research and practice 3 40020327
2024 Whole-exome sequencing uncovers a novel EFEMP2 gene variant (c.C247T) associated with dominant nonsyndromic thoracic aortic aneurysm. Laboratory medicine 2 38113391
2019 Keratoglobus with ARCL1B (EFEMP2 gene) cutis laxa. American journal of ophthalmology case reports 2 31194159
2025 Integrative multi-omics analysis identifies AEBP1 and EFEMP2 as key regulators of immune heterogeneity and therapeutic response in glioblastoma. Discover oncology 1 41026376
2025 Corrigendum: Case report and literature review: delayed diagnosis of ARCL1B due to a newly reported homozygous mutation c.464A>C p. (Tyr155Ser) in the EFEMP2 gene. Frontiers in genetics 0 40151198
2024 The extracellular matrix protein EFEMP2 is involved in the response to VHSV infection in the olive flounder Paralichthys olivaceus. Fish & shellfish immunology 0 38871142
2024 Case Report and literature review: Delayed diagnosis of ARCL1B due to a newly reported homozygous mutation c.464A>C p. (Tyr155Ser) in the EFEMP2 gene. Frontiers in genetics 0 39764439
2022 Erratum: EFEMP2 suppresses epithelial-mesenchymal transition via Wnt/β-catenin signaling pathway in human bladder cancer: Erratum. International journal of biological sciences 0 35813466

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