{"gene":"EFEMP2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2015,"finding":"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.","method":"Smooth muscle-specific Efemp2 knockout mouse model, proteomic screening for binding partners, in vitro binding assays, collagen cross-linking analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mouse phenotype, proteomics, in vitro binding), replicated across tissues","pmids":["26220971"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Proteomic screening, in vitro binding assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification plus in vitro binding confirmed, single lab, but interaction's functional consequence was negative in vitro","pmids":["26220971"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Double knockout mouse model (Fbln4SMKO; Egr1-/-), Ingenuity Pathway Analysis, in vitro cyclic stretch assay of primary vascular smooth muscle cells, western blot","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double knockout plus in vitro mechanistic assays confirming PAR1-Egr1 axis","pmids":["32580633"],"is_preprint":false},{"year":2019,"finding":"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).","method":"RNA interference, overexpression transfection, western blot, in vitro and in vivo functional assays, pharmacological rescue with LiCl/XAV939","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/OE with defined cellular phenotype plus pharmacological epistasis, single lab","pmids":["31592144"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Yeast two-hybrid, in vitro and in vivo binding assays (co-immunoprecipitation), glycosylation assay, knockdown experiments, invasion assays","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid identification confirmed by reciprocal co-IP and functional rescue, single lab","pmids":["29428518"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Immunoprecipitation, phosphorylation pathway profiling array, KEGG analysis, lentiviral overexpression/knockdown, in vitro and in vivo functional assays","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirmed EFEMP2-EGFR interaction, pathway profiling, in vivo validation, single lab","pmids":["37420173"],"is_preprint":false},{"year":2021,"finding":"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.","method":"RNA immunoprecipitation (RISC enrichment assay), miRNA mimic/inhibitor transfection, luciferase 3'-UTR reporter (implied), western blot, in vivo mouse model","journal":"ASN neuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA immunoprecipitation confirmed miR-211-5p:Efemp2 mRNA interaction, in vivo rescue experiment, single lab","pmids":["34730432"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Yeast two-hybrid screening of human trabecular meshwork cDNA library, co-immunoprecipitation in COS-7 cells","journal":"Molecular vision","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid confirmed by co-IP in mammalian cells, single lab, two orthogonal methods","pmids":["22919265"],"is_preprint":false},{"year":2020,"finding":"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.","method":"RNA interference (siRNA), cell proliferation assay, flow cytometry (apoptosis/cell cycle), invasion assay, western blot","journal":"International journal of clinical and experimental pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with multiple defined cellular phenotype readouts, single lab, single method type","pmids":["26617746"],"is_preprint":false},{"year":2020,"finding":"EFEMP2 overexpression in lung cancer cells inhibited invasion, blocked EMT, and decreased MMP2 and MMP9 expression and activity; knockdown had the opposite effects.","method":"RNA interference, overexpression transfection, invasion assay, western blot, gelatin zymography, in vivo xenograft","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal KD/OE with defined molecular readouts in vitro and in vivo, single lab","pmids":["32110039"],"is_preprint":false},{"year":2019,"finding":"EFEMP2 knockdown in colon cancer cells attenuated ERK1/2 activation and decreased MMP-3 expression, suppressing cancer cell growth and invasion.","method":"RNA interference, western blot (ERK1/2 phosphorylation), invasion assay","journal":"International journal of clinical and experimental pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (KD only), limited mechanistic follow-up","pmids":["31933893"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Overexpression and knockdown transfection, western blot, invasion assay, in vivo xenograft","journal":"Neoplasma","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD/OE with pathway measurement but no direct mechanistic link established between EFEMP2 and Raf","pmids":["36004647"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Overexpression and knockdown experiments, western blot, in vitro invasion/migration assays, in vivo xenograft","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic epistasis via double KD placing STEAP2 downstream, but no direct binding assay; single lab","pmids":["36316642"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Overexpression and knockdown (lentiviral), western blot, CCK8 proliferation assay, glucose uptake/lactate production assays, in vivo xenograft","journal":"Pathology, research and practice","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epistasis via genetic rescue, single lab, no direct mechanistic link between EFEMP2 and β-catenin established","pmids":["40020327"],"is_preprint":false}],"current_model":"EFEMP2/Fibulin-4 is a secreted extracellular matrix glycoprotein that functions as a scaffolding protein during elastic fiber and collagen maturation by binding lysyl oxidase (LOX) to facilitate cross-linking and by interacting with procollagen processing factors; in the vasculature, its loss triggers a PAR1→Egr1 mechanosensing pathway leading to aortic aneurysm, while in various cancer contexts it modulates invasion and EMT through interactions with EGFR (activating ERK1/2/c-Jun/PD-L1), Wnt/β-catenin signaling, and MMP regulation, and its stability is controlled by GALNT14-mediated O-glycosylation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2012,"claim":"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","pmids":["22919265"],"confidence":"Medium","gaps":["Functional consequence of the PITX2 interaction not established","No demonstration this interaction occurs at endogenous levels in relevant tissue"]},{"year":2015,"claim":"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","pmids":["26220971"],"confidence":"High","gaps":["Mechanism by which scaffolding promotes LOX activity not resolved","Pcolce binding identified but functionally negative in vitro for procollagen cleavage"]},{"year":2020,"claim":"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","pmids":["32580633"],"confidence":"High","gaps":["Egr1 deletion rescued only a subset of animals","Direct link from matrix defect to PAR1 upregulation not fully mapped"]},{"year":2018,"claim":"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","pmids":["29428518"],"confidence":"Medium","gaps":["Specific glycosylated residues not mapped","Single lab; effect on secreted vs intracellular pools unclear"]},{"year":2019,"claim":"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","pmids":["31592144"],"confidence":"Medium","gaps":["No direct molecular link between EFEMP2 and Wnt pathway components","Directionality opposite to other cancer contexts"]},{"year":2020,"claim":"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","pmids":["32110039","26617746"],"confidence":"Medium","gaps":["Mechanism of MMP regulation not defined","Contradicts pro-invasive roles seen elsewhere"]},{"year":2023,"claim":"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","pmids":["37420173"],"confidence":"Medium","gaps":["Whether EGFR binding is direct or matrix-mediated unclear","Single lab; reconciliation with tumor-suppressive contexts unresolved"]},{"year":2021,"claim":"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","pmids":["34730432"],"confidence":"Medium","gaps":["How EFEMP2 mechanistically restrains Smad2/3 signaling not defined","Single lab"]},{"year":2022,"claim":"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","pmids":["36004647","36316642"],"confidence":"Low","gaps":["No direct binding between EFEMP2 and Raf or STEAP2 established","Low-confidence single-lab studies"]},{"year":2025,"claim":"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","pmids":["40020327"],"confidence":"Low","gaps":["No direct mechanistic link between EFEMP2 and β-catenin shown","Single lab, epistasis only"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2]}],"complexes":[],"partners":["LOX","PCOLCE","GALNT14","EGFR","PITX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95967","full_name":"EGF-containing fibulin-like extracellular matrix protein 2","aliases":["Fibulin-4","FIBL-4","Protein UPH1"],"length_aa":443,"mass_kda":49.4,"function":"Plays a crucial role in elastic fiber formation in tissue, and in the formation of ultrastructural connections between elastic laminae and smooth muscle cells in the aorta, therefore participates in terminal differentiation and maturation of smooth muscle cell (SMC) and in the mechanical properties and wall integrity maintenance of the aorta (PubMed:27339457). In addition, is involved in the control of collagen fibril assembly in tissue throught proteolytic activation of LOX leading to cross- linking of collagen and elastin (By similarity). Also promotes ELN coacervation and participates in the deposition of ELN coacervates on to microfibrils but also regulates ELN cross- linking through LOX interaction (PubMed:18973305, PubMed:19570982). Moreover adheres to the cells through heparin binding in a calcium-dependent manner and regulates vascularlar smooth muscle cells proliferation through angiotensin signaling (PubMed:23782690)","subcellular_location":"Secreted, extracellular space, extracellular matrix; Secreted, extracellular space, extracellular matrix, basement membrane","url":"https://www.uniprot.org/uniprotkb/O95967/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EFEMP2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EFEMP2","total_profiled":1310},"omim":[{"mim_id":"620908","title":"ARTERIAL TORTUOSITY-BONE FRAGILITY SYNDROME; ATBFS","url":"https://www.omim.org/entry/620908"},{"mim_id":"614437","title":"CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IB; ARCL1B","url":"https://www.omim.org/entry/614437"},{"mim_id":"604633","title":"EGF-CONTAINING FIBULIN-LIKE EXTRACELLULAR MATRIX PROTEIN 2; EFEMP2","url":"https://www.omim.org/entry/604633"},{"mim_id":"601548","title":"EGF-CONTAINING FIBULIN-LIKE EXTRACELLULAR MATRIX PROTEIN 1; EFEMP1","url":"https://www.omim.org/entry/601548"},{"mim_id":"278250","title":"WRINKLY SKIN SYNDROME; WSS","url":"https://www.omim.org/entry/278250"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EFEMP2"},"hgnc":{"alias_symbol":["FBLN4","UPH1"],"prev_symbol":[]},"alphafold":{"accession":"O95967","domains":[{"cath_id":"2.10.25","chopping":"41-83","consensus_level":"medium","plddt":78.7605,"start":41,"end":83},{"cath_id":"2.10.25.10","chopping":"205-242","consensus_level":"medium","plddt":89.8913,"start":205,"end":242},{"cath_id":"2.60.40.60","chopping":"319-437","consensus_level":"high","plddt":92.1552,"start":319,"end":437},{"cath_id":"2.10.25","chopping":"247-282","consensus_level":"high","plddt":94.5217,"start":247,"end":282}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95967","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95967-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95967-F1-predicted_aligned_error_v6.png","plddt_mean":82.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EFEMP2","jax_strain_url":"https://www.jax.org/strain/search?query=EFEMP2"},"sequence":{"accession":"O95967","fasta_url":"https://rest.uniprot.org/uniprotkb/O95967.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95967/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95967"}},"corpus_meta":[{"pmid":"32396873","id":"PMC_32396873","title":"EFEMP2 indicates assembly of M0 macrophage and more malignant phenotypes of glioma.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32396873","citation_count":53,"is_preprint":false},{"pmid":"31592144","id":"PMC_31592144","title":"EFEMP2 suppresses epithelial-mesenchymal transition via Wnt/β-catenin signaling pathway in human bladder cancer.","date":"2019","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31592144","citation_count":52,"is_preprint":false},{"pmid":"26220971","id":"PMC_26220971","title":"Loss of fibulin-4 disrupts collagen synthesis and maturation: implications for pathology resulting from EFEMP2 mutations.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26220971","citation_count":44,"is_preprint":false},{"pmid":"22506683","id":"PMC_22506683","title":"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.","date":"2012","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/22506683","citation_count":43,"is_preprint":false},{"pmid":"22943132","id":"PMC_22943132","title":"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.","date":"2012","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22943132","citation_count":38,"is_preprint":false},{"pmid":"26617746","id":"PMC_26617746","title":"EFEMP2 is upregulated in gliomas and promotes glioma cell proliferation and invasion.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26617746","citation_count":31,"is_preprint":false},{"pmid":"32580633","id":"PMC_32580633","title":"Role of PAR1-Egr1 in the Initiation of Thoracic Aortic Aneurysm in Fbln4-Deficient Mice.","date":"2020","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32580633","citation_count":20,"is_preprint":false},{"pmid":"37420173","id":"PMC_37420173","title":"EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells.","date":"2023","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/37420173","citation_count":19,"is_preprint":false},{"pmid":"32110039","id":"PMC_32110039","title":"EFEMP2 Suppresses the Invasion of Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition (EMT) and Down-Regulating MMPs.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32110039","citation_count":19,"is_preprint":false},{"pmid":"22440127","id":"PMC_22440127","title":"Recessively inherited severe aortic aneurysm caused by mutated EFEMP2.","date":"2012","source":"The American journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/22440127","citation_count":19,"is_preprint":false},{"pmid":"23532871","id":"PMC_23532871","title":"Longer term survival of a child with autosomal recessive cutis laxa due to a mutation in FBLN4.","date":"2013","source":"American journal of medical genetics. 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(Tyr155Ser) in the EFEMP2 gene.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39764439","citation_count":0,"is_preprint":false},{"pmid":"35813466","id":"PMC_35813466","title":"Erratum: EFEMP2 suppresses epithelial-mesenchymal transition via Wnt/β-catenin signaling pathway in human bladder cancer: Erratum.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35813466","citation_count":0,"is_preprint":false},{"pmid":"40151198","id":"PMC_40151198","title":"Corrigendum: Case report and literature review: delayed diagnosis of ARCL1B due to a newly reported homozygous mutation c.464A>C p. 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Deletion of Egr1 in Fbln4SMKO mice prevented aneurysm in a subset of animals.\",\n      \"method\": \"Double knockout mouse model (Fbln4SMKO; Egr1-/-), Ingenuity Pathway Analysis, in vitro cyclic stretch assay of primary vascular smooth muscle cells, western blot\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double knockout plus in vitro mechanistic assays confirming PAR1-Egr1 axis\",\n      \"pmids\": [\"32580633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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).\",\n      \"method\": \"RNA interference, overexpression transfection, western blot, in vitro and in vivo functional assays, pharmacological rescue with LiCl/XAV939\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/OE with defined cellular phenotype plus pharmacological epistasis, single lab\",\n      \"pmids\": [\"31592144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, in vitro and in vivo binding assays (co-immunoprecipitation), glycosylation assay, knockdown experiments, invasion assays\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid identification confirmed by reciprocal co-IP and functional rescue, single lab\",\n      \"pmids\": [\"29428518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation, phosphorylation pathway profiling array, KEGG analysis, lentiviral overexpression/knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirmed EFEMP2-EGFR interaction, pathway profiling, in vivo validation, single lab\",\n      \"pmids\": [\"37420173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"RNA immunoprecipitation (RISC enrichment assay), miRNA mimic/inhibitor transfection, luciferase 3'-UTR reporter (implied), western blot, in vivo mouse model\",\n      \"journal\": \"ASN neuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA immunoprecipitation confirmed miR-211-5p:Efemp2 mRNA interaction, in vivo rescue experiment, single lab\",\n      \"pmids\": [\"34730432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screening of human trabecular meshwork cDNA library, co-immunoprecipitation in COS-7 cells\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid confirmed by co-IP in mammalian cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"22919265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"RNA interference (siRNA), cell proliferation assay, flow cytometry (apoptosis/cell cycle), invasion assay, western blot\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with multiple defined cellular phenotype readouts, single lab, single method type\",\n      \"pmids\": [\"26617746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EFEMP2 overexpression in lung cancer cells inhibited invasion, blocked EMT, and decreased MMP2 and MMP9 expression and activity; knockdown had the opposite effects.\",\n      \"method\": \"RNA interference, overexpression transfection, invasion assay, western blot, gelatin zymography, in vivo xenograft\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal KD/OE with defined molecular readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"32110039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EFEMP2 knockdown in colon cancer cells attenuated ERK1/2 activation and decreased MMP-3 expression, suppressing cancer cell growth and invasion.\",\n      \"method\": \"RNA interference, western blot (ERK1/2 phosphorylation), invasion assay\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (KD only), limited mechanistic follow-up\",\n      \"pmids\": [\"31933893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression and knockdown transfection, western blot, invasion assay, in vivo xenograft\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD/OE with pathway measurement but no direct mechanistic link established between EFEMP2 and Raf\",\n      \"pmids\": [\"36004647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression and knockdown experiments, western blot, in vitro invasion/migration assays, in vivo xenograft\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic epistasis via double KD placing STEAP2 downstream, but no direct binding assay; single lab\",\n      \"pmids\": [\"36316642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression and knockdown (lentiviral), western blot, CCK8 proliferation assay, glucose uptake/lactate production assays, in vivo xenograft\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epistasis via genetic rescue, single lab, no direct mechanistic link between EFEMP2 and β-catenin established\",\n      \"pmids\": [\"40020327\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EFEMP2/Fibulin-4 is a secreted extracellular matrix glycoprotein that functions as a scaffolding protein during elastic fiber and collagen maturation by binding lysyl oxidase (LOX) to facilitate cross-linking and by interacting with procollagen processing factors; in the vasculature, its loss triggers a PAR1→Egr1 mechanosensing pathway leading to aortic aneurysm, while in various cancer contexts it modulates invasion and EMT through interactions with EGFR (activating ERK1/2/c-Jun/PD-L1), Wnt/β-catenin signaling, and MMP regulation, and its stability is controlled by GALNT14-mediated O-glycosylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0]. It also binds the procollagen-processing enhancer Pcolce, although this interaction does not measurably alter procollagen cleavage in vitro [#1]. In the vasculature, loss of EFEMP2 drives ascending aortic aneurysm through a thrombin/MMP-9\\u2192PAR1\\u2192Egr1 mechanosensing axis, and genetic deletion of Egr1 prevents aneurysm in a subset of Fbln4SMKO mice [#2]. 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 [#5], and it suppresses or promotes EMT through Wnt/\\u03b2-catenin signaling and MMP regulation depending on cancer type [#3, #9]. Its protein stability is governed by GALNT14-mediated O-glycosylation, which is required for GALNT14-driven breast cancer invasion [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid of trabecular meshwork cDNA plus co-IP in COS-7 cells\",\n      \"pmids\": [\"22919265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the PITX2 interaction not established\", \"No demonstration this interaction occurs at endogenous levels in relevant tissue\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Smooth-muscle-specific Efemp2 knockout mice, proteomic partner screen, in vitro binding and collagen cross-linking assays\",\n      \"pmids\": [\"26220971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which scaffolding promotes LOX activity not resolved\", \"Pcolce binding identified but functionally negative in vitro for procollagen cleavage\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected EFEMP2 loss to a defined mechanosensing signaling cascade in the aorta, identifying PAR1\\u2192Egr1 as the effector axis of aneurysm initiation.\",\n      \"evidence\": \"Fbln4SMKO;Egr1-/- double knockout, pathway analysis, cyclic stretch of primary VSMCs, western blot\",\n      \"pmids\": [\"32580633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Egr1 deletion rescued only a subset of animals\", \"Direct link from matrix defect to PAR1 upregulation not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified post-translational control of EFEMP2: GALNT14-mediated O-glycosylation regulates EFEMP2 stability and is required for cancer cell invasion.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, glycosylation and invasion assays with knockdown\",\n      \"pmids\": [\"29428518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific glycosylated residues not mapped\", \"Single lab; effect on secreted vs intracellular pools unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Began establishing EFEMP2 as a context-dependent regulator of tumor EMT, here acting as a Wnt/\\u03b2-catenin suppressor in bladder cancer.\",\n      \"evidence\": \"KD/OE with EMT marker panel and pharmacological Wnt rescue (LiCl/XAV939) in vitro and in vivo\",\n      \"pmids\": [\"31592144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct molecular link between EFEMP2 and Wnt pathway components\", \"Directionality opposite to other cancer contexts\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the tumor-suppressive role to lung cancer and glioma, linking EFEMP2 to MMP-2/MMP-9 downregulation and reduced invasion.\",\n      \"evidence\": \"Reciprocal KD/OE, invasion assays, zymography, xenografts, flow cytometry\",\n      \"pmids\": [\"32110039\", \"26617746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of MMP regulation not defined\", \"Contradicts pro-invasive roles seen elsewhere\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, phospho-pathway profiling array, lentiviral OE/KD, in vitro and in vivo invasion assays in ovarian cancer\",\n      \"pmids\": [\"37420173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EGFR binding is direct or matrix-mediated unclear\", \"Single lab; reconciliation with tumor-suppressive contexts unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed Efemp2 in a neuronal apoptosis pathway as a miR-211-5p target, linking its loss to Smad2/3-Bim-cytochrome C signaling.\",\n      \"evidence\": \"RISC enrichment RNA-IP, miRNA mimic/inhibitor, 3'-UTR reporter, in vivo mouse model\",\n      \"pmids\": [\"34730432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How EFEMP2 mechanistically restrains Smad2/3 signaling not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Further mapped context-dependent pro-tumor signaling axes (Raf/MEK/ERK, PI3K/AKT/mTOR via STEAP2) downstream of EFEMP2 in cervical cancer and osteosarcoma.\",\n      \"evidence\": \"OE/KD, western blot, invasion assays, double knockdown epistasis, xenografts\",\n      \"pmids\": [\"36004647\", \"36316642\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding between EFEMP2 and Raf or STEAP2 established\", \"Low-confidence single-lab studies\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned EFEMP2 as an intermediate node downstream of MFAP5 and upstream of Wnt/\\u03b2-catenin in papillary thyroid cancer metabolism.\",\n      \"evidence\": \"Lentiviral OE/KD, proliferation and glycolysis assays, xenograft\",\n      \"pmids\": [\"40020327\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct mechanistic link between EFEMP2 and \\u03b2-catenin shown\", \"Single lab, epistasis only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LOX\", \"PCOLCE\", \"GALNT14\", \"EGFR\", \"PITX2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}