{"gene":"EPB41L5","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2008,"finding":"EPB41L5 binds p120-catenin through its N-terminal FERM domain, thereby inhibiting p120ctn-E-cadherin binding and causing E-cadherin relocalization into Rab5-positive endocytic vesicles, while simultaneously binding paxillin through its C-terminus to enhance integrin/paxillin association and stimulate focal adhesion formation during EMT.","method":"siRNA knockdown, co-immunoprecipitation, domain mapping, fluorescence microscopy (Rab5-positive vesicle localization), mouse genetic mutant analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding experiments with domain mapping, loss-of-function in cells and mouse mutants, multiple orthogonal methods, independently consistent findings","pmids":["18794329"],"is_preprint":false},{"year":2007,"finding":"EPB41L5 is a component of the mammalian Crumbs polarity complex; its FERM domain binds directly to the intracellular domains of all three Crumbs homologs and also to the HOOK domain of MPP5/PALS1. Overexpression of EPB41L5 in polarized MDCK cells disrupts tight junction markers ZO-1 and PATJ.","method":"Co-immunoprecipitation, co-expression, co-localization studies, domain mapping, overexpression in polarized MDCK cells","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mapping plus functional overexpression phenotype, single lab","pmids":["17920587"],"is_preprint":false},{"year":2016,"finding":"EPB41L5 is an integral component of the ARF6-AMAP1 invasion pathway; EPB41L5 binds AMAP1, and ZEB1 transcriptionally induces EPB41L5 expression. This ZEB1-EPB41L5-AMAP1 axis drives mesenchymal-type invasion, metastasis, and drug resistance in breast cancer cells.","method":"Co-immunoprecipitation (EPB41L5-AMAP1 binding), siRNA knockdown, overexpression, TCGA RNAseq correlation, ZEB1 induction experiments in cancer and normal cells","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for binding plus loss/gain-of-function assays, single lab with multiple methods","pmids":["27617643"],"is_preprint":false},{"year":2017,"finding":"EPB41L5 recruits the RhoGEF ARHGEF18 to the leading edge of podocytes, directly controlling actomyosin contractility and subsequent maturation of focal adhesions. Genetic deletion of Epb41l5 in podocytes causes severe proteinuria, podocyte detachment, and focal segmental glomerulosclerosis.","method":"Conditional knockout mouse model, iTRAQ-based mass spectrometry of focal adhesome, co-immunoprecipitation (EPB41L5-ARHGEF18), cell spreading/migration assays, proteomics","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic deletion with defined phenotype, proteomic adhesome analysis, co-IP for binding partner, multiple orthogonal methods","pmids":["28536193"],"is_preprint":false},{"year":2016,"finding":"Epb41l5 is a substrate for the E3 ubiquitin ligase Mind bomb 1 (Mib1), which ubiquitylates Epb41l5 to promote its degradation. DeltaD competes with Epb41l5 for Mib1, such that high Delta levels stabilize Epb41l5 in neural progenitor cells. Loss of Epb41l5 delays delamination and neuronal differentiation in zebrafish hindbrain, an effect rescued by N-cadherin knockdown.","method":"Zebrafish genetic knockdown/overexpression, ubiquitylation assays, competition assays (Delta vs Epb41l5 for Mib1), epistasis with N-cadherin knockdown","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct ubiquitylation assay identifying Mib1 as E3 ligase, genetic epistasis in zebrafish, competition experiment, multiple orthogonal methods","pmids":["27510968"],"is_preprint":false},{"year":2019,"finding":"TGFβ1 induces EPB41L5 expression via Smad-dependent signaling (phospho-Smad3 recruitment to EPB41L5 promoter). EPB41L5 promotes gastric cancer cell migration and invasion through interaction with p120-catenin; p120-catenin knockdown abolishes EPB41L5-enhanced metastasis, and anti-EPB41L5 monoclonal antibody blocks EPB41L5-p120-catenin association.","method":"ChIP (phospho-Smad3 at EPB41L5 promoter), co-immunoprecipitation (EPB41L5-p120-catenin), siRNA knockdown, antibody blockade, in vivo lung metastasis mouse model","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for transcriptional regulation, co-IP for binding, in vivo model with antibody rescue, single lab","pmids":["30814110"],"is_preprint":false},{"year":2020,"finding":"EPB41L5 forms a complex with IQCB1 (NPHP5); EPB41L5 overexpression reduces IQCB1 localization at the ciliary base while knockdown increases it. Epb41l5-deficient zebrafish embryos develop cilia with reduced motility and left-right patterning defects. EPB41L5 also decreases the IQCB1-CEP290 interaction, regulating the composition of the ciliary base and centrosome.","method":"Co-immunoprecipitation (EPB41L5-IQCB1, IQCB1-CEP290), overexpression/knockdown in cultured epithelial cells, zebrafish morpholino knockdown, genetic synergy analysis, fluorescence microscopy of ciliary base","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, loss- and gain-of-function in two systems (cells and zebrafish), genetic epistasis, multiple orthogonal methods","pmids":["32501287"],"is_preprint":false},{"year":2021,"finding":"Loss of EPB41L5 in podocytes impairs extracellular matrix assembly, causing diminished deposition of core GBM components including LAMA5. EPB41L5 recruits PDLIM5 and ACTN4 to integrin adhesion complexes; its loss causes insufficient maturation of integrin adhesion sites, impaired force transmission, and defective ECM assembly.","method":"EPB41L5 knockout podocytes (in vitro and in vivo), quantitative proteomics of secretome/matrisome, integrin adhesome proteomics (mass spectrometry), traction force microscopy","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — quantitative proteomics with KO controls, in vitro and in vivo models, traction force microscopy, multiple orthogonal methods","pmids":["33761352"],"is_preprint":false},{"year":2021,"finding":"EPB41L5 promotes EMT, proliferation, migration, and invasion in esophageal squamous cell carcinoma through activation of ERK/p38 MAPK signaling pathway phosphorylation.","method":"siRNA knockdown, overexpression in ESCC cells, nude mouse xenograft model, Western blotting for ERK/p38 phosphorylation, in vitro migration/invasion assays","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional KD/OE with defined signaling readout and in vivo model, pathway placement via inhibitor/phospho-Western, single lab","pmids":["34784520"],"is_preprint":false},{"year":2023,"finding":"The transcription factor ZBTB7A directly binds to the EPB41L5 gene promoter to repress its transcription, thereby suppressing glioblastoma progression; ZBTB7A depletion induces EPB41L5 expression and promotes GBM progression.","method":"ChIP (ZBTB7A binding to EPB41L5 promoter), RNA sequencing, siRNA knockdown of ZBTB7A, overexpression experiments, in vivo tumor growth assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence for transcriptional regulation, supported by loss-of-function and RNA-seq, single lab","pmids":["36596853"],"is_preprint":false},{"year":2017,"finding":"The ARF6-AMAP1-EPB41L5 axis and ZEB1 are required for both mesenchymal-type and amoeboid-type cancer cell invasion, indicating EPB41L5 participates in a core mesenchymal program necessary for both modes of invasion regardless of RhoA vs Rac1 activity.","method":"siRNA knockdown, overexpression, invasion assays under different matrix conditions, pharmacological inhibition of receptor tyrosine kinase and GPCR signaling","journal":"Small GTPases","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function experiments in multiple invasion mode contexts, single lab, extends prior Co-IP findings for the complex","pmids":["27754741"],"is_preprint":false},{"year":2025,"finding":"miR-184, when expressed following promoter demethylation, directly targets EPB41L5 mRNA to suppress its expression, thereby downregulating Notch signaling and inhibiting EMT, migration, and invasion in colorectal cancer cells.","method":"5-Aza demethylation treatment, bisulfite sequencing (methylation status), qRT-PCR/Western blotting, luciferase reporter assays (miR-184 targeting EPB41L5), functional migration/invasion assays","journal":"Journal of molecular histology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — luciferase reporter validates direct miR-184/EPB41L5 targeting, functional assays performed, single lab single study","pmids":["40342066"],"is_preprint":false}],"current_model":"EPB41L5 is a FERM-domain adaptor protein that operates at the interface of cell-cell adhesion and cell-matrix adhesion: its FERM domain binds p120-catenin (displacing it from E-cadherin to promote cadherin endocytosis into Rab5+ vesicles), Crumbs homologs, and MPP5/PALS1 (anchoring it to the apical polarity complex), while its C-terminus binds paxillin and AMAP1 to enhance focal adhesion maturation and ARF6-driven invasion; EPB41L5 recruits ARHGEF18 to control RhoA/actomyosin contractility and recruits PDLIM5/ACTN4 to integrin adhesion complexes for force transmission and ECM assembly in podocytes; it is ubiquitylated by Mib1 (competitively stabilized by Delta) to coordinate neuronal delamination, and it regulates ciliary function by modulating IQCB1-CEP290 composition at the ciliary base; its transcription is induced by TGFβ/Smad3 and ZEB1, and repressed by ZBTB7A, placing EPB41L5 as a central effector of EMT and mesenchymal invasiveness across multiple cell types."},"narrative":{"mechanistic_narrative":"EPB41L5 is a FERM-domain adaptor protein that couples cell-cell adhesion, cell-matrix adhesion, and apical polarity, functioning as a central effector of epithelial-mesenchymal transition (EMT) and mesenchymal invasiveness [PMID:18794329, PMID:27617643]. Through its N-terminal FERM domain it binds p120-catenin, displacing it from E-cadherin and driving E-cadherin internalization into Rab5-positive endocytic vesicles, while its C-terminus binds paxillin to stimulate focal adhesion formation [PMID:18794329]. The same FERM domain anchors EPB41L5 to the apical Crumbs polarity complex by binding the Crumbs intracellular domains and the HOOK domain of MPP5/PALS1, with its overexpression disrupting tight-junction organization [PMID:17920587]. At integrin adhesion sites it recruits the RhoGEF ARHGEF18 to control actomyosin contractility and focal adhesion maturation, and recruits PDLIM5 and ACTN4 to enable force transmission and extracellular matrix assembly; loss of EPB41L5 in podocytes causes impaired GBM/LAMA5 deposition, proteinuria, podocyte detachment, and focal segmental glomerulosclerosis [PMID:28536193, PMID:33761352]. EPB41L5 also acts in invasion through the ARF6-AMAP1 pathway, binding AMAP1 to drive mesenchymal- and amoeboid-type invasion, metastasis, and drug resistance [PMID:27617643, PMID:27754741]. In neural progenitors it is a substrate of the E3 ligase Mib1, whose ubiquitylation targets it for degradation but is competitively antagonized by Delta, coordinating delamination and neuronal differentiation via N-cadherin [PMID:27510968], and it regulates ciliary base composition by binding IQCB1/NPHP5 and modulating the IQCB1-CEP290 interaction, affecting cilia motility and left-right patterning [PMID:32501287]. EPB41L5 transcription is induced by TGFβ1/Smad3 and ZEB1, repressed by ZBTB7A, and suppressed post-transcriptionally by miR-184, integrating it into EMT and invasion programs across gastric, breast, esophageal, colorectal, and glioblastoma cancers [PMID:27617643, PMID:30814110, PMID:36596853, PMID:40342066].","teleology":[{"year":2007,"claim":"Establishing that EPB41L5 is part of the apical Crumbs polarity machinery defined its earliest mechanistic role in epithelial organization.","evidence":"Co-IP, domain mapping, and overexpression in polarized MDCK cells","pmids":["17920587"],"confidence":"Medium","gaps":["Single-lab finding without in vivo polarity loss-of-function","Functional consequence shown only by overexpression disruption, not endogenous depletion"]},{"year":2008,"claim":"Identifying the dual FERM-p120-catenin and C-terminal-paxillin interactions revealed how a single adaptor simultaneously dismantles adherens junctions and builds focal adhesions during EMT.","evidence":"siRNA knockdown, reciprocal co-IP with domain mapping, Rab5-vesicle microscopy, and mouse mutants","pmids":["18794329"],"confidence":"High","gaps":["Mechanism of E-cadherin endocytic trafficking downstream of Rab5 not resolved","Structural basis of FERM-p120ctn binding not defined"]},{"year":2016,"claim":"Linking EPB41L5 to the ARF6-AMAP1 invasion pathway and ZEB1 induction placed it within a defined transcription-to-invasion axis in cancer.","evidence":"Co-IP for EPB41L5-AMAP1, siRNA/overexpression, ZEB1 induction, and TCGA correlation in breast cancer","pmids":["27617643"],"confidence":"Medium","gaps":["Direct binding interface with AMAP1 not mapped","Single-lab evidence"]},{"year":2016,"claim":"Showing EPB41L5 is a Mib1 ubiquitylation substrate antagonized by Delta connected its stability to Notch-ligand dynamics and neuronal delamination.","evidence":"Zebrafish knockdown/overexpression, ubiquitylation and Mib1-competition assays, N-cadherin epistasis","pmids":["27510968"],"confidence":"High","gaps":["Ubiquitylation sites on Epb41l5 not identified","Whether mammalian EPB41L5 is regulated identically not addressed"]},{"year":2017,"claim":"Defining EPB41L5 recruitment of ARHGEF18 to control actomyosin contractility and the FSGS phenotype of podocyte knockout established its in vivo role in adhesion maturation and glomerular integrity.","evidence":"Conditional KO mouse, iTRAQ adhesome proteomics, co-IP, and migration assays","pmids":["28536193"],"confidence":"High","gaps":["How EPB41L5 spatially targets ARHGEF18 to the leading edge not detailed","Direct GEF activation mechanism not shown"]},{"year":2017,"claim":"Demonstrating the ARF6-AMAP1-EPB41L5-ZEB1 axis operates in both mesenchymal and amoeboid invasion positioned EPB41L5 as a core invasion-program component independent of RhoA/Rac1 mode.","evidence":"siRNA/overexpression invasion assays under varying matrix and pharmacological conditions","pmids":["27754741"],"confidence":"Medium","gaps":["Mechanistic distinction between invasion modes not resolved at molecular level","Single-lab extension of prior complex findings"]},{"year":2019,"claim":"Mapping TGFβ1/Smad3 induction of EPB41L5 and the p120-catenin-dependent metastasis it drives connected upstream EMT signaling to the adaptor's pro-metastatic output.","evidence":"ChIP for phospho-Smad3, co-IP, antibody blockade, and lung metastasis mouse model in gastric cancer","pmids":["30814110"],"confidence":"Medium","gaps":["Single-lab study","Generality of antibody blockade across tumor types untested"]},{"year":2020,"claim":"Identifying the EPB41L5-IQCB1 complex and its modulation of IQCB1-CEP290 revealed a role at the ciliary base governing cilia motility and left-right patterning.","evidence":"Reciprocal co-IP, overexpression/knockdown in epithelial cells, zebrafish morpholino, and ciliary-base microscopy","pmids":["32501287"],"confidence":"High","gaps":["How EPB41L5 mechanistically displaces IQCB1 from the ciliary base not resolved","Relationship between ciliary and adhesion functions unclear"]},{"year":2021,"claim":"Defining recruitment of PDLIM5 and ACTN4 to integrin adhesions and the resulting matrix-assembly defect linked EPB41L5 to force transmission and basement-membrane production.","evidence":"Podocyte KO, secretome/matrisome and adhesome proteomics, and traction force microscopy","pmids":["33761352"],"confidence":"High","gaps":["Direct binding hierarchy among PDLIM5/ACTN4/integrin not fully ordered","Mechanism connecting adhesion maturation to LAMA5 secretion not detailed"]},{"year":2021,"claim":"Connecting EPB41L5 to ERK/p38 MAPK activation in esophageal carcinoma added a signaling readout to its pro-EMT and pro-invasion phenotype.","evidence":"siRNA/overexpression, xenograft model, and phospho-Western for ERK/p38 in ESCC","pmids":["34784520"],"confidence":"Medium","gaps":["Whether MAPK activation is direct or downstream of adhesion changes not resolved","Single-lab study"]},{"year":2023,"claim":"Identifying ZBTB7A as a direct transcriptional repressor of EPB41L5 added a tumor-suppressive control point in glioblastoma.","evidence":"ChIP for ZBTB7A at the EPB41L5 promoter, RNA-seq, knockdown/overexpression, and in vivo tumor assays","pmids":["36596853"],"confidence":"Medium","gaps":["Single-lab study","Interplay with ZEB1/Smad3 inputs at the promoter not examined"]},{"year":2025,"claim":"Showing miR-184 directly targets EPB41L5 mRNA following promoter demethylation added a post-transcriptional, epigenetically-gated brake on Notch-driven EMT.","evidence":"5-Aza demethylation, bisulfite sequencing, luciferase reporter, and migration/invasion assays in colorectal cancer","pmids":["40342066"],"confidence":"Medium","gaps":["Single-lab single-study evidence","How EPB41L5 loss feeds back on Notch signaling mechanistically not detailed"]},{"year":null,"claim":"It remains unresolved how EPB41L5's distinct interaction modules (junctional, focal-adhesion, polarity, and ciliary) are selectively engaged and spatially partitioned within a single cell.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating FERM and C-terminal interactions","No data on how upstream signals switch EPB41L5 between adhesion, polarity, and ciliary functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,6,7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,5,8,9,11]}],"complexes":["Crumbs polarity complex","integrin adhesion complex"],"partners":["CTNND1","PALS1","CRB3","PXN","ARHGEF18","AMAP1","PDLIM5","ACTN4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HCM4","full_name":"Band 4.1-like protein 5","aliases":["Erythrocyte membrane protein band 4.1-like 5"],"length_aa":733,"mass_kda":81.9,"function":"Plays a role in the formation and organization of tight junctions during the establishment of polarity in epithelial cells","subcellular_location":"Cytoplasm; Cell junction, adherens junction; Cell membrane; Photoreceptor inner segment","url":"https://www.uniprot.org/uniprotkb/Q9HCM4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EPB41L5","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NPM1","stoichiometry":0.2},{"gene":"NPM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EPB41L5","total_profiled":1310},"omim":[{"mim_id":"611730","title":"ERYTHROCYTE MEMBRANE PROTEIN BAND 4.1-LIKE 5; EPB41L5","url":"https://www.omim.org/entry/611730"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EPB41L5"},"hgnc":{"alias_symbol":["KIAA1548","FLJ12957","BE37","YMO1","YRT","LULU","LULU1"],"prev_symbol":[]},"alphafold":{"accession":"Q9HCM4","domains":[{"cath_id":"3.10.20.90","chopping":"25-123","consensus_level":"high","plddt":92.5767,"start":25,"end":123},{"cath_id":"1.20.80.10","chopping":"129-226","consensus_level":"high","plddt":95.8284,"start":129,"end":226},{"cath_id":"2.30.29.30","chopping":"234-333_342-359","consensus_level":"high","plddt":87.7575,"start":234,"end":359}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCM4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCM4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCM4-F1-predicted_aligned_error_v6.png","plddt_mean":63.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EPB41L5","jax_strain_url":"https://www.jax.org/strain/search?query=EPB41L5"},"sequence":{"accession":"Q9HCM4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HCM4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HCM4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCM4"}},"corpus_meta":[{"pmid":"34285192","id":"PMC_34285192","title":"TGF-β1-mediated exosomal lnc-MMP2-2 increases blood-brain barrier permeability via the miRNA-1207-5p/EPB41L5 axis to promote non-small cell lung cancer brain metastasis.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34285192","citation_count":91,"is_preprint":false},{"pmid":"18794329","id":"PMC_18794329","title":"EPB41L5 functions to post-transcriptionally regulate cadherin and integrin during epithelial-mesenchymal transition.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18794329","citation_count":77,"is_preprint":false},{"pmid":"28536193","id":"PMC_28536193","title":"The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28536193","citation_count":60,"is_preprint":false},{"pmid":"17920587","id":"PMC_17920587","title":"FERM protein EPB41L5 is a novel member of the mammalian CRB-MPP5 polarity complex.","date":"2007","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/17920587","citation_count":54,"is_preprint":false},{"pmid":"31905344","id":"PMC_31905344","title":"Circ-EPB41L5 regulates the host gene EPB41L5 via sponging miR-19a to repress glioblastoma tumorigenesis.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31905344","citation_count":41,"is_preprint":false},{"pmid":"27617643","id":"PMC_27617643","title":"ZEB1 induces EPB41L5 in the cancer mesenchymal program that drives ARF6-based invasion, metastasis and drug resistance.","date":"2016","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/27617643","citation_count":37,"is_preprint":false},{"pmid":"30814110","id":"PMC_30814110","title":"EPB41L5 Mediates TGFβ-Induced Metastasis of Gastric Cancer.","date":"2019","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30814110","citation_count":29,"is_preprint":false},{"pmid":"33761352","id":"PMC_33761352","title":"EPB41L5 controls podocyte extracellular matrix assembly by adhesome-dependent force transmission.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33761352","citation_count":27,"is_preprint":false},{"pmid":"27510968","id":"PMC_27510968","title":"Epb41l5 competes with Delta as a substrate for Mib1 to coordinate specification and differentiation of neurons.","date":"2016","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27510968","citation_count":17,"is_preprint":false},{"pmid":"36596853","id":"PMC_36596853","title":"ZBTB7A suppresses glioblastoma tumorigenesis through the transcriptional repression of EPB41L5.","date":"2023","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36596853","citation_count":14,"is_preprint":false},{"pmid":"34784520","id":"PMC_34784520","title":"EPB41L5 promotes EMT through the ERK/p38 MAPK signaling pathway in esophageal squamous cell carcinoma.","date":"2021","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/34784520","citation_count":14,"is_preprint":false},{"pmid":"27754741","id":"PMC_27754741","title":"Arf6 and its ZEB1-EPB41L5 mesenchymal axis are required for both mesenchymal- and amoeboid-type invasion of cancer cells.","date":"2017","source":"Small GTPases","url":"https://pubmed.ncbi.nlm.nih.gov/27754741","citation_count":8,"is_preprint":false},{"pmid":"32501287","id":"PMC_32501287","title":"Epb41l5 interacts with Iqcb1 and regulates ciliary function in zebrafish embryos.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/32501287","citation_count":3,"is_preprint":false},{"pmid":"31467225","id":"PMC_31467225","title":"EPB41L5 is Associated With the Metastatic Potential of Low-grade Pancreatic Neuroendocrine Tumors.","date":"2019","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/31467225","citation_count":3,"is_preprint":false},{"pmid":"40342066","id":"PMC_40342066","title":"Demethylated miR-184 regulates EPB41L5 and downregulates Notch signaling to inhibit metastasis in colorectal cancer.","date":"2025","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/40342066","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.09.663814","title":"Regulation of the transcriptome, miRNAs, and alternative splicing in a FSGS zebrafish injury model","date":"2025-07-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.09.663814","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10286,"output_tokens":3387,"usd":0.040831,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10846,"output_tokens":4053,"usd":0.077777,"stage2_stop_reason":"end_turn"},"total_usd":0.118608,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"EPB41L5 binds p120-catenin through its N-terminal FERM domain, thereby inhibiting p120ctn-E-cadherin binding and causing E-cadherin relocalization into Rab5-positive endocytic vesicles, while simultaneously binding paxillin through its C-terminus to enhance integrin/paxillin association and stimulate focal adhesion formation during EMT.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, domain mapping, fluorescence microscopy (Rab5-positive vesicle localization), mouse genetic mutant analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding experiments with domain mapping, loss-of-function in cells and mouse mutants, multiple orthogonal methods, independently consistent findings\",\n      \"pmids\": [\"18794329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EPB41L5 is a component of the mammalian Crumbs polarity complex; its FERM domain binds directly to the intracellular domains of all three Crumbs homologs and also to the HOOK domain of MPP5/PALS1. Overexpression of EPB41L5 in polarized MDCK cells disrupts tight junction markers ZO-1 and PATJ.\",\n      \"method\": \"Co-immunoprecipitation, co-expression, co-localization studies, domain mapping, overexpression in polarized MDCK cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mapping plus functional overexpression phenotype, single lab\",\n      \"pmids\": [\"17920587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EPB41L5 is an integral component of the ARF6-AMAP1 invasion pathway; EPB41L5 binds AMAP1, and ZEB1 transcriptionally induces EPB41L5 expression. This ZEB1-EPB41L5-AMAP1 axis drives mesenchymal-type invasion, metastasis, and drug resistance in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (EPB41L5-AMAP1 binding), siRNA knockdown, overexpression, TCGA RNAseq correlation, ZEB1 induction experiments in cancer and normal cells\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for binding plus loss/gain-of-function assays, single lab with multiple methods\",\n      \"pmids\": [\"27617643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EPB41L5 recruits the RhoGEF ARHGEF18 to the leading edge of podocytes, directly controlling actomyosin contractility and subsequent maturation of focal adhesions. Genetic deletion of Epb41l5 in podocytes causes severe proteinuria, podocyte detachment, and focal segmental glomerulosclerosis.\",\n      \"method\": \"Conditional knockout mouse model, iTRAQ-based mass spectrometry of focal adhesome, co-immunoprecipitation (EPB41L5-ARHGEF18), cell spreading/migration assays, proteomics\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic deletion with defined phenotype, proteomic adhesome analysis, co-IP for binding partner, multiple orthogonal methods\",\n      \"pmids\": [\"28536193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Epb41l5 is a substrate for the E3 ubiquitin ligase Mind bomb 1 (Mib1), which ubiquitylates Epb41l5 to promote its degradation. DeltaD competes with Epb41l5 for Mib1, such that high Delta levels stabilize Epb41l5 in neural progenitor cells. Loss of Epb41l5 delays delamination and neuronal differentiation in zebrafish hindbrain, an effect rescued by N-cadherin knockdown.\",\n      \"method\": \"Zebrafish genetic knockdown/overexpression, ubiquitylation assays, competition assays (Delta vs Epb41l5 for Mib1), epistasis with N-cadherin knockdown\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct ubiquitylation assay identifying Mib1 as E3 ligase, genetic epistasis in zebrafish, competition experiment, multiple orthogonal methods\",\n      \"pmids\": [\"27510968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TGFβ1 induces EPB41L5 expression via Smad-dependent signaling (phospho-Smad3 recruitment to EPB41L5 promoter). EPB41L5 promotes gastric cancer cell migration and invasion through interaction with p120-catenin; p120-catenin knockdown abolishes EPB41L5-enhanced metastasis, and anti-EPB41L5 monoclonal antibody blocks EPB41L5-p120-catenin association.\",\n      \"method\": \"ChIP (phospho-Smad3 at EPB41L5 promoter), co-immunoprecipitation (EPB41L5-p120-catenin), siRNA knockdown, antibody blockade, in vivo lung metastasis mouse model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for transcriptional regulation, co-IP for binding, in vivo model with antibody rescue, single lab\",\n      \"pmids\": [\"30814110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EPB41L5 forms a complex with IQCB1 (NPHP5); EPB41L5 overexpression reduces IQCB1 localization at the ciliary base while knockdown increases it. Epb41l5-deficient zebrafish embryos develop cilia with reduced motility and left-right patterning defects. EPB41L5 also decreases the IQCB1-CEP290 interaction, regulating the composition of the ciliary base and centrosome.\",\n      \"method\": \"Co-immunoprecipitation (EPB41L5-IQCB1, IQCB1-CEP290), overexpression/knockdown in cultured epithelial cells, zebrafish morpholino knockdown, genetic synergy analysis, fluorescence microscopy of ciliary base\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, loss- and gain-of-function in two systems (cells and zebrafish), genetic epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"32501287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of EPB41L5 in podocytes impairs extracellular matrix assembly, causing diminished deposition of core GBM components including LAMA5. EPB41L5 recruits PDLIM5 and ACTN4 to integrin adhesion complexes; its loss causes insufficient maturation of integrin adhesion sites, impaired force transmission, and defective ECM assembly.\",\n      \"method\": \"EPB41L5 knockout podocytes (in vitro and in vivo), quantitative proteomics of secretome/matrisome, integrin adhesome proteomics (mass spectrometry), traction force microscopy\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — quantitative proteomics with KO controls, in vitro and in vivo models, traction force microscopy, multiple orthogonal methods\",\n      \"pmids\": [\"33761352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EPB41L5 promotes EMT, proliferation, migration, and invasion in esophageal squamous cell carcinoma through activation of ERK/p38 MAPK signaling pathway phosphorylation.\",\n      \"method\": \"siRNA knockdown, overexpression in ESCC cells, nude mouse xenograft model, Western blotting for ERK/p38 phosphorylation, in vitro migration/invasion assays\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional KD/OE with defined signaling readout and in vivo model, pathway placement via inhibitor/phospho-Western, single lab\",\n      \"pmids\": [\"34784520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The transcription factor ZBTB7A directly binds to the EPB41L5 gene promoter to repress its transcription, thereby suppressing glioblastoma progression; ZBTB7A depletion induces EPB41L5 expression and promotes GBM progression.\",\n      \"method\": \"ChIP (ZBTB7A binding to EPB41L5 promoter), RNA sequencing, siRNA knockdown of ZBTB7A, overexpression experiments, in vivo tumor growth assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence for transcriptional regulation, supported by loss-of-function and RNA-seq, single lab\",\n      \"pmids\": [\"36596853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The ARF6-AMAP1-EPB41L5 axis and ZEB1 are required for both mesenchymal-type and amoeboid-type cancer cell invasion, indicating EPB41L5 participates in a core mesenchymal program necessary for both modes of invasion regardless of RhoA vs Rac1 activity.\",\n      \"method\": \"siRNA knockdown, overexpression, invasion assays under different matrix conditions, pharmacological inhibition of receptor tyrosine kinase and GPCR signaling\",\n      \"journal\": \"Small GTPases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function experiments in multiple invasion mode contexts, single lab, extends prior Co-IP findings for the complex\",\n      \"pmids\": [\"27754741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-184, when expressed following promoter demethylation, directly targets EPB41L5 mRNA to suppress its expression, thereby downregulating Notch signaling and inhibiting EMT, migration, and invasion in colorectal cancer cells.\",\n      \"method\": \"5-Aza demethylation treatment, bisulfite sequencing (methylation status), qRT-PCR/Western blotting, luciferase reporter assays (miR-184 targeting EPB41L5), functional migration/invasion assays\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — luciferase reporter validates direct miR-184/EPB41L5 targeting, functional assays performed, single lab single study\",\n      \"pmids\": [\"40342066\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EPB41L5 is a FERM-domain adaptor protein that operates at the interface of cell-cell adhesion and cell-matrix adhesion: its FERM domain binds p120-catenin (displacing it from E-cadherin to promote cadherin endocytosis into Rab5+ vesicles), Crumbs homologs, and MPP5/PALS1 (anchoring it to the apical polarity complex), while its C-terminus binds paxillin and AMAP1 to enhance focal adhesion maturation and ARF6-driven invasion; EPB41L5 recruits ARHGEF18 to control RhoA/actomyosin contractility and recruits PDLIM5/ACTN4 to integrin adhesion complexes for force transmission and ECM assembly in podocytes; it is ubiquitylated by Mib1 (competitively stabilized by Delta) to coordinate neuronal delamination, and it regulates ciliary function by modulating IQCB1-CEP290 composition at the ciliary base; its transcription is induced by TGFβ/Smad3 and ZEB1, and repressed by ZBTB7A, placing EPB41L5 as a central effector of EMT and mesenchymal invasiveness across multiple cell types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EPB41L5 is a FERM-domain adaptor protein that couples cell-cell adhesion, cell-matrix adhesion, and apical polarity, functioning as a central effector of epithelial-mesenchymal transition (EMT) and mesenchymal invasiveness [#0, #2]. Through its N-terminal FERM domain it binds p120-catenin, displacing it from E-cadherin and driving E-cadherin internalization into Rab5-positive endocytic vesicles, while its C-terminus binds paxillin to stimulate focal adhesion formation [#0]. The same FERM domain anchors EPB41L5 to the apical Crumbs polarity complex by binding the Crumbs intracellular domains and the HOOK domain of MPP5/PALS1, with its overexpression disrupting tight-junction organization [#1]. At integrin adhesion sites it recruits the RhoGEF ARHGEF18 to control actomyosin contractility and focal adhesion maturation, and recruits PDLIM5 and ACTN4 to enable force transmission and extracellular matrix assembly; loss of EPB41L5 in podocytes causes impaired GBM/LAMA5 deposition, proteinuria, podocyte detachment, and focal segmental glomerulosclerosis [#3, #7]. EPB41L5 also acts in invasion through the ARF6-AMAP1 pathway, binding AMAP1 to drive mesenchymal- and amoeboid-type invasion, metastasis, and drug resistance [#2, #10]. In neural progenitors it is a substrate of the E3 ligase Mib1, whose ubiquitylation targets it for degradation but is competitively antagonized by Delta, coordinating delamination and neuronal differentiation via N-cadherin [#4], and it regulates ciliary base composition by binding IQCB1/NPHP5 and modulating the IQCB1-CEP290 interaction, affecting cilia motility and left-right patterning [#6]. EPB41L5 transcription is induced by TGF\\u03b21/Smad3 and ZEB1, repressed by ZBTB7A, and suppressed post-transcriptionally by miR-184, integrating it into EMT and invasion programs across gastric, breast, esophageal, colorectal, and glioblastoma cancers [#2, #5, #9, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that EPB41L5 is part of the apical Crumbs polarity machinery defined its earliest mechanistic role in epithelial organization.\",\n      \"evidence\": \"Co-IP, domain mapping, and overexpression in polarized MDCK cells\",\n      \"pmids\": [\"17920587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without in vivo polarity loss-of-function\", \"Functional consequence shown only by overexpression disruption, not endogenous depletion\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying the dual FERM-p120-catenin and C-terminal-paxillin interactions revealed how a single adaptor simultaneously dismantles adherens junctions and builds focal adhesions during EMT.\",\n      \"evidence\": \"siRNA knockdown, reciprocal co-IP with domain mapping, Rab5-vesicle microscopy, and mouse mutants\",\n      \"pmids\": [\"18794329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of E-cadherin endocytic trafficking downstream of Rab5 not resolved\", \"Structural basis of FERM-p120ctn binding not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking EPB41L5 to the ARF6-AMAP1 invasion pathway and ZEB1 induction placed it within a defined transcription-to-invasion axis in cancer.\",\n      \"evidence\": \"Co-IP for EPB41L5-AMAP1, siRNA/overexpression, ZEB1 induction, and TCGA correlation in breast cancer\",\n      \"pmids\": [\"27617643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface with AMAP1 not mapped\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing EPB41L5 is a Mib1 ubiquitylation substrate antagonized by Delta connected its stability to Notch-ligand dynamics and neuronal delamination.\",\n      \"evidence\": \"Zebrafish knockdown/overexpression, ubiquitylation and Mib1-competition assays, N-cadherin epistasis\",\n      \"pmids\": [\"27510968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitylation sites on Epb41l5 not identified\", \"Whether mammalian EPB41L5 is regulated identically not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining EPB41L5 recruitment of ARHGEF18 to control actomyosin contractility and the FSGS phenotype of podocyte knockout established its in vivo role in adhesion maturation and glomerular integrity.\",\n      \"evidence\": \"Conditional KO mouse, iTRAQ adhesome proteomics, co-IP, and migration assays\",\n      \"pmids\": [\"28536193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EPB41L5 spatially targets ARHGEF18 to the leading edge not detailed\", \"Direct GEF activation mechanism not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating the ARF6-AMAP1-EPB41L5-ZEB1 axis operates in both mesenchymal and amoeboid invasion positioned EPB41L5 as a core invasion-program component independent of RhoA/Rac1 mode.\",\n      \"evidence\": \"siRNA/overexpression invasion assays under varying matrix and pharmacological conditions\",\n      \"pmids\": [\"27754741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic distinction between invasion modes not resolved at molecular level\", \"Single-lab extension of prior complex findings\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapping TGF\\u03b21/Smad3 induction of EPB41L5 and the p120-catenin-dependent metastasis it drives connected upstream EMT signaling to the adaptor's pro-metastatic output.\",\n      \"evidence\": \"ChIP for phospho-Smad3, co-IP, antibody blockade, and lung metastasis mouse model in gastric cancer\",\n      \"pmids\": [\"30814110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Generality of antibody blockade across tumor types untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying the EPB41L5-IQCB1 complex and its modulation of IQCB1-CEP290 revealed a role at the ciliary base governing cilia motility and left-right patterning.\",\n      \"evidence\": \"Reciprocal co-IP, overexpression/knockdown in epithelial cells, zebrafish morpholino, and ciliary-base microscopy\",\n      \"pmids\": [\"32501287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EPB41L5 mechanistically displaces IQCB1 from the ciliary base not resolved\", \"Relationship between ciliary and adhesion functions unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining recruitment of PDLIM5 and ACTN4 to integrin adhesions and the resulting matrix-assembly defect linked EPB41L5 to force transmission and basement-membrane production.\",\n      \"evidence\": \"Podocyte KO, secretome/matrisome and adhesome proteomics, and traction force microscopy\",\n      \"pmids\": [\"33761352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding hierarchy among PDLIM5/ACTN4/integrin not fully ordered\", \"Mechanism connecting adhesion maturation to LAMA5 secretion not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connecting EPB41L5 to ERK/p38 MAPK activation in esophageal carcinoma added a signaling readout to its pro-EMT and pro-invasion phenotype.\",\n      \"evidence\": \"siRNA/overexpression, xenograft model, and phospho-Western for ERK/p38 in ESCC\",\n      \"pmids\": [\"34784520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAPK activation is direct or downstream of adhesion changes not resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying ZBTB7A as a direct transcriptional repressor of EPB41L5 added a tumor-suppressive control point in glioblastoma.\",\n      \"evidence\": \"ChIP for ZBTB7A at the EPB41L5 promoter, RNA-seq, knockdown/overexpression, and in vivo tumor assays\",\n      \"pmids\": [\"36596853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Interplay with ZEB1/Smad3 inputs at the promoter not examined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing miR-184 directly targets EPB41L5 mRNA following promoter demethylation added a post-transcriptional, epigenetically-gated brake on Notch-driven EMT.\",\n      \"evidence\": \"5-Aza demethylation, bisulfite sequencing, luciferase reporter, and migration/invasion assays in colorectal cancer\",\n      \"pmids\": [\"40342066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab single-study evidence\", \"How EPB41L5 loss feeds back on Notch signaling mechanistically not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how EPB41L5's distinct interaction modules (junctional, focal-adhesion, polarity, and ciliary) are selectively engaged and spatially partitioned within a single cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating FERM and C-terminal interactions\", \"No data on how upstream signals switch EPB41L5 between adhesion, polarity, and ciliary functions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 6, 7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 5, 8, 9, 11]}\n    ],\n    \"complexes\": [\"Crumbs polarity complex\", \"integrin adhesion complex\"],\n    \"partners\": [\"CTNND1\", \"PALS1\", \"CRB3\", \"PXN\", \"ARHGEF18\", \"AMAP1\", \"PDLIM5\", \"ACTN4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}