{"gene":"EPB41L5","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2008,"finding":"EPB41L5 binds p120-catenin through its N-terminal FERM domain, inhibiting p120ctn-E-cadherin binding, and causes E-cadherin relocalization into Rab5-positive endosomal vesicles; simultaneously, EPB41L5 binds paxillin through its C-terminus, enhancing integrin/paxillin association and stimulating focal adhesion formation during EMT.","method":"siRNA knockdown, co-immunoprecipitation, domain-mapping pulldown, fluorescence microscopy with Rab5-positive vesicle marker, mouse gastrulation mutant analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (co-IP, domain mutagenesis, in vivo mutant, cell imaging) in a single rigorous study; foundational mechanism paper","pmids":["18794329"],"is_preprint":false},{"year":2007,"finding":"EPB41L5 FERM domain associates with the intracellular domains of all three Crumbs homologs and with the HOOK domain of MPP5/PALS1, forming a conserved Crumbs-MPP5-EPB41L5 polarity complex; overexpression in polarized MDCK cells disrupts tight junction markers ZO-1 and PATJ.","method":"Co-immunoprecipitation, co-expression and co-localization studies, domain-mapping, overexpression in MDCK cells with tight junction marker analysis","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP with domain mapping and functional overexpression phenotype; moderate evidence from single lab with multiple methods","pmids":["17920587"],"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, cell spreading, and migration; EPB41L5 is a podocyte-specific focal adhesome component identified by iTRAQ-based mass spectrometry, and its genetic deletion causes severe proteinuria and focal segmental glomerulosclerosis.","method":"Podocyte-specific genetic knockout (Epb41l5 deletion), iTRAQ-based mass spectrometry of focal adhesome, co-immunoprecipitation for ARHGEF18 binding, cell spreading/migration assays, in vivo mouse model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO with defined in vivo phenotype plus mass spectrometry and co-IP identification of ARHGEF18 as binding partner; multiple orthogonal methods","pmids":["28536193"],"is_preprint":false},{"year":2016,"finding":"ZEB1 transcription factor induces EPB41L5 expression in cancer cells; EPB41L5 is an integral component of the ARF6-AMAP1 invasion pathway by directly binding AMAP1, driving mesenchymal-type invasion, metastasis, and drug resistance in breast cancer.","method":"Co-immunoprecipitation for EPB41L5-AMAP1 binding, ZEB1 overexpression/knockdown, gene expression correlation with TCGA RNAseq data, invasion/metastasis assays","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP for binding plus functional invasion assays, single lab but multiple methods","pmids":["27617643"],"is_preprint":false},{"year":2016,"finding":"EPB41L5 is a substrate of the E3 ubiquitin ligase Mind bomb 1 (Mib1), which ubiquitylates EPB41L5 to promote its degradation; DeltaD competes with EPB41L5 for Mib1 binding, thereby stabilizing EPB41L5 in neural progenitor cells specified as neurons; EPB41L5 facilitates disassembly of N-cadherin-dependent adherens junctions to enable neuronal delamination and differentiation in zebrafish hindbrain.","method":"Genetic epistasis in zebrafish (epb41l5 morpholino knockdown, N-cadherin knockdown rescue), ubiquitylation assay, substrate-ligase competition assay, in vivo imaging","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 — ubiquitylation assay establishing Mib1 as E3 ligase for EPB41L5 plus genetic epistasis rescue in vivo; moderate-strong evidence","pmids":["27510968"],"is_preprint":false},{"year":2021,"finding":"EPB41L5 recruits PDLIM5 and ACTN4 to integrin adhesion complexes (IACs) in podocytes; loss of EPB41L5 results in insufficient maturation of integrin adhesion sites, impaired force transmission, and diminished deposition of core glomerular basement membrane components (including LAMA5), leading to podocyte detachment.","method":"EPB41L5 knockout in vitro and in vivo models, quantitative proteomics of secretome/matrisome (iTRAQ), integrin adhesome proteomics, traction force microscopy","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — quantitative proteomics plus force measurements plus in vivo KO phenotype; multiple orthogonal methods in single study","pmids":["33761352"],"is_preprint":false},{"year":2019,"finding":"TGFβ1 induces EPB41L5 expression via Smad-dependent signaling with phospho-Smad3 recruitment to the EPB41L5 promoter; EPB41L5 promotes gastric cancer metastasis through interaction with p120-catenin, and anti-EPB41L5 monoclonal antibody blocks the EPB41L5-p120-catenin association and reverses metastasis.","method":"ChIP for phospho-Smad3 at EPB41L5 promoter, co-immunoprecipitation of EPB41L5 with p120-catenin, p120-catenin siRNA knockdown epistasis, anti-EPB41L5 antibody treatment in nude mouse metastasis model","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP establishing transcriptional mechanism plus co-IP plus in vivo epistasis; single lab with multiple orthogonal methods","pmids":["30814110"],"is_preprint":false},{"year":2020,"finding":"EPB41L5 forms a protein complex with IQCB1 (NPHP5), a ciliopathy protein; EPB41L5 overexpression reduces IQCB1 localization at the ciliary base, while EPB41L5 knockdown increases it; EPB41L5 also decreases the IQCB1-CEP290 interaction; loss of epb41l5 in zebrafish causes cilia with reduced motility and left-right patterning defects, revealing a role in regulating ciliary base composition.","method":"Co-immunoprecipitation of EPB41L5-IQCB1 complex, fluorescence microscopy of IQCB1 at ciliary base upon EPB41L5 overexpression/knockdown, zebrafish morpholino knockdown with cilia motility and laterality phenotype, genetic interaction analysis with iqcb1","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus localization experiment plus in vivo genetic phenotype in zebrafish; single lab with multiple methods","pmids":["32501287"],"is_preprint":false},{"year":2017,"finding":"The ARF6-AMAP1-EPB41L5 mesenchymal axis (induced by ZEB1) is required not only for mesenchymal-type but also for amoeboid-type cancer cell invasion, demonstrating that EPB41L5 functions downstream of both RhoA and Rac1 invasion programs.","method":"siRNA knockdown of pathway components, amoeboid and mesenchymal invasion assays, receptor tyrosine kinase and GPCR signaling perturbations","journal":"Small GTPases","confidence":"Medium","confidence_rationale":"Tier 3 — functional invasion assays with pathway knockdown; single lab, moderate mechanistic detail","pmids":["27754741"],"is_preprint":false},{"year":2021,"finding":"Exosomal lnc-MMP2-2 acts as a competing endogenous RNA (ceRNA) sponge for miR-1207-5p, relieving miR-1207-5p-mediated repression of EPB41L5, thereby increasing blood-brain barrier permeability and promoting NSCLC brain metastasis.","method":"Luciferase reporter assay, RNA pulldown assay, Ago2 RNA immunoprecipitation, endothelial monolayer permeability assay, mouse brain metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple RNA-binding assays (luciferase, pulldown, RIP) plus in vivo model; single lab","pmids":["34285192"],"is_preprint":false},{"year":2021,"finding":"EPB41L5 promotes EMT in esophageal squamous cell carcinoma through activation of the ERK/p38 MAPK signaling pathway, as measured by phosphorylation of ERK and p38.","method":"EPB41L5 knockdown/overexpression in ESCC cells, Western blot for phospho-ERK/p38, in vivo nude mouse xenograft model","journal":"Pathology, research and practice","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single signaling readout without direct biochemical mechanism linking EPB41L5 to MAPK activation","pmids":["34784520"],"is_preprint":false},{"year":2023,"finding":"ZBTB7A transcription factor directly binds the EPB41L5 gene promoter to transcriptionally repress EPB41L5 expression, thereby suppressing glioblastoma progression and metastasis.","method":"RNA sequencing after ZBTB7A depletion, chromatin immunoprecipitation (ChIP) of ZBTB7A at EPB41L5 promoter, ZBTB7A knockdown/overexpression with EPB41L5 expression readout","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP establishing direct promoter binding plus functional knockdown data; single lab","pmids":["36596853"],"is_preprint":false}],"current_model":"EPB41L5 is a FERM-domain adaptor protein that functions at the interface of cell-cell and cell-matrix adhesion: its FERM domain binds Crumbs homologs, MPP5/PALS1, and p120-catenin (displacing E-cadherin for endosomal degradation via Rab5 vesicles), while its C-terminus binds paxillin and AMAP1 to promote focal adhesion maturation; in podocytes it recruits ARHGEF18 to activate actomyosin contractility and recruits PDLIM5/ACTN4 to integrin adhesion complexes to control force transmission and ECM assembly; EPB41L5 expression is induced downstream of TGFβ/Smad3 and ZEB1 to drive EMT, and it is subject to ubiquitylation by the E3 ligase Mib1, which targets it for degradation and is counteracted by Delta/Notch signaling to coordinate neuronal delamination."},"narrative":{"teleology":[{"year":2007,"claim":"Identifying EPB41L5 as a component of the Crumbs polarity complex established its first known molecular interactions and linked it to epithelial junction regulation.","evidence":"Co-immunoprecipitation with domain mapping in MDCK cells showing FERM domain binds Crumbs intracellular domains and MPP5/PALS1 HOOK domain; overexpression disrupts ZO-1 and PATJ at tight junctions","pmids":["17920587"],"confidence":"High","gaps":["Endogenous stoichiometry of the Crumbs-MPP5-EPB41L5 complex not determined","Loss-of-function effect on tight junctions not tested"]},{"year":2008,"claim":"Demonstrating that EPB41L5 simultaneously dismantles cadherin adhesions and promotes integrin adhesions revealed a dual-arm mechanism for EMT execution through a single adaptor.","evidence":"Co-IP and domain mapping show FERM domain binds p120-catenin (displacing E-cadherin to Rab5+ endosomes) and C-terminus binds paxillin (enhancing integrin/paxillin association); validated in mouse gastrulation mutants","pmids":["18794329"],"confidence":"High","gaps":["Kinetic relationship between cadherin loss and focal adhesion gain not resolved","Whether EPB41L5 directly enters Rab5 vesicles or acts catalytically is unclear"]},{"year":2016,"claim":"Discovery that Mib1 ubiquitylates EPB41L5 for degradation—counteracted by Delta competition—revealed a post-translational switch coordinating Notch signaling with junction disassembly during neuronal delamination.","evidence":"Ubiquitylation assay in zebrafish; DeltaD-Mib1 competition stabilizes EPB41L5; genetic epistasis with N-cadherin knockdown rescues delamination defects","pmids":["27510968"],"confidence":"High","gaps":["Specific ubiquitylation sites on EPB41L5 not mapped","Whether Mib1-mediated regulation operates in mammalian systems not tested"]},{"year":2016,"claim":"Placing EPB41L5 downstream of ZEB1 and within the ARF6-AMAP1 invasion axis connected EMT transcription factor programs to a specific membrane-trafficking mechanism for cancer cell invasion.","evidence":"Co-IP of EPB41L5-AMAP1 binding; ZEB1 overexpression/knockdown controls EPB41L5 levels; functional invasion and metastasis assays in breast cancer cells","pmids":["27617643","27754741"],"confidence":"Medium","gaps":["Direct ZEB1 binding to EPB41L5 promoter not shown by ChIP in this study","AMAP1 binding domain on EPB41L5 not precisely mapped"]},{"year":2017,"claim":"Identifying EPB41L5 as a podocyte-specific adhesome component that recruits ARHGEF18 linked it to actomyosin contractility control and provided an in vivo disease model (FSGS) for its adhesion-maturation function.","evidence":"Podocyte-specific Epb41l5 knockout in mice causes proteinuria and FSGS; iTRAQ mass spectrometry of focal adhesome; co-IP confirms ARHGEF18 recruitment","pmids":["28536193"],"confidence":"High","gaps":["Whether ARHGEF18 activation is direct or scaffolded through additional factors is unresolved","Human EPB41L5 mutations in FSGS patients not reported"]},{"year":2019,"claim":"ChIP demonstration that phospho-Smad3 binds the EPB41L5 promoter established TGFβ as a direct transcriptional inducer, completing the signaling axis from ligand to junction remodeling.","evidence":"ChIP for phospho-Smad3 at EPB41L5 promoter; anti-EPB41L5 antibody blocks p120-catenin interaction and reverses gastric cancer metastasis in mouse model","pmids":["30814110"],"confidence":"Medium","gaps":["Smad3 binding site in the EPB41L5 promoter not finely mapped","Relative contributions of ZEB1 versus Smad3 to EPB41L5 induction not disentangled"]},{"year":2020,"claim":"Finding that EPB41L5 regulates IQCB1 localization at the ciliary base and cilia motility expanded its functional repertoire beyond adhesion to ciliary biology.","evidence":"Co-IP of EPB41L5-IQCB1; overexpression reduces IQCB1 at ciliary base; zebrafish morpholino knockdown causes laterality defects and reduced cilia motility","pmids":["32501287"],"confidence":"Medium","gaps":["Mechanism by which EPB41L5 displaces IQCB1 from CEP290 is unclear","Whether ciliary role is conserved in mammals not established"]},{"year":2021,"claim":"Proteomics and traction force microscopy in podocytes showed that EPB41L5 recruits PDLIM5 and ACTN4 to integrin adhesion complexes, directly controlling mechanical force transmission and ECM assembly.","evidence":"EPB41L5 KO with iTRAQ-based adhesome and matrisome proteomics; traction force microscopy shows reduced force; loss of LAMA5 deposition and podocyte detachment","pmids":["33761352"],"confidence":"High","gaps":["Direct binding interfaces between EPB41L5 and PDLIM5/ACTN4 not structurally resolved","Whether force-transmission role extends beyond podocytes not tested"]},{"year":2023,"claim":"Identification of ZBTB7A as a direct transcriptional repressor of EPB41L5 added a negative regulatory arm to the transcriptional control of this adaptor.","evidence":"ChIP of ZBTB7A at EPB41L5 promoter; ZBTB7A knockdown increases EPB41L5 expression and promotes glioblastoma progression","pmids":["36596853"],"confidence":"Medium","gaps":["ZBTB7A binding site relative to Smad3/ZEB1 elements not mapped","Whether ZBTB7A regulation is context-specific to glioblastoma not clarified"]},{"year":null,"claim":"No high-resolution structural model of the EPB41L5 FERM domain in complex with any of its partners exists, and the molecular basis for how a single adaptor simultaneously coordinates cadherin endocytosis, integrin adhesion maturation, and ciliary base regulation remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal/cryo-EM structure of EPB41L5 or its complexes","Relative affinities for p120-catenin, paxillin, AMAP1, and IQCB1 not quantitatively compared","In vivo separation-of-function alleles distinguishing adhesion versus ciliary roles not generated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1,4,6]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,3]}],"complexes":["Crumbs-MPP5-EPB41L5 polarity complex","ARF6-AMAP1-EPB41L5 invasion complex"],"partners":["CTNND1","PXN","MPP5","AMAP1","ARHGEF18","PDLIM5","ACTN4","IQCB1"],"other_free_text":[]},"mechanistic_narrative":"EPB41L5 is a FERM-domain adaptor protein that orchestrates the switch between cell-cell adhesion and cell-matrix adhesion during epithelial-mesenchymal transition, neuronal delamination, and podocyte foot process maintenance. Its N-terminal FERM domain binds p120-catenin to displace E-cadherin into Rab5-positive endosomes for degradation and associates with Crumbs homologs and MPP5/PALS1 to regulate apical polarity, while its C-terminus engages paxillin and AMAP1 to promote integrin-based focal adhesion maturation and mesenchymal invasion [PMID:18794329, PMID:17920587, PMID:27617643]. In podocytes, EPB41L5 recruits ARHGEF18 to activate actomyosin contractility and assembles PDLIM5/ACTN4 at integrin adhesion complexes for force transmission and glomerular basement membrane deposition; its genetic deletion causes focal segmental glomerulosclerosis [PMID:28536193, PMID:33761352]. EPB41L5 expression is transcriptionally induced by TGFβ/Smad3 and ZEB1 and repressed by ZBTB7A, and the protein is targeted for ubiquitin-dependent degradation by the E3 ligase Mib1, a process antagonized by Delta/Notch signaling during neuronal differentiation [PMID:30814110, PMID:27617643, PMID:36596853, PMID:27510968]."},"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":89,"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":25,"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":9490,"output_tokens":3315,"usd":0.039098},"stage2":{"model":"claude-opus-4-6","input_tokens":6664,"output_tokens":2791,"usd":0.154642},"total_usd":0.19374,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","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, inhibiting p120ctn-E-cadherin binding, and causes E-cadherin relocalization into Rab5-positive endosomal vesicles; simultaneously, EPB41L5 binds paxillin through its C-terminus, enhancing integrin/paxillin association and stimulating focal adhesion formation during EMT.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, domain-mapping pulldown, fluorescence microscopy with Rab5-positive vesicle marker, mouse gastrulation mutant analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (co-IP, domain mutagenesis, in vivo mutant, cell imaging) in a single rigorous study; foundational mechanism paper\",\n      \"pmids\": [\"18794329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EPB41L5 FERM domain associates with the intracellular domains of all three Crumbs homologs and with the HOOK domain of MPP5/PALS1, forming a conserved Crumbs-MPP5-EPB41L5 polarity complex; overexpression in polarized MDCK cells disrupts tight junction markers ZO-1 and PATJ.\",\n      \"method\": \"Co-immunoprecipitation, co-expression and co-localization studies, domain-mapping, overexpression in MDCK cells with tight junction marker analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with domain mapping and functional overexpression phenotype; moderate evidence from single lab with multiple methods\",\n      \"pmids\": [\"17920587\"],\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, cell spreading, and migration; EPB41L5 is a podocyte-specific focal adhesome component identified by iTRAQ-based mass spectrometry, and its genetic deletion causes severe proteinuria and focal segmental glomerulosclerosis.\",\n      \"method\": \"Podocyte-specific genetic knockout (Epb41l5 deletion), iTRAQ-based mass spectrometry of focal adhesome, co-immunoprecipitation for ARHGEF18 binding, cell spreading/migration assays, in vivo mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO with defined in vivo phenotype plus mass spectrometry and co-IP identification of ARHGEF18 as binding partner; multiple orthogonal methods\",\n      \"pmids\": [\"28536193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZEB1 transcription factor induces EPB41L5 expression in cancer cells; EPB41L5 is an integral component of the ARF6-AMAP1 invasion pathway by directly binding AMAP1, driving mesenchymal-type invasion, metastasis, and drug resistance in breast cancer.\",\n      \"method\": \"Co-immunoprecipitation for EPB41L5-AMAP1 binding, ZEB1 overexpression/knockdown, gene expression correlation with TCGA RNAseq data, invasion/metastasis assays\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP for binding plus functional invasion assays, single lab but multiple methods\",\n      \"pmids\": [\"27617643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EPB41L5 is a substrate of the E3 ubiquitin ligase Mind bomb 1 (Mib1), which ubiquitylates EPB41L5 to promote its degradation; DeltaD competes with EPB41L5 for Mib1 binding, thereby stabilizing EPB41L5 in neural progenitor cells specified as neurons; EPB41L5 facilitates disassembly of N-cadherin-dependent adherens junctions to enable neuronal delamination and differentiation in zebrafish hindbrain.\",\n      \"method\": \"Genetic epistasis in zebrafish (epb41l5 morpholino knockdown, N-cadherin knockdown rescue), ubiquitylation assay, substrate-ligase competition assay, in vivo imaging\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ubiquitylation assay establishing Mib1 as E3 ligase for EPB41L5 plus genetic epistasis rescue in vivo; moderate-strong evidence\",\n      \"pmids\": [\"27510968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EPB41L5 recruits PDLIM5 and ACTN4 to integrin adhesion complexes (IACs) in podocytes; loss of EPB41L5 results in insufficient maturation of integrin adhesion sites, impaired force transmission, and diminished deposition of core glomerular basement membrane components (including LAMA5), leading to podocyte detachment.\",\n      \"method\": \"EPB41L5 knockout in vitro and in vivo models, quantitative proteomics of secretome/matrisome (iTRAQ), integrin adhesome proteomics, traction force microscopy\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — quantitative proteomics plus force measurements plus in vivo KO phenotype; multiple orthogonal methods in single study\",\n      \"pmids\": [\"33761352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TGFβ1 induces EPB41L5 expression via Smad-dependent signaling with phospho-Smad3 recruitment to the EPB41L5 promoter; EPB41L5 promotes gastric cancer metastasis through interaction with p120-catenin, and anti-EPB41L5 monoclonal antibody blocks the EPB41L5-p120-catenin association and reverses metastasis.\",\n      \"method\": \"ChIP for phospho-Smad3 at EPB41L5 promoter, co-immunoprecipitation of EPB41L5 with p120-catenin, p120-catenin siRNA knockdown epistasis, anti-EPB41L5 antibody treatment in nude mouse metastasis model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP establishing transcriptional mechanism plus co-IP plus in vivo epistasis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30814110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EPB41L5 forms a protein complex with IQCB1 (NPHP5), a ciliopathy protein; EPB41L5 overexpression reduces IQCB1 localization at the ciliary base, while EPB41L5 knockdown increases it; EPB41L5 also decreases the IQCB1-CEP290 interaction; loss of epb41l5 in zebrafish causes cilia with reduced motility and left-right patterning defects, revealing a role in regulating ciliary base composition.\",\n      \"method\": \"Co-immunoprecipitation of EPB41L5-IQCB1 complex, fluorescence microscopy of IQCB1 at ciliary base upon EPB41L5 overexpression/knockdown, zebrafish morpholino knockdown with cilia motility and laterality phenotype, genetic interaction analysis with iqcb1\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus localization experiment plus in vivo genetic phenotype in zebrafish; single lab with multiple methods\",\n      \"pmids\": [\"32501287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The ARF6-AMAP1-EPB41L5 mesenchymal axis (induced by ZEB1) is required not only for mesenchymal-type but also for amoeboid-type cancer cell invasion, demonstrating that EPB41L5 functions downstream of both RhoA and Rac1 invasion programs.\",\n      \"method\": \"siRNA knockdown of pathway components, amoeboid and mesenchymal invasion assays, receptor tyrosine kinase and GPCR signaling perturbations\",\n      \"journal\": \"Small GTPases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional invasion assays with pathway knockdown; single lab, moderate mechanistic detail\",\n      \"pmids\": [\"27754741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Exosomal lnc-MMP2-2 acts as a competing endogenous RNA (ceRNA) sponge for miR-1207-5p, relieving miR-1207-5p-mediated repression of EPB41L5, thereby increasing blood-brain barrier permeability and promoting NSCLC brain metastasis.\",\n      \"method\": \"Luciferase reporter assay, RNA pulldown assay, Ago2 RNA immunoprecipitation, endothelial monolayer permeability assay, mouse brain metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple RNA-binding assays (luciferase, pulldown, RIP) plus in vivo model; single lab\",\n      \"pmids\": [\"34285192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EPB41L5 promotes EMT in esophageal squamous cell carcinoma through activation of the ERK/p38 MAPK signaling pathway, as measured by phosphorylation of ERK and p38.\",\n      \"method\": \"EPB41L5 knockdown/overexpression in ESCC cells, Western blot for phospho-ERK/p38, in vivo nude mouse xenograft model\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single signaling readout without direct biochemical mechanism linking EPB41L5 to MAPK activation\",\n      \"pmids\": [\"34784520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZBTB7A transcription factor directly binds the EPB41L5 gene promoter to transcriptionally repress EPB41L5 expression, thereby suppressing glioblastoma progression and metastasis.\",\n      \"method\": \"RNA sequencing after ZBTB7A depletion, chromatin immunoprecipitation (ChIP) of ZBTB7A at EPB41L5 promoter, ZBTB7A knockdown/overexpression with EPB41L5 expression readout\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP establishing direct promoter binding plus functional knockdown data; single lab\",\n      \"pmids\": [\"36596853\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EPB41L5 is a FERM-domain adaptor protein that functions at the interface of cell-cell and cell-matrix adhesion: its FERM domain binds Crumbs homologs, MPP5/PALS1, and p120-catenin (displacing E-cadherin for endosomal degradation via Rab5 vesicles), while its C-terminus binds paxillin and AMAP1 to promote focal adhesion maturation; in podocytes it recruits ARHGEF18 to activate actomyosin contractility and recruits PDLIM5/ACTN4 to integrin adhesion complexes to control force transmission and ECM assembly; EPB41L5 expression is induced downstream of TGFβ/Smad3 and ZEB1 to drive EMT, and it is subject to ubiquitylation by the E3 ligase Mib1, which targets it for degradation and is counteracted by Delta/Notch signaling to coordinate neuronal delamination.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EPB41L5 is a FERM-domain adaptor protein that orchestrates the switch between cell-cell adhesion and cell-matrix adhesion during epithelial-mesenchymal transition, neuronal delamination, and podocyte foot process maintenance. Its N-terminal FERM domain binds p120-catenin to displace E-cadherin into Rab5-positive endosomes for degradation and associates with Crumbs homologs and MPP5/PALS1 to regulate apical polarity, while its C-terminus engages paxillin and AMAP1 to promote integrin-based focal adhesion maturation and mesenchymal invasion [PMID:18794329, PMID:17920587, PMID:27617643]. In podocytes, EPB41L5 recruits ARHGEF18 to activate actomyosin contractility and assembles PDLIM5/ACTN4 at integrin adhesion complexes for force transmission and glomerular basement membrane deposition; its genetic deletion causes focal segmental glomerulosclerosis [PMID:28536193, PMID:33761352]. EPB41L5 expression is transcriptionally induced by TGFβ/Smad3 and ZEB1 and repressed by ZBTB7A, and the protein is targeted for ubiquitin-dependent degradation by the E3 ligase Mib1, a process antagonized by Delta/Notch signaling during neuronal differentiation [PMID:30814110, PMID:27617643, PMID:36596853, PMID:27510968].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying EPB41L5 as a component of the Crumbs polarity complex established its first known molecular interactions and linked it to epithelial junction regulation.\",\n      \"evidence\": \"Co-immunoprecipitation with domain mapping in MDCK cells showing FERM domain binds Crumbs intracellular domains and MPP5/PALS1 HOOK domain; overexpression disrupts ZO-1 and PATJ at tight junctions\",\n      \"pmids\": [\"17920587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous stoichiometry of the Crumbs-MPP5-EPB41L5 complex not determined\", \"Loss-of-function effect on tight junctions not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that EPB41L5 simultaneously dismantles cadherin adhesions and promotes integrin adhesions revealed a dual-arm mechanism for EMT execution through a single adaptor.\",\n      \"evidence\": \"Co-IP and domain mapping show FERM domain binds p120-catenin (displacing E-cadherin to Rab5+ endosomes) and C-terminus binds paxillin (enhancing integrin/paxillin association); validated in mouse gastrulation mutants\",\n      \"pmids\": [\"18794329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetic relationship between cadherin loss and focal adhesion gain not resolved\", \"Whether EPB41L5 directly enters Rab5 vesicles or acts catalytically is unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that Mib1 ubiquitylates EPB41L5 for degradation—counteracted by Delta competition—revealed a post-translational switch coordinating Notch signaling with junction disassembly during neuronal delamination.\",\n      \"evidence\": \"Ubiquitylation assay in zebrafish; DeltaD-Mib1 competition stabilizes EPB41L5; genetic epistasis with N-cadherin knockdown rescues delamination defects\",\n      \"pmids\": [\"27510968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ubiquitylation sites on EPB41L5 not mapped\", \"Whether Mib1-mediated regulation operates in mammalian systems not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placing EPB41L5 downstream of ZEB1 and within the ARF6-AMAP1 invasion axis connected EMT transcription factor programs to a specific membrane-trafficking mechanism for cancer cell invasion.\",\n      \"evidence\": \"Co-IP of EPB41L5-AMAP1 binding; ZEB1 overexpression/knockdown controls EPB41L5 levels; functional invasion and metastasis assays in breast cancer cells\",\n      \"pmids\": [\"27617643\", \"27754741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ZEB1 binding to EPB41L5 promoter not shown by ChIP in this study\", \"AMAP1 binding domain on EPB41L5 not precisely mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying EPB41L5 as a podocyte-specific adhesome component that recruits ARHGEF18 linked it to actomyosin contractility control and provided an in vivo disease model (FSGS) for its adhesion-maturation function.\",\n      \"evidence\": \"Podocyte-specific Epb41l5 knockout in mice causes proteinuria and FSGS; iTRAQ mass spectrometry of focal adhesome; co-IP confirms ARHGEF18 recruitment\",\n      \"pmids\": [\"28536193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARHGEF18 activation is direct or scaffolded through additional factors is unresolved\", \"Human EPB41L5 mutations in FSGS patients not reported\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ChIP demonstration that phospho-Smad3 binds the EPB41L5 promoter established TGFβ as a direct transcriptional inducer, completing the signaling axis from ligand to junction remodeling.\",\n      \"evidence\": \"ChIP for phospho-Smad3 at EPB41L5 promoter; anti-EPB41L5 antibody blocks p120-catenin interaction and reverses gastric cancer metastasis in mouse model\",\n      \"pmids\": [\"30814110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Smad3 binding site in the EPB41L5 promoter not finely mapped\", \"Relative contributions of ZEB1 versus Smad3 to EPB41L5 induction not disentangled\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Finding that EPB41L5 regulates IQCB1 localization at the ciliary base and cilia motility expanded its functional repertoire beyond adhesion to ciliary biology.\",\n      \"evidence\": \"Co-IP of EPB41L5-IQCB1; overexpression reduces IQCB1 at ciliary base; zebrafish morpholino knockdown causes laterality defects and reduced cilia motility\",\n      \"pmids\": [\"32501287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which EPB41L5 displaces IQCB1 from CEP290 is unclear\", \"Whether ciliary role is conserved in mammals not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Proteomics and traction force microscopy in podocytes showed that EPB41L5 recruits PDLIM5 and ACTN4 to integrin adhesion complexes, directly controlling mechanical force transmission and ECM assembly.\",\n      \"evidence\": \"EPB41L5 KO with iTRAQ-based adhesome and matrisome proteomics; traction force microscopy shows reduced force; loss of LAMA5 deposition and podocyte detachment\",\n      \"pmids\": [\"33761352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interfaces between EPB41L5 and PDLIM5/ACTN4 not structurally resolved\", \"Whether force-transmission role extends beyond podocytes not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of ZBTB7A as a direct transcriptional repressor of EPB41L5 added a negative regulatory arm to the transcriptional control of this adaptor.\",\n      \"evidence\": \"ChIP of ZBTB7A at EPB41L5 promoter; ZBTB7A knockdown increases EPB41L5 expression and promotes glioblastoma progression\",\n      \"pmids\": [\"36596853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ZBTB7A binding site relative to Smad3/ZEB1 elements not mapped\", \"Whether ZBTB7A regulation is context-specific to glioblastoma not clarified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structural model of the EPB41L5 FERM domain in complex with any of its partners exists, and the molecular basis for how a single adaptor simultaneously coordinates cadherin endocytosis, integrin adhesion maturation, and ciliary base regulation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal/cryo-EM structure of EPB41L5 or its complexes\", \"Relative affinities for p120-catenin, paxillin, AMAP1, and IQCB1 not quantitatively compared\", \"In vivo separation-of-function alleles distinguishing adhesion versus ciliary roles not generated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 4, 6]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 3]}\n    ],\n    \"complexes\": [\n      \"Crumbs-MPP5-EPB41L5 polarity complex\",\n      \"ARF6-AMAP1-EPB41L5 invasion complex\"\n    ],\n    \"partners\": [\n      \"CTNND1\",\n      \"PXN\",\n      \"MPP5\",\n      \"AMAP1\",\n      \"ARHGEF18\",\n      \"PDLIM5\",\n      \"ACTN4\",\n      \"IQCB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}