Affinage

EPB41L5

Band 4.1-like protein 5 · UniProt Q9HCM4

Length
733 aa
Mass
81.9 kDa
Annotated
2026-04-28
15 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 High

    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

    PMID:17920587

    Open questions at the time
    • Endogenous stoichiometry of the Crumbs-MPP5-EPB41L5 complex not determined
    • Loss-of-function effect on tight junctions not tested
  2. 2008 High

    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

    PMID:18794329

    Open questions at the time
    • Kinetic relationship between cadherin loss and focal adhesion gain not resolved
    • Whether EPB41L5 directly enters Rab5 vesicles or acts catalytically is unclear
  3. 2016 High

    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

    PMID:27510968

    Open questions at the time
    • Specific ubiquitylation sites on EPB41L5 not mapped
    • Whether Mib1-mediated regulation operates in mammalian systems not tested
  4. 2016 Medium

    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

    PMID:27617643 PMID:27754741

    Open questions at the time
    • Direct ZEB1 binding to EPB41L5 promoter not shown by ChIP in this study
    • AMAP1 binding domain on EPB41L5 not precisely mapped
  5. 2017 High

    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

    PMID:28536193

    Open questions at the time
    • Whether ARHGEF18 activation is direct or scaffolded through additional factors is unresolved
    • Human EPB41L5 mutations in FSGS patients not reported
  6. 2019 Medium

    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

    PMID:30814110

    Open questions at the time
    • Smad3 binding site in the EPB41L5 promoter not finely mapped
    • Relative contributions of ZEB1 versus Smad3 to EPB41L5 induction not disentangled
  7. 2020 Medium

    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

    PMID:32501287

    Open questions at the time
    • Mechanism by which EPB41L5 displaces IQCB1 from CEP290 is unclear
    • Whether ciliary role is conserved in mammals not established
  8. 2021 High

    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

    PMID:33761352

    Open questions at the time
    • Direct binding interfaces between EPB41L5 and PDLIM5/ACTN4 not structurally resolved
    • Whether force-transmission role extends beyond podocytes not tested
  9. 2023 Medium

    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

    PMID:36596853

    Open questions at the time
    • ZBTB7A binding site relative to Smad3/ZEB1 elements not mapped
    • Whether ZBTB7A regulation is context-specific to glioblastoma not clarified

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005886 plasma membrane 3 GO:0005929 cilium 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1500931 Cell-Cell communication 4 R-HSA-162582 Signal Transduction 2 R-HSA-1474244 Extracellular matrix organization 1
Partners
ACTN4AMAP1ARHGEF18CTNND1IQCB1MPP5PDLIM5PXN
Complex memberships
ARF6-AMAP1-EPB41L5 invasion complexCrumbs-MPP5-EPB41L5 polarity complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 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. siRNA knockdown, co-immunoprecipitation, domain-mapping pulldown, fluorescence microscopy with Rab5-positive vesicle marker, mouse gastrulation mutant analysis The Journal of cell biology High 18794329
2007 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. Co-immunoprecipitation, co-expression and co-localization studies, domain-mapping, overexpression in MDCK cells with tight junction marker analysis Experimental cell research High 17920587
2017 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. 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 Proceedings of the National Academy of Sciences of the United States of America High 28536193
2016 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. Co-immunoprecipitation for EPB41L5-AMAP1 binding, ZEB1 overexpression/knockdown, gene expression correlation with TCGA RNAseq data, invasion/metastasis assays Oncogenesis Medium 27617643
2016 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. Genetic epistasis in zebrafish (epb41l5 morpholino knockdown, N-cadherin knockdown rescue), ubiquitylation assay, substrate-ligase competition assay, in vivo imaging Development (Cambridge, England) High 27510968
2021 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. EPB41L5 knockout in vitro and in vivo models, quantitative proteomics of secretome/matrisome (iTRAQ), integrin adhesome proteomics, traction force microscopy Cell reports High 33761352
2019 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. 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 Clinical cancer research Medium 30814110
2020 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. 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 of cell science Medium 32501287
2017 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. siRNA knockdown of pathway components, amoeboid and mesenchymal invasion assays, receptor tyrosine kinase and GPCR signaling perturbations Small GTPases Medium 27754741
2021 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. Luciferase reporter assay, RNA pulldown assay, Ago2 RNA immunoprecipitation, endothelial monolayer permeability assay, mouse brain metastasis model Cell death & disease Medium 34285192
2021 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. EPB41L5 knockdown/overexpression in ESCC cells, Western blot for phospho-ERK/p38, in vivo nude mouse xenograft model Pathology, research and practice Low 34784520
2023 ZBTB7A transcription factor directly binds the EPB41L5 gene promoter to transcriptionally repress EPB41L5 expression, thereby suppressing glioblastoma progression and metastasis. RNA sequencing after ZBTB7A depletion, chromatin immunoprecipitation (ChIP) of ZBTB7A at EPB41L5 promoter, ZBTB7A knockdown/overexpression with EPB41L5 expression readout Experimental & molecular medicine Medium 36596853

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 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. Cell death & disease 89 34285192
2008 EPB41L5 functions to post-transcriptionally regulate cadherin and integrin during epithelial-mesenchymal transition. The Journal of cell biology 77 18794329
2017 The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier. Proceedings of the National Academy of Sciences of the United States of America 60 28536193
2007 FERM protein EPB41L5 is a novel member of the mammalian CRB-MPP5 polarity complex. Experimental cell research 54 17920587
2020 Circ-EPB41L5 regulates the host gene EPB41L5 via sponging miR-19a to repress glioblastoma tumorigenesis. Aging 41 31905344
2016 ZEB1 induces EPB41L5 in the cancer mesenchymal program that drives ARF6-based invasion, metastasis and drug resistance. Oncogenesis 37 27617643
2019 EPB41L5 Mediates TGFβ-Induced Metastasis of Gastric Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 29 30814110
2021 EPB41L5 controls podocyte extracellular matrix assembly by adhesome-dependent force transmission. Cell reports 25 33761352
2016 Epb41l5 competes with Delta as a substrate for Mib1 to coordinate specification and differentiation of neurons. Development (Cambridge, England) 17 27510968
2023 ZBTB7A suppresses glioblastoma tumorigenesis through the transcriptional repression of EPB41L5. Experimental & molecular medicine 14 36596853
2021 EPB41L5 promotes EMT through the ERK/p38 MAPK signaling pathway in esophageal squamous cell carcinoma. Pathology, research and practice 14 34784520
2017 Arf6 and its ZEB1-EPB41L5 mesenchymal axis are required for both mesenchymal- and amoeboid-type invasion of cancer cells. Small GTPases 8 27754741
2020 Epb41l5 interacts with Iqcb1 and regulates ciliary function in zebrafish embryos. Journal of cell science 3 32501287
2019 EPB41L5 is Associated With the Metastatic Potential of Low-grade Pancreatic Neuroendocrine Tumors. Cancer genomics & proteomics 3 31467225
2025 Demethylated miR-184 regulates EPB41L5 and downregulates Notch signaling to inhibit metastasis in colorectal cancer. Journal of molecular histology 0 40342066