Affinage

EPB41L5

Band 4.1-like protein 5 · UniProt Q9HCM4

Length
733 aa
Mass
81.9 kDa
Annotated
2026-06-09
15 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2007 Medium

    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

    PMID:17920587

    Open questions at the time
    • Single-lab finding without in vivo polarity loss-of-function
    • Functional consequence shown only by overexpression disruption, not endogenous depletion
  2. 2008 High

    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

    PMID:18794329

    Open questions at the time
    • Mechanism of E-cadherin endocytic trafficking downstream of Rab5 not resolved
    • Structural basis of FERM-p120ctn binding not defined
  3. 2016 Medium

    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

    PMID:27617643

    Open questions at the time
    • Direct binding interface with AMAP1 not mapped
    • Single-lab evidence
  4. 2016 High

    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

    PMID:27510968

    Open questions at the time
    • Ubiquitylation sites on Epb41l5 not identified
    • Whether mammalian EPB41L5 is regulated identically not addressed
  5. 2017 High

    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

    PMID:28536193

    Open questions at the time
    • How EPB41L5 spatially targets ARHGEF18 to the leading edge not detailed
    • Direct GEF activation mechanism not shown
  6. 2017 Medium

    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

    PMID:27754741

    Open questions at the time
    • Mechanistic distinction between invasion modes not resolved at molecular level
    • Single-lab extension of prior complex findings
  7. 2019 Medium

    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

    PMID:30814110

    Open questions at the time
    • Single-lab study
    • Generality of antibody blockade across tumor types untested
  8. 2020 High

    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

    PMID:32501287

    Open questions at the time
    • How EPB41L5 mechanistically displaces IQCB1 from the ciliary base not resolved
    • Relationship between ciliary and adhesion functions unclear
  9. 2021 High

    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

    PMID:33761352

    Open questions at the time
    • Direct binding hierarchy among PDLIM5/ACTN4/integrin not fully ordered
    • Mechanism connecting adhesion maturation to LAMA5 secretion not detailed
  10. 2021 Medium

    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

    PMID:34784520

    Open questions at the time
    • Whether MAPK activation is direct or downstream of adhesion changes not resolved
    • Single-lab study
  11. 2023 Medium

    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

    PMID:36596853

    Open questions at the time
    • Single-lab study
    • Interplay with ZEB1/Smad3 inputs at the promoter not examined
  12. 2025 Medium

    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

    PMID:40342066

    Open questions at the time
    • Single-lab single-study evidence
    • How EPB41L5 loss feeds back on Notch signaling mechanistically not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 2 R-HSA-1474244 Extracellular matrix organization 2
Partners
ACTN4AMAP1ARHGEF18CRB3CTNND1PALS1PDLIM5PXN
Complex memberships
Crumbs polarity complexintegrin adhesion 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, 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. siRNA knockdown, co-immunoprecipitation, domain mapping, fluorescence microscopy (Rab5-positive vesicle localization), mouse genetic mutant analysis The Journal of cell biology High 18794329
2007 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. Co-immunoprecipitation, co-expression, co-localization studies, domain mapping, overexpression in polarized MDCK cells Experimental cell research Medium 17920587
2016 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. Co-immunoprecipitation (EPB41L5-AMAP1 binding), siRNA knockdown, overexpression, TCGA RNAseq correlation, ZEB1 induction experiments in cancer and normal cells Oncogenesis Medium 27617643
2017 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. Conditional knockout mouse model, iTRAQ-based mass spectrometry of focal adhesome, co-immunoprecipitation (EPB41L5-ARHGEF18), cell spreading/migration assays, proteomics Proceedings of the National Academy of Sciences of the United States of America High 28536193
2016 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. Zebrafish genetic knockdown/overexpression, ubiquitylation assays, competition assays (Delta vs Epb41l5 for Mib1), epistasis with N-cadherin knockdown Development (Cambridge, England) High 27510968
2019 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. ChIP (phospho-Smad3 at EPB41L5 promoter), co-immunoprecipitation (EPB41L5-p120-catenin), siRNA knockdown, antibody blockade, in vivo lung metastasis mouse model Clinical cancer research Medium 30814110
2020 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. Co-immunoprecipitation (EPB41L5-IQCB1, IQCB1-CEP290), overexpression/knockdown in cultured epithelial cells, zebrafish morpholino knockdown, genetic synergy analysis, fluorescence microscopy of ciliary base Journal of cell science High 32501287
2021 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. EPB41L5 knockout podocytes (in vitro and in vivo), quantitative proteomics of secretome/matrisome, integrin adhesome proteomics (mass spectrometry), traction force microscopy Cell reports High 33761352
2021 EPB41L5 promotes EMT, proliferation, migration, and invasion in esophageal squamous cell carcinoma through activation of ERK/p38 MAPK signaling pathway phosphorylation. siRNA knockdown, overexpression in ESCC cells, nude mouse xenograft model, Western blotting for ERK/p38 phosphorylation, in vitro migration/invasion assays Pathology, research and practice Medium 34784520
2023 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. ChIP (ZBTB7A binding to EPB41L5 promoter), RNA sequencing, siRNA knockdown of ZBTB7A, overexpression experiments, in vivo tumor growth assays Experimental & molecular medicine Medium 36596853
2017 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. siRNA knockdown, overexpression, invasion assays under different matrix conditions, pharmacological inhibition of receptor tyrosine kinase and GPCR signaling Small GTPases Medium 27754741
2025 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. 5-Aza demethylation treatment, bisulfite sequencing (methylation status), qRT-PCR/Western blotting, luciferase reporter assays (miR-184 targeting EPB41L5), functional migration/invasion assays Journal of molecular histology Medium 40342066

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 91 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 27 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

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