Affinage

EPS8

Epidermal growth factor receptor kinase substrate 8 · UniProt Q12929

Length
822 aa
Mass
91.9 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EPS8 is a multifunctional actin regulatory protein and RTK signaling adaptor that integrates receptor tyrosine kinase activation with cytoskeletal remodeling, receptor trafficking, and cell motility. As a direct EGFR substrate that binds the receptor juxtamembrane domain in a phosphotyrosine-independent manner, EPS8 assembles with Abi1 and Sos-1 into a trimeric complex possessing Rac-specific GEF activity downstream of Ras, with PI3K recruitment through p85 further unmasking this activity (PMID:10499589, PMID:12515821). The C-terminal effector domain caps actin barbed ends with nanomolar affinity in an auto-inhibited manner relieved by Abi1, while EPS8 also bundles actin filaments synergistically with IRSp53; MAPK phosphorylation at S624/T628 toggles the capping-to-bundling balance to regulate filopodia formation, cortical tension, and bleb-based migration (PMID:15558031, PMID:17115031, PMID:19564905, PMID:26163656). These dual actin activities underpin EPS8's roles in stereocilia elongation as part of the MyoXVa–whirlin–Eps8 tip complex (whose assembly involves liquid–liquid phase separation), in dendritic spine morphogenesis and LTP-dependent synaptic plasticity, in dendritic cell chemotactic migration, and in cell-cycle progression through SCF(Fbxw5)-mediated G2 degradation (PMID:21526224, PMID:33626355, PMID:23685357, PMID:21835647, PMID:23314863).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1993 High

    The identity of EPS8 as a novel EGFR kinase substrate was unknown; its cloning revealed a tyrosine-phosphorylated protein that associates with EGFR and amplifies EGF-dependent mitogenic signaling, establishing EPS8 as an RTK effector.

    Evidence In vivo phosphorylation assay, co-immunoprecipitation, and overexpression mitogenesis in fibroblasts/hematopoietic cells

    PMID:8404850

    Open questions at the time
    • Mechanism of EGFR association was unclear given lack of SH2 domain
    • Downstream signaling pathway not identified
  2. 1995 High

    How EPS8 binds EGFR without SH2 domains was resolved: EPS8 directly engages the EGFR juxtamembrane region through a phosphotyrosine-independent mechanism, defining a novel mode of RTK-substrate interaction.

    Evidence In vitro direct binding assay with EGFR juxtamembrane fragments and EGFR mutagenesis

    PMID:7532293

    Open questions at the time
    • Structural basis of juxtamembrane binding not determined
    • Relevance to other RTKs unknown
  3. 1997 High

    How EPS8 engages downstream effectors was addressed by identification of Abi1/E3B1 and RN-tre as SH3 domain binding partners, and the crystal structure of the SH3 domain revealed an unusual strand-exchange dimer suggesting oligomerization-dependent signaling.

    Evidence SH3 domain library screen, co-immunoprecipitation, X-ray crystallography of SH3 domain dimer

    PMID:8700527 PMID:9010225 PMID:9303002

    Open questions at the time
    • Functional significance of SH3 dimerization for signaling output not tested
    • How Abi1 vs. RN-tre binding is regulated was unknown
  4. 1999 High

    The central question of how EPS8 connects RTK signaling to cytoskeletal remodeling was answered: EPS8, Abi1, and Sos-1 form a trimeric complex with Rac-specific GEF activity, placing EPS8 in the Ras-to-Rac signaling axis.

    Evidence In vivo co-immunoprecipitation of tri-complex, in vitro Rac-GEF reconstitution assay, genetic epistasis

    PMID:10499589

    Open questions at the time
    • How GEF activity is regulated remained unclear
    • Whether EPS8 has direct actin-modifying activity was unknown
  5. 2000 High

    Competition between Abi1/Sos-1 and RN-tre for EPS8's SH3 domain was shown to switch EPS8 function between Rac-GEF signaling and Rab5-GAP-dependent inhibition of EGFR endocytosis, establishing EPS8 as a molecular switch coordinating signaling with receptor trafficking.

    Evidence Co-immunoprecipitation, in vitro Rab5-GAP assay, EGFR internalization assay

    PMID:11099046

    Open questions at the time
    • Signals determining the Abi1/Sos-1 vs. RN-tre choice not identified
    • Whether this switch operates in non-EGFR contexts unknown
  6. 2003 High

    The question of how the trimeric Rac-GEF complex is activated was resolved: PI3K/p85 is recruited via Abi1, and both p85 binding and PIP3 production are required to unmask Rac-GEF activity, linking lipid signaling to Rac activation through EPS8.

    Evidence In vitro GEF reconstitution with purified components, genetic validation in p85-null cells

    PMID:12515821

    Open questions at the time
    • Structural basis of PIP3-mediated unmasking not determined
    • Whether other PIP species contribute was untested
  7. 2004 High

    A direct actin-regulatory activity of EPS8 was discovered: the C-terminal effector domain caps actin barbed ends with nanomolar affinity, and this activity is auto-inhibited in full-length EPS8 but relieved by Abi1 binding, revealing EPS8 as a regulated actin capper beyond its adaptor roles.

    Evidence In vitro barbed-end capping kinetics, domain mapping and mutagenesis, loss-of-function in cells, conserved in C. elegans genetics

    PMID:15558031 PMID:15558032

    Open questions at the time
    • Whether capping and Rac-GEF activities are coordinated in the same cell remained unclear
    • Bundling activity not yet recognized
  8. 2006 High

    EPS8 was found to possess a second actin activity—crosslinking/bundling—that synergizes with IRSp53 under Cdc42 control to drive filopodia formation, establishing EPS8 as a dual actin regulator (capping and bundling) with distinct morphological outputs.

    Evidence In vitro actin bundling assay, siRNA knockdown, Cdc42-dependent filopodia quantification

    PMID:17115031

    Open questions at the time
    • How capping vs. bundling are differentially regulated was unknown
    • In vivo significance of bundling vs. capping not separated
  9. 2006 High

    EPS8's role extended beyond epithelial/fibroblast contexts to the nervous system: EPS8 was shown to be part of the NMDA receptor complex at postsynaptic sites, and Eps8-null mice exhibited abnormal NMDA currents and altered ethanol sensitivity, establishing a neuronal function.

    Evidence Co-immunoprecipitation from brain, electrophysiology in Eps8-null mice, actin remodeling assays in neurons

    PMID:17018287

    Open questions at the time
    • Precise molecular role of EPS8 in NMDA receptor complex (capping vs. scaffolding) not distinguished
    • Behavioral consequences beyond ethanol sensitivity not explored
  10. 2009 High

    MAPK-dependent phosphorylation at S624/T628 was identified as the switch between capping and bundling: phosphorylation inhibits barbed-end capping, permitting BDNF-induced filopodia in hippocampal neurons, resolving how extracellular signals toggle EPS8's dual actin activities.

    Evidence Phosphosite mutagenesis (phosphomimetic and non-phosphorylatable), rescue experiments in primary hippocampal neurons, MAPK inhibition

    PMID:19564905

    Open questions at the time
    • Whether this phospho-switch operates in non-neuronal cells was untested
    • Structural mechanism of phosphorylation-induced capping inhibition unknown
  11. 2011 High

    EPS8's essential role in hearing was established: Eps8-null mice are profoundly deaf due to failure of stereocilia elongation, and EPS8 was shown to function at stereocilia tips as part of a MyoXVa–whirlin–Eps8 complex where MyoXVa delivers EPS8 to barbed ends.

    Evidence Knockout mouse audiological and electrophysiological phenotyping, co-immunoprecipitation, localization in MyoXVa-deficient mice

    PMID:21236676 PMID:21526224

    Open questions at the time
    • Relative contributions of capping vs. bundling to stereocilia elongation not separated
    • Whether EPS8 loss in humans causes deafness was not shown
  12. 2012 High

    EPS8's actin-capping activity was shown to control dendritic spine morphogenesis and LTP: loss of EPS8 accelerates actin turnover at spines, prevents spine enlargement during plasticity, and reduces mushroom spine density, mechanistically linking barbed-end capping to synaptic plasticity.

    Evidence Genetic KO and RNAi, FRAP of actin in spines, free-barbed-end assay, electrophysiology (LTP recording), spine morphometry

    PMID:23392693 PMID:23685357

    Open questions at the time
    • Whether capping-independent functions of EPS8 also contribute to spine plasticity not excluded
    • Upstream signals controlling EPS8 at synapses during LTP not identified
  13. 2013 High

    Cell-cycle regulation of EPS8 was uncovered: SCF(Fbxw5) ubiquitin ligase degrades EPS8 specifically in G2 phase; failure to degrade EPS8 delays cortical retraction and prometaphase entry, while EPS8 capping activity prevents blebbing during cytokinesis.

    Evidence In vivo ubiquitination assay, cell-cycle synchronization, Eps8 stability measurements, capping-defective mutant analysis, live-cell imaging

    PMID:23314863

    Open questions at the time
    • How Fbxw5 recognizes EPS8 (degron identity) not mapped
    • Whether other Eps8 family members compensate in mitosis unknown
  14. 2015 High

    Erk phosphorylation was shown to differentially regulate EPS8 capping and bundling in confined migration: bundling activity generates cortex tension for leader bleb formation, while capping organizes actin within blebs, and these activities act antagonistically, enabling bleb-based motility under non-adhesive conditions.

    Evidence Erk FRET biosensor, capping-defective and bundling-defective EPS8 mutants, AFM cortex tension measurement, live imaging under confinement

    PMID:26163656

    Open questions at the time
    • Whether the capping-bundling antagonism operates in physiological confined migration in vivo not tested
  15. 2015 High

    EPS8 was found to couple actin dynamics to transcriptional regulation at endothelial junctions: EPS8 associates with VE-cadherin at remodeling junctions to promote YAP nuclear translocation, while at stable junctions EPS8 is excluded and 14-3-3/YAP replaces it, controlling vascular permeability.

    Evidence Co-immunoprecipitation with VE-cadherin, YAP reporter assay, Eps8-null mouse vascular permeability

    PMID:26668327

    Open questions at the time
    • Whether EPS8's actin activities directly or indirectly regulate YAP not resolved
    • Mechanism of EPS8 exclusion from stable junctions unknown
  16. 2021 High

    The biophysical mechanism of the stereocilia tip complex was advanced: whirlin–Myo15–Eps8 undergoes liquid–liquid phase separation to form condensates that efficiently promote actin bundling, and a deafness-causing Myo15 mutation disrupts condensate formation.

    Evidence In vitro phase-separation reconstitution with purified proteins, actin bundling assay, disease-variant mutagenesis

    PMID:33626355

    Open questions at the time
    • Whether phase separation occurs in vivo at stereocilia tips not demonstrated
    • How condensate properties are regulated physiologically unknown
  17. 2022 High

    Bacterial pathogens exploit EPS8 actin-regulatory activities: Chlamydia effector TepP hijacks EPS8 to disassemble tight junctions enabling secondary invasion, while EPEC effector kinases NleH1/NleH2 phosphorylate Eps8 at S775 to inhibit its bundling activity at attaching-effacing lesions.

    Evidence EPS8 KO cells/organoids with TepP sufficiency assay, in vivo infection model; crystal structure of Eps8 SH3–NleH peptide, in vitro kinase and bundling assays

    PMID:35976880 PMID:36395759

    Open questions at the time
    • Whether other tight junction components are co-targeted with EPS8 by TepP not fully characterized
    • Structural basis of S775 phosphorylation inhibiting bundling not determined
  18. 2023 Medium

    EPS8 was identified as a positive effector of tunnelling nanotube (TNT) formation: upon Arp2/3 inhibition, EPS8 interaction with IRSp53 increases, and this complex drives linear actin polymerization to form TNTs, revealing a context where branched-network suppression redirects EPS8 to intercellular conduits.

    Evidence Micropatterning, optical tweezers, proteomic analysis of EPS8 interactome, Arp2/3 inhibition, live microscopy

    PMID:38009333

    Open questions at the time
    • Whether EPS8 capping or bundling activity specifically drives TNT elongation not resolved
    • Physiological contexts of TNT formation dependent on EPS8 not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: what structural basis underlies the auto-inhibition of capping and its release by Abi1; how EPS8's capping, bundling, and Rac-GEF scaffolding activities are spatiotemporally coordinated in single cells; and whether EPS8 mutations cause human deafness or other Mendelian disease.
  • No full-length EPS8 structure showing auto-inhibition mechanism
  • No human genetic disease linked to EPS8 mutations in the literature
  • Spatiotemporal coordination of multiple EPS8 activities in single cells not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 8 GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005856 cytoskeleton 5 GO:0005886 plasma membrane 2 GO:0005764 lysosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-112316 Neuronal System 3 R-HSA-168256 Immune System 2 R-HSA-1640170 Cell Cycle 1 R-HSA-392499 Metabolism of proteins 1
Partners
ABI1EGFRFBXW5IRSP53MYO15ARNTREUSH3BP5SOS1WHRN
Complex memberships
Eps8-Abi1-Sos1 Rac-GEF complexEps8-IRSp53 actin bundling complexEps8-RN-tre Rab5-GAP complexMyoXVa-whirlin-Eps8 stereocilia tip complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Eps8 is a substrate for the EGFR kinase; it is tyrosine-phosphorylated in vivo following EGF stimulation and associates with the EGFR despite lacking a functional SH2 domain. Overexpression of Eps8 in fibroblasts or hematopoietic cells expressing EGFR increased mitogenic response to EGF. In vivo phosphorylation assay, co-immunoprecipitation, adoptive expression/overexpression in cell lines The EMBO journal High 8404850
1995 Eps8 binds directly to the juxtamembrane region of EGFR through a non-SH2 domain by a mechanism that does not require phosphotyrosine residues, representing a novel RTK-substrate interaction modality. In vitro direct binding assay with EGFR juxtamembrane domain fragments, mutagenesis of EGFR Oncogene High 7532293
1995 Eps8 is constitutively tyrosine-phosphorylated in human tumor cell lines at stoichiometry similar to potent mitogenic EGF stimulation; overexpression of Eps8 transforms NIH 3T3 cells under limiting EGFR pathway activation. Eps8 associates in vivo with Shc, partly mediated by the SH3 domain of Eps8. Phosphotyrosine analysis, NIH 3T3 transformation assay, co-immunoprecipitation Molecular and cellular biology High 7791787
1996 RN-tre binds specifically and with high affinity (Kd 10^-8–10^-7 M) to the SH3 domain of Eps8 in vitro and associates stably with Eps8 in vivo. In vitro SH3 domain binding assay, co-immunoprecipitation Oncogene High 8700527
1997 The SH3 domain of Eps8 forms an intertwined dimer by strand exchange in its crystal structure, and intact Eps8 is multimeric in vivo, suggesting the SH3 domain functions as a dimerization motif. X-ray crystallography, co-immunoprecipitation Nature structural biology High 9303002
1997 E3B1 (Abi-1) was identified as an Eps8 SH3-domain binding protein; E3B1 associates with Eps8 in vivo and is a phosphoserine-containing protein whose hyperphosphorylated forms accumulate upon EGF stimulation. SH3 domain library screen, co-immunoprecipitation, phosphoamino acid analysis Oncogene High 9010225
1998 Eps8 localizes to the cell cortex, membrane ruffles, lamellipodia, and dynamic actin-rich structures upon cytoskeleton remodeling; a detergent-resistant pool of Eps8 is associated with podosomes in v-Src-transformed cells. Immunofluorescence, cell fractionation/detergent extraction, subcellular localization in response to serum/phorbol esters Experimental cell research Medium 9665816
1999 Eps8 and E3b1/Abi-1 transduce signals from Ras to Rac: Eps8, E3b1, and Sos-1 form a trimeric complex in vivo that exhibits Rac-specific GEF activity in vitro. In vivo co-immunoprecipitation of tri-complex, in vitro Rac-GEF activity assay, genetic epistasis Nature High 10499589
1999 Eps8 interacts with Dishevelled-1 (Dvl1) through the PDZ domain of Dvl1; in the presence of Eps8, Dvl1 is hyperphosphorylated, and in the presence of Dvl1, EGF-induced tyrosine phosphorylation of Eps8 is inhibited. Yeast two-hybrid screen, in vitro binding, co-transfection functional assays Biochemical and biophysical research communications Medium 10581192
2000 Eps8 connects EGFR signaling to receptor trafficking: through its SH3 domain, Eps8 binds RN-tre (a Rab5 GAP), and this interaction inhibits EGFR internalization and attenuates Rac signaling by diverting Eps8 from the E3b1/Sos-1 Rac-GEF complex. Thus Eps8 participates in both Rac signaling (via E3b1/Sos-1) and Rab5-mediated trafficking (via RN-tre) depending on its binding partner. Co-immunoprecipitation, in vitro Rab5-GAP assay, EGFR internalization assay, epistasis Nature High 11099046
2003 PI3K (via p85) is recruited into the Eps8-Abi1-Sos-1 complex through Abi1; both p85 recruitment and PIP3 (the PI3K product) concur to unmask the Rac-GEF activity of the complex in vitro and are required for Rac activation and actin remodeling in vivo. Co-immunoprecipitation, in vitro Rac-GEF assay, dominant-negative/loss-of-function in p85-null cells, colocalization The Journal of cell biology High 12515821
2003 Eps8 family members Eps8L1 and Eps8L2, but not Eps8L3, interact with Abi1 and Sos-1, activate Rac-GEF activity of Sos-1, bind actin, and rescue RTK-mediated actin remodeling in eps8-/- fibroblasts, revealing functional redundancy within the Ras/Rac pathway. Co-immunoprecipitation, Rac-GEF activity assay, rescue experiments in eps8-/- fibroblasts Molecular biology of the cell High 14565974
2004 Eps8 family proteins cap actin filament barbed ends; the isolated C-terminal effector domain of Eps8 caps barbed ends with nanomolar affinity in vitro. Full-length Eps8 is auto-inhibited, and interaction with Abi1 relieves this inhibition. In vivo, Eps8 is recruited to actin dynamic sites and its removal impairs actin-based propulsion. In vitro actin barbed-end capping assay (kinetics), mutagenesis, loss-of-function in cells, live imaging Nature cell biology High 15558031
2004 In C. elegans, the EPS-8A isoform has a novel actin barbed-end capping activity residing in its C-terminus that is required for proper apical morphogenesis in intestinal cells; EPS-8B lacks this activity. eps-8 is essential for embryonic development in the nematode. C. elegans genetics (null mutants, isoform-specific rescue), in vitro actin capping assay Nature cell biology High 15558032
2004 IRSp53 binds to Eps8 via its SH3 domain interacting with the N-terminal proline-rich sequence of Eps8; this complex synergistically activates Rac by reinforcing Eps8/Abi-1/Sos-1 GEF complex formation, and forms at the leading edge of motile cells as shown by FRET. Co-immunoprecipitation, pulldown, FRET, Rac activation assay, loss-of-function (motility/invasion inhibition) Cancer research High 15289329
2006 Eps8 has a novel actin-crosslinking/bundling activity; the Eps8-IRSp53 complex has synergistic actin bundling activity in vitro and enhances IRSp53-dependent membrane extensions in vivo. Cdc42 binds to and controls the cellular distribution of the IRSp53-Eps8 complex, and Cdc42-induced filopodia are inhibited by removal of either IRSp53 or Eps8. In vitro actin bundling assay, co-immunoprecipitation, loss-of-function (siRNA), live cell imaging, filopodia quantification Nature cell biology High 17115031
2006 Palladin directly interacts with Eps8 (identified by yeast two-hybrid and confirmed by co-immunoprecipitation); both proteins colocalize in dorsal ruffles, and palladin knockdown reduces ruffle formation and Rac activation after PDGF treatment. Yeast two-hybrid, co-immunoprecipitation, colocalization, RNAi knockdown with functional readouts Journal of cell science Medium 16868024
2006 Eps8 is localized to postsynaptic structures and is part of the NMDA receptor complex in neurons; Eps8 null mice show abnormal NMDA receptor currents and their sensitivity to inhibition by ethanol is reduced, and Eps8-null neurons are resistant to NMDA- and ethanol-induced actin remodeling. Co-immunoprecipitation (NMDA receptor complex), electrophysiology in null mice, actin remodeling assay Cell High 17018287
2009 LanCL1 (lanthionine synthetase C-like protein 1) specifically binds to the SH3 domain of Eps8 in vitro; LanCL1 mutants defective in Eps8 interaction inhibit NGF-induced neurite outgrowth. Crystal structure of LanCL1, in vitro affinity binding assay, mutagenesis with functional readout (neurite outgrowth) Genes & development High 19528316
2009 Eps8 is localized to actin-based cell junctions at the blood-testis barrier (BTB) and apical ectoplasmic specialization; RNAi knockdown of Eps8 in Sertoli cells causes F-actin disorganization and mislocalization of tight junction proteins occludin and ZO-1, disrupting BTB integrity. In vivo knockdown causes germ cell sloughing and BTB damage. RNAi knockdown, immunofluorescence/localization, in vivo animal model, permeability assay FASEB journal High 19293393
2009 Eps8 actin barbed-end capping activity is inhibited by BDNF treatment through MAPK-dependent phosphorylation of Eps8 at residues S624 and T628; a capping-defective Eps8 mutant fails to restore WT filopodia levels, and phosphomimetic (S624E/T628E) or non-phosphorylatable (S624A/T628A) mutants have opposite effects on BDNF-induced filopodia formation. Site-directed mutagenesis, primary hippocampal neuron cultures, loss-of-function rescue experiments, MAPK inhibition PLoS biology High 19564905
2010 The SOS1/EPS8/ABI1 tri-complex mediates LPA-induced Rac activation in ovarian cancer cells; integrity of this complex is required for LPA-stimulated cell migration and peritoneal metastatic colonization. ABI1 acts as a scaffold holding SOS1 and EPS8 together. Co-immunoprecipitation, Rac activation assay, knockdown of individual components, metastatic colonization assay in vivo Cancer research High 21118970
2010 Eps8 localizes to lysosomes in cancer cells via a region encompassing aa 184–535 that contains KFERQ-like motifs; Eps8 co-immunoprecipitates with Hsc70 and LAMP-2 and is a substrate for chaperone-mediated autophagy (CMA), with dynamic lysosomal membrane recruitment demonstrated by FRAP. Co-immunoprecipitation, in vitro lysosome binding/uptake assay, FRAP, fractionation, immunofluorescence Experimental cell research Medium 20184880
2011 Eps8 interacts with myosin XVa (MyoXVa) and whirlin at stereocilia tips; Eps8 fails to accumulate at stereocilia tips in MyoXVa-deficient mice, and overexpression of MyoXVa increases Eps8 tip localization and stereocilia elongation. MyoXVa and whirlin are required for Eps8 tip targeting, establishing a tip complex that regulates stereocilia length. Co-immunoprecipitation, knockout mouse analysis, overexpression rescue, fluorescence localization Current biology : CB High 21236676
2011 Eps8 is localized predominantly at stereocilia tips and is essential for their normal elongation; Eps8 knockout mice are profoundly deaf and inner hair cells fail to mature into functional sensory receptors. Knockout mouse model, immunolocalization, electrophysiology, audiological testing PLoS biology High 21526224
2011 Eps8 actin-capping activity is required for dendritic cell polarization and formation of elongated migratory protrusions; Eps8-deficient DCs are impaired in directional and chemotactic 3D migration in vitro and are delayed in reaching draining lymph nodes in vivo, rendering Eps8-null mice unable to mount a contact hypersensitivity response. Knockout mouse model, live 3D migration assays, in vivo skin sensitization model, actin cytoskeleton analysis Immunity High 21835647
2012 Eps8 controls actin barbed-end capping and spine morphogenesis; loss of Eps8 increases actin polymerization and fast actin turnover in dendritic spines, impairs spine enlargement during LTP, and reduces mushroom spine density. Eps8 capping activity is required for LTP-induced structural and functional synaptic plasticity. RNAi and genetic KO, free-barbed end assay, FRAP, electrophysiology, spine morphometry The EMBO journal High 23685357
2012 Eps8 interacts with the clathrin-mediated endocytosis machinery; Src-mediated phosphorylation of Eps8 mediates FGFR-stimulated clathrin-coated pit formation, and depletion of Eps8 inhibits FGFR trafficking and immediate Erk signaling. Live-cell imaging, siRNA depletion, phosphorylation assay, co-immunoprecipitation with endocytic machinery Journal of cell science Medium 23203811
2012 Ezrin differentially modulates the actin-capping and -bundling activities of Eps8 and Eps8L1a during microvillus assembly; coexpression of ezrin with Eps8 promotes membrane ruffles/microvilli tufts, while Eps8 bundling-defective mutants or ezrin-binding-defective mutants fail to induce these structures. Co-immunoprecipitation, overexpression with activity mutants, morphological quantification of microvilli Molecular biology of the cell Medium 22262457
2012 Eps8 facilitates LPS-stimulated macrophage phagocytosis by increasing TLR4-MyD88 protein interaction; Eps8 co-immunoprecipitates with TLR4, and overexpression of a truncated Eps8 lacking the pleckstrin homology domain decreases LPS-induced TLR4-MyD88 interaction and downstream Src, FAK, and p38 MAPK activation. Co-immunoprecipitation, confocal colocalization, dominant-negative truncation, RNAi, phagocytosis/bactericidal assay The Journal of biological chemistry Medium 22493489
2013 SCF(Fbxw5) ubiquitin E3 ligase mediates proteasomal degradation of Eps8 specifically in G2 phase; failure to degrade Eps8 prolongs its localization at the cell cortex, delays cell rounding and prometaphase entry. During late mitosis and cytokinesis, Eps8 capping activity is required to prevent membrane blebbing. In vivo ubiquitination assay, cell cycle synchronization, Eps8 stability assay, capping-defective mutant, live-cell imaging Nature cell biology High 23314863
2013 Activity-dependent Eps8 actin-capping function is required for spine morphogenesis: gain- and loss-of-function in rat hippocampal neurons show Eps8 promotes spine formation while inhibiting filopodia, and Eps8 loss-of-function impairs LTP-induced structural and functional plasticity. Gain/loss-of-function in primary neurons, FRAP, free-barbed end assay, electrophysiology The Journal of neuroscience High 23392693
2014 EPS8 is required for αvβ6 integrin-dependent Rac1 activation and cell migration; in complex with Abi1/Sos1, Eps8 switches the balance between Rac1 and Rho activation. Knockdown of Eps8 suppresses integrin-dependent cell movement while increasing αvβ6-dependent TGF-β1 activation through increased Rho-dependent cell tension. Co-immunoprecipitation, Rac1 GTP-pulldown assay, siRNA knockdown, GTPase activity assays The Journal of pathology Medium 28608476
2015 Erk phosphorylation of Eps8 inhibits its actin-capping activity; Eps8 bundling activity promotes cortex tension and intracellular pressure driving leader bleb formation, while capping and bundling activities act antagonistically within leader blebs to organize actin and drive bleb-based migration under non-adhesive confinement. Erk biosensor (FRET), Eps8 mutants (capping-defective, bundling-defective), atomic force microscopy for cortex tension, live-cell imaging eLife High 26163656
2015 EPS8 associates with the VE-cadherin complex at remodeling junctions and promotes YAP nuclear translocation and transcriptional activation; in stabilized junctions, EPS8 is excluded and 14-3-3-YAP associates with VE-cadherin, inhibiting YAP nuclear localization. Eps8-null mice show increased vascular permeability. Co-immunoprecipitation, imaging, knockout mouse vascular permeability assay, YAP reporter assay The Journal of cell biology High 26668327
2015 Eps8 directly interacts with Dvl1 (Dishevelled-1); Eps8 gain-of-function mimics Wnt-mediated axon remodeling, Eps8 silencing blocks Wnt3a-induced axon remodeling, and blockade of the Dvl1-Eps8 interaction abolishes Wnt3a-mediated axonal remodeling in DRG neurons. Yeast two-hybrid screen, loss-of-function/gain-of-function, interaction blockade, time-lapse imaging PloS one Medium 26252776
2017 PTK6 (Brk) phosphorylates Eps8 at Tyr497, Tyr524, and Tyr534; a phosphorylation-defective Eps8 3YF mutant reverts PTK6-mediated increases in cell proliferation, migration, and ERK/FAK phosphorylation. Proteomics identification of phosphosites, site-directed mutagenesis (3YF mutant), co-immunoprecipitation, functional cell assays Journal of cellular biochemistry Medium 28214294
2018 IRTKS (BAIAP2L1) promotes microvillar elongation partly through its SH3 domain recruiting the actin-bundling protein EPS8 to microvillar tips; super-resolution microscopy showed IRTKS localizes to actively growing microvillar tips. Super-resolution microscopy, live imaging, domain deletion/mutagenesis, overexpression Current biology : CB Medium 30197089
2019 EPS8 physically associates with incoming influenza A virion components and is specifically required for virion uncoating; loss of EPS8 significantly delays nuclear import of released ribonucleoprotein complexes without affecting virion attachment, uptake, or fusion. EPS8 knockout/overexpression, biochemical co-immunoprecipitation with viral components, nuclear import assay, FLUAV infection assay Cell reports High 31747592
2021 Whirlin-Myo15-Eps8 complex undergoes liquid-liquid phase separation to form TCD-like condensates that effectively promote actin bundling; a deafness-associated Myo15 mutation interferes with condensate formation and consequently impairs actin bundling. In vitro phase separation reconstitution, actin bundling assay, mutagenesis of disease-associated variant Cell reports High 33626355
2022 Chlamydia trachomatis effector TepP alters tyrosine phosphorylation of Eps8; TepP and EPS8 are necessary and sufficient to remodel tight junctions (disassemble them), promoting secondary invasion. Genetic deletion of EPS8 renders epithelial cells resistant to TepP-mediated tight junction remodeling. Genetic knockout (EPS8-/- cells and organoids), phosphoproteomics, sufficiency assay (TepP + EPS8 co-expression), in vivo murine infection model Cell host & microbe High 36395759
2022 EPEC effector kinases NleH1 and NleH2 phosphorylate Eps8 at Ser775 through interaction with the Eps8 SH3 domain via noncanonical PxxDY motifs; Ser775 phosphorylation hinders Eps8 bundling activity and drives Eps8 dispersal from the AE lesion during EPEC infection. Phosphoproteomics, in vitro kinase assay, crystal structure of Eps8 SH3 domain-peptide complex, bundling assay with phosphomimetic mutant Proceedings of the National Academy of Sciences of the United States of America High 35976880
2023 Eps8 is a positive effector of tunnelling nanotube (TNT) formation through linear actin polymerization; Eps8 exhibits heightened interaction with IRSp53 (I-BAR domain protein) upon Arp2/3 inhibition, forming a complex that drives TNT formation via linear actin growth rather than branched Arp2/3-dependent pathways. Micropatterning, optical tweezers, proteomic analysis of Eps8 interactome, Arp2/3 inhibition, live microscopy The EMBO journal Medium 38009333

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 EPS8 and E3B1 transduce signals from Ras to Rac. Nature 289 10499589
2000 The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Nature 244 11099046
2003 Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1. The Journal of cell biology 215 12515821
2006 Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex. Nature cell biology 205 17115031
2004 Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nature cell biology 174 15558031
2011 Regulation of stereocilia length by myosin XVa and whirlin depends on the actin-regulatory protein Eps8. Current biology : CB 173 21236676
1993 Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals. The EMBO journal 169 8404850
2009 Epidermal growth factor receptor pathway substrate 8 (Eps8) is a novel regulator of cell adhesion and the blood-testis barrier integrity in the seminiferous epithelium. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 141 19293393
2011 Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells. PLoS biology 114 21526224
2003 The eps8 family of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the Ras/Rac pathway. Molecular biology of the cell 111 14565974
2004 IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness. Cancer research 105 15289329
2006 Increased ethanol resistance and consumption in Eps8 knockout mice correlates with altered actin dynamics. Cell 98 17018287
2004 A novel actin barbed-end-capping activity in EPS-8 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans. Nature cell biology 98 15558032
2015 Erk regulation of actin capping and bundling by Eps8 promotes cortex tension and leader bleb-based migration. eLife 97 26163656
2011 Regulation of spermiogenesis, spermiation and blood-testis barrier dynamics: novel insights from studies on Eps8 and Arp3. The Biochemical journal 95 21486226
1997 Isolation and characterization of e3B1, an eps8 binding protein that regulates cell growth. Oncogene 88 9010225
2009 Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF). PLoS biology 84 19564905
2006 Palladin binds to Eps8 and enhances the formation of dorsal ruffles and podosomes in vascular smooth muscle cells. Journal of cell science 84 16868024
2010 Integrity of SOS1/EPS8/ABI1 tri-complex determines ovarian cancer metastasis. Cancer research 79 21118970
1997 The SH3 domain of Eps8 exists as a novel intertwined dimer. Nature structural biology 79 9303002
2002 Eps8 in the midst of GTPases. The international journal of biochemistry & cell biology 76 12127568
2012 Regulation of fibroblast growth factor receptor signalling and trafficking by Src and Eps8. Journal of cell science 73 23203811
1995 Constitutive phosphorylation of eps8 in tumor cell lines: relevance to malignant transformation. Molecular and cellular biology 71 7791787
2009 Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation. Oncogene 66 19448673
2007 Eps8 facilitates cellular growth and motility of colon cancer cells by increasing the expression and activity of focal adhesion kinase. The Journal of biological chemistry 66 17496330
2015 The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling. The Journal of cell biology 64 26668327
2007 Eps8 is increased in pancreatic cancer and required for dynamic actin-based cell protrusions and intercellular cytoskeletal organization. Cancer letters 60 17537571
2018 IRTKS (BAIAP2L1) Elongates Epithelial Microvilli Using EPS8-Dependent and Independent Mechanisms. Current biology : CB 58 30197089
2009 Structure of human lanthionine synthetase C-like protein 1 and its interaction with Eps8 and glutathione. Genes & development 54 19528316
2008 Role for EPS8 in squamous carcinogenesis. Carcinogenesis 53 19008210
2013 Eps8 controls dendritic spine density and synaptic plasticity through its actin-capping activity. The EMBO journal 51 23685357
1995 Direct binding of eps8 to the juxtamembrane domain of EGFR is phosphotyrosine- and SH2-independent. Oncogene 49 7532293
2011 The Eps8/IRSp53/VASP network differentially controls actin capping and bundling in filopodia formation. PLoS computational biology 48 21814501
2014 EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness. Orphanet journal of rare diseases 44 24741995
2011 The signaling adaptor Eps8 is an essential actin capping protein for dendritic cell migration. Immunity 43 21835647
2010 Loss of the actin remodeler Eps8 causes intestinal defects and improved metabolic status in mice. PloS one 43 20209148
2008 Eps8 decreases chemosensitivity and affects survival of cervical cancer patients. Molecular cancer therapeutics 42 18566210
2012 Ezrin regulates microvillus morphogenesis by promoting distinct activities of Eps8 proteins. Molecular biology of the cell 40 22262457
2012 Eps8 protein facilitates phagocytosis by increasing TLR4-MyD88 protein interaction in lipopolysaccharide-stimulated macrophages. The Journal of biological chemistry 39 22493489
2010 Eps8 is recruited to lysosomes and subjected to chaperone-mediated autophagy in cancer cells. Experimental cell research 39 20184880
2005 Regulation of actin cytoskeleton architecture by Eps8 and Abi1. BMC cell biology 39 16225669
2010 EPS8 upregulates FOXM1 expression, enhancing cell growth and motility. Carcinogenesis 38 20351091
2019 EPS8 Facilitates Uncoating of Influenza A Virus. Cell reports 36 31747592
2014 Eps8 regulates cellular proliferation and migration of breast cancer. International journal of oncology 36 25333707
2013 Activity-dependent spine morphogenesis: a role for the actin-capping protein Eps8. The Journal of neuroscience : the official journal of the Society for Neuroscience 34 23392693
1996 RN-tre specifically binds to the SH3 domain of eps8 with high affinity and confers growth advantage to NIH3T3 upon carboxy-terminal truncation. Oncogene 33 8700527
1997 Regulation of the tyrosine kinase substrate Eps8 expression by growth factors, v-Src and terminal differentiation. Oncogene 32 9365239
1994 Evolutionary conservation of the EPS8 gene and its mapping to human chromosome 12q23-q24. Oncogene 31 8084614
2011 Adjudin disrupts spermatogenesis via the action of some unlikely partners: Eps8, Arp2/3 complex, drebrin E, PAR6 and 14-3-3. Spermatogenesis 30 22332112
2019 Gene regulation by antitumor miR-130b-5p in pancreatic ductal adenocarcinoma: the clinical significance of oncogenic EPS8. Journal of human genetics 29 30858505
2023 Tunnelling nanotube formation is driven by Eps8/IRSp53-dependent linear actin polymerization. The EMBO journal 28 38009333
2017 Pro-migratory and TGF-β-activating functions of αvβ6 integrin in pancreatic cancer are differentially regulated via an Eps8-dependent GTPase switch. The Journal of pathology 28 28608476
2013 SCFFbxw5 mediates transient degradation of actin remodeller Eps8 to allow proper mitotic progression. Nature cell biology 28 23314863
2021 Phase separation-mediated condensation of Whirlin-Myo15-Eps8 stereocilia tip complex. Cell reports 26 33626355
2018 Comparative proteomic analysis identifies exosomal Eps8 protein as a potential metastatic biomarker for pancreatic cancer. Oncology reports 26 30431134
2011 c-Jun N-terminal kinase 2 (JNK2) enhances cell migration through epidermal growth factor substrate 8 (EPS8). The Journal of biological chemistry 26 21357683
2010 The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation. Oncogene 26 20418908
2010 P66shc and its downstream Eps8 and Rac1 proteins are upregulated in esophageal cancers. Cell communication and signaling : CCS 26 20565814
1998 Eps8, a tyrosine kinase substrate, is recruited to the cell cortex and dynamic F-actin upon cytoskeleton remodeling. Experimental cell research 26 9665816
2016 The Rho GTPase Rif signals through IRTKS, Eps8 and WAVE2 to generate dorsal membrane ruffles and filopodia. Journal of cell science 24 27278019
2014 Dynamin1 is a novel target for IRSp53 protein and works with mammalian enabled (Mena) protein and Eps8 to regulate filopodial dynamics. The Journal of biological chemistry 22 25031323
2014 Eps8 controls Src- and FAK-dependent phenotypes in squamous carcinoma cells. Journal of cell science 22 25359883
2012 Eps8 promotes cellular growth of human malignant gliomas. Oncology reports 22 23229386
2019 FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signaling. EBioMedicine 21 30738830
2022 Chlamydia repurposes the actin-binding protein EPS8 to disassemble epithelial tight junctions and promote infection. Cell host & microbe 20 36395759
2013 Novel oncoprotein EPS8: a new target for anticancer therapy. Future oncology (London, England) 20 24106906
2017 PTK6 Localized at the Plasma Membrane Promotes Cell Proliferation and MigratiOn Through Phosphorylation of Eps8. Journal of cellular biochemistry 19 28214294
2017 EPS8 regulates proliferation, apoptosis and chemosensitivity in BCR-ABL positive cells via the BCR-ABL/PI3K/AKT/mTOR pathway. Oncology reports 19 29192326
2010 Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression. Chemico-biological interactions 19 19799886
2018 A synthetic cell-penetrating peptide derived from nuclear localization signal of EPS8 exerts anticancer activity against acute myeloid leukemia. Journal of experimental & clinical cancer research : CR 18 29357910
2015 Wnt Signalling Promotes Actin Dynamics during Axon Remodelling through the Actin-Binding Protein Eps8. PloS one 18 26252776
2012 Silencing of Eps8 blocks migration and invasion in human glioblastoma cell lines. Experimental cell research 18 22683923
2022 AAV-mediated rescue of Eps8 expression in vivo restores hair-cell function in a mouse model of recessive deafness. Molecular therapy. Methods & clinical development 17 36034774
2013 EPS8 inhibition increases cisplatin sensitivity in lung cancer cells. PloS one 17 24367505
2008 The cell signaling adaptor protein EPS-8 is essential for C. elegans epidermal elongation and interacts with the ankyrin repeat protein VAB-19. PloS one 17 18833327
1999 Identification of EPS8 as a Dvl1-associated molecule. Biochemical and biophysical research communications 17 10581192
1995 Expression of the receptor tyrosine kinase substrate genes eps8 and eps15 during mouse development. Oncogene 17 7566980
2019 Inhibitory short peptides targeting EPS8/ABI1/SOS1 tri-complex suppress invasion and metastasis of ovarian cancer cells. BMC cancer 15 31488087
1995 Structural requirements of the epidermal growth factor receptor for tyrosine phosphorylation of eps8 and eps15, substrates lacking Src SH2 homology domains. The Journal of biological chemistry 15 7608194
2018 A dual-function epidermal growth factor receptor pathway substrate 8 (Eps8)-derived peptide exhibits a potent cytotoxic T lymphocyte-activating effect and a specific inhibitory activity. Cell death & disease 14 29515106
2014 The actin-binding proteins eps8 and gelsolin have complementary roles in regulating the growth and stability of mechanosensory hair bundles of mammalian cochlear outer hair cells. PloS one 14 24475274
2007 Postsynaptic enrichment of Eps8 at dendritic shaft synapses of unipolar brush cells in rat cerebellum. Neuroscience 14 17223277
2021 Effects and mechanisms of Eps8 on the biological behaviour of malignant tumours (Review). Oncology reports 13 33432368
2021 Cross-species screening platforms identify EPS-8 as a critical link for mitochondrial stress and actin stabilization. Science advances 13 34714674
2016 Conditional deletion of Eps8 reduces hippocampal synaptic plasticity and impairs cognitive function. Neuropharmacology 13 27450093
2015 Silencing of Eps8 inhibits in vitro angiogenesis. Life sciences 13 25896663
2019 A low-molecular-weight compound exerts anticancer activity against breast and lung cancers by disrupting EGFR/Eps8 complex formation. Journal of experimental & clinical cancer research : CR 12 31118055
2013 Novel binding partners and differentially regulated phosphorylation sites clarify Eps8 as a multi-functional adaptor. PloS one 12 23626693
2021 EPS8 supports pancreatic cancer growth by inhibiting BMI1 mediated proteasomal degradation of ALDH7A1. Experimental cell research 11 34391775
2020 miR-345 inhibits migration and stem-like cell phenotype in gastric cancer via inactivation of Rac1 by targeting EPS8. Acta biochimica et biophysica Sinica 11 32147678
2020 EPS8 regulates an NLRP3 inflammasome-independent caspase-1 activation pathway in monosodium urate crystal-treated RAW264.7 macrophages. Biochemical and biophysical research communications 11 32595041
2022 Targeting of microvillus protein Eps8 by the NleH effector kinases from enteropathogenic E. coli. Proceedings of the National Academy of Sciences of the United States of America 9 35976880
2019 EPS8-mediated regulation of multiple myeloma cell growth and survival. American journal of cancer research 8 31497346
2018 Hnrnpab regulates neural cell motility through transcription of Eps8. RNA (New York, N.Y.) 8 30314980
2011 Eps8 involvement in neuregulin1-ErbB4 mediated migration in the neuronal progenitor cell line ST14A. Experimental cell research 8 21281626
2019 EPS8 is a Potential Oncogene in Glioblastoma. OncoTargets and therapy 7 31819533
2018 Lack of the Actin Capping Protein, Eps8, Affects NMDA-Type Glutamate Receptor Function and Composition. Frontiers in molecular neuroscience 7 30233314
2014 The angiopoietin1-Akt pathway regulates barrier function of the cultured spinal cord microvascular endothelial cells through Eps8. Experimental cell research 7 25149679
2012 Human intersectin 2 (ITSN2) binds to Eps8 protein and enhances its degradation. BMB reports 7 22449706
2014 Cell type-specific expression of Eps8 in the mouse hippocampus. BMC neuroscience 6 24533597