Affinage

EPS8

Epidermal growth factor receptor kinase substrate 8 · UniProt Q12929

Length
822 aa
Mass
91.9 kDa
Annotated
2026-06-09
100 papers in source corpus 49 papers cited in narrative 49 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EPS8 is a multifunctional actin-regulatory adaptor that couples receptor tyrosine kinase signaling to Rho-family GTPase activation and direct remodeling of the actin cytoskeleton (PMID:8404850, PMID:10499589, PMID:15558031). It was first identified as an EGFR substrate that binds the receptor juxtamembrane region through a non-SH2 mechanism independent of phosphotyrosine, with phosphorylation enhancing mitogenic and transforming responses (PMID:8404850, PMID:7532293, PMID:7608194, PMID:7791787). EPS8 nucleates a tri-complex with Abi1/E3b1 and Sos1 that possesses intrinsic Rac-specific GEF activity, transmitting signals from Ras to Rac; this GEF activity is unmasked by PI3K recruitment through Abi1 and the lipid product PIP3 (PMID:9010225, PMID:10499589, PMID:12515821). EPS8 directly shapes actin filaments through a conserved C-terminal effector domain that caps barbed ends with nanomolar affinity—an activity autoinhibited in full-length protein and relieved by Abi1—and through an actin-bundling activity that synergizes with IRSp53 downstream of Cdc42 to build filopodia and microvilli (PMID:15558031, PMID:17115031, PMID:30197089). The balance between capping and bundling is regulated by phosphorylation: MAPK/Erk phosphorylation at S624/T628 inhibits capping to favor filopodia and bleb-based migration, and bacterial effector kinases similarly target EPS8 to disable its actin activities during infection (PMID:19564905, PMID:26163656, PMID:35976880). EPS8 protein levels are cell-cycle controlled by SCF(Fbxw5)-mediated proteasomal degradation in G2, which permits timely cell rounding and mitotic entry while its capping activity prevents membrane blebbing during cytokinesis (PMID:23314863). Through these activities EPS8 operates in diverse cellular contexts including stereocilia tip complexes with Myo15/whirlin that form actin-bundling phase-separated condensates required for hearing (PMID:21236676, PMID:21526224, PMID:33626355), postsynaptic NMDA receptor complexes and dendritic spine plasticity (PMID:17018287, PMID:23685357), dendritic cell and confined cell migration (PMID:21835647, PMID:26163656), VE-cadherin junctions controlling YAP/TAZ signaling and vascular permeability (PMID:26668327), and macrophage TLR4-MyD88 phagocytic signaling (PMID:22493489). EPS8 is also exploited by pathogens, associating with influenza virion components to license RNP nuclear import and serving as a target of bacterial effectors that remodel epithelial tight junctions (PMID:31747592, PMID:36395759).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1993 High

    Established EPS8 as a direct RTK substrate, answering whether it functions in growth-factor signaling: it is tyrosine-phosphorylated by and associates with EGFR and amplifies mitogenic output.

    Evidence cDNA cloning, in vivo phosphorylation, co-IP, and overexpression mitogenesis assays in fibroblasts/hematopoietic cells

    PMID:8404850

    Open questions at the time
    • Mechanism of EGFR association undefined at this stage
    • No actin or downstream effector function yet identified
  2. 1995 Medium

    Defined the unusual phosphotyrosine-independent mode of EGFR engagement, showing EPS8 binds the receptor juxtamembrane domain rather than autophosphorylation sites and that constitutive phosphorylation accompanies transformation.

    Evidence EGFR deletion/point-mutant binding and kinase assays, transformation assays, co-IP with Shc

    PMID:7532293 PMID:7608194 PMID:7791787

    Open questions at the time
    • Single-lab biochemistry
    • Structural basis of juxtamembrane binding not resolved
  3. 1997 High

    Identified the SH3-domain interactome and oligomerization mode, revealing EPS8 binds Abi-1/E3B1 and RN-tre and self-associates through an intertwined SH3 dimer.

    Evidence X-ray crystallography, SH3 library screen, co-IP, quantitative in vitro binding

    PMID:8700527 PMID:9010225 PMID:9303002

    Open questions at the time
    • Functional consequence of dimerization not established
    • Hierarchy among competing SH3 ligands unknown
  4. 1999 High

    Resolved how EPS8 links Ras to actin remodeling: the EPS8-Abi1-Sos1 tri-complex carries intrinsic Rac-specific GEF activity.

    Evidence In vivo co-IP, reconstituted in vitro Rac-GEF assay, genetic epistasis

    PMID:10499589

    Open questions at the time
    • How GEF activity is switched on left unexplained
    • Spatial regulation of the complex unaddressed
  5. 2000 High

    Showed EPS8 is a node partitioned between endocytic and signaling functions, with RN-tre binding diverting it from the GEF complex and inhibiting EGFR internalization.

    Evidence Co-IP, Rab5 GAP assay, EGFR endocytosis assay, Rac activation assay

    PMID:11099046

    Open questions at the time
    • Quantitative balance between pools not defined
    • Triggers for switching not mapped
  6. 2003 High

    Defined the activation switch for the GEF complex and established family redundancy: PI3K/PIP3 unmasks Rac-GEF activity, and EPS8L1/L2 can substitute for EPS8.

    Evidence Co-IP, in vitro GEF assays with PI3K inhibitors and p85 knockout, rescue in eps8-/- fibroblasts

    PMID:12515821 PMID:14565974

    Open questions at the time
    • Distinct in vivo roles of paralogs not fully separated
    • Lipid-binding determinants on the complex unmapped
  7. 2004 High

    Identified the core actin biochemistry of EPS8: its C-terminal effector domain caps barbed ends with nanomolar affinity, is autoinhibited and de-repressed by Abi1, with capping required in vivo for actin-based motility and morphogenesis.

    Evidence Reconstituted in vitro capping with domain mapping, loss-of-function in cells, C. elegans isoform genetic rescue

    PMID:15558031 PMID:15558032

    Open questions at the time
    • Structural mechanism of autoinhibition not solved
    • Regulation of capping by other partners not yet known
  8. 2006 High

    Revealed the second actin activity—bundling—and its integration with Cdc42 signaling: EPS8 bundles filaments and synergizes with IRSp53 to drive Cdc42-dependent filopodia.

    Evidence In vitro bundling assay, co-IP, siRNA loss-of-function, live imaging; palladin and IRSp53 binding mapping

    PMID:15289329 PMID:17115031

    Open questions at the time
    • Switch between capping and bundling not yet defined
    • Domain basis of bundling versus capping not separated
  9. 2006 High

    Extended EPS8 into neuronal function, placing it in postsynaptic NMDA receptor complexes governing actin remodeling and behavior.

    Evidence Co-IP of NMDA complex, electrophysiology in Eps8 KO neurons, behavioral assays

    PMID:17018287

    Open questions at the time
    • Direct binding partner within the complex unresolved
    • Molecular link to channel function indirect
  10. 2009 High

    Identified phospho-regulation of the capping/bundling balance and tissue-specific actin junction roles: MAPK phosphorylation at S624/T628 inhibits capping to control axonal filopodia, and EPS8 maintains seminiferous-epithelium junctions.

    Evidence Phospho-mutant capping assays, hippocampal neuron imaging, RNAi with junction-protein readouts in vitro and in vivo

    PMID:19293393 PMID:19528316 PMID:19564905

    Open questions at the time
    • Upstream kinase identity in each context not fully resolved
    • Coordination of the two phospho-sites unclear
  11. 2011 High

    Established EPS8 as an essential stereocilia component, building the Myo15a-whirlin-EPS8 tip complex required for stereocilia elongation, hair-cell maturation, and hearing.

    Evidence Co-IP, knockout mouse analysis, overexpression rescue, electrophysiology, hearing thresholds; EPS8 roles in dendritic cell migration

    PMID:21236676 PMID:21526224 PMID:21835647

    Open questions at the time
    • Stoichiometry and assembly order of the tip complex not fully defined
    • How tip targeting couples to capping versus bundling not resolved
  12. 2013 High

    Defined cell-cycle control of EPS8 levels and its role in spine plasticity: SCF(Fbxw5) degrades EPS8 in G2 to enable mitotic rounding, and EPS8 capping is required for LTP-driven spine enlargement and cognition.

    Evidence E3 ligase identification, proteasome inhibition, cell-cycle synchronization, live imaging; KO mouse LTP, spine morphometry, behavior

    PMID:23314863 PMID:23685357

    Open questions at the time
    • Degron recognition motif for Fbxw5 not mapped
    • Link between human autism and EPS8 correlative only
  13. 2015 High

    Connected EPS8 actin activities to mechanics and adhesion signaling: Erk phosphorylation tips EPS8 toward bundling to drive leader-bleb migration, and EPS8 links VE-cadherin junctions to YAP/TAZ signaling and vascular permeability.

    Evidence Live imaging with Erk biosensor, cortex-tension measurements, capping/bundling mutants; reciprocal co-IP, KO mouse with permeability and YAP reporter assays

    PMID:26163656 PMID:26252776 PMID:26668327

    Open questions at the time
    • Mechanism coupling EPS8 to YAP nuclear translocation incompletely defined
    • How junction state controls EPS8 displacement not fully resolved
  14. 2017 Medium

    Expanded the kinase regulation of EPS8 to additional RTK pathways, showing PTK6 phosphorylates EPS8 to enhance proliferation, migration, and ERK/FAK activation.

    Evidence Phosphoproteomics, 3YF mutagenesis, kinase assay, PTK6 knockdown; FAK/Src complex and clathrin/AP-2 interactome studies

    PMID:23626693 PMID:25359883 PMID:28214294

    Open questions at the time
    • Functional integration of many phospho-sites unresolved
    • In vivo relevance of PTK6 phosphorylation untested
  15. 2018 Medium

    Defined how EPS8 is targeted to specialized actin protrusions: I-BAR proteins IRTKS/IRSp53 recruit EPS8 via SH3 interactions to drive microvillus and nanotube elongation through linear actin polymerization.

    Evidence Super-resolution microscopy, SH3-dependent co-IP, depletion assays; optical tweezers and Arp2/3 inhibition for TNTs

    PMID:30197089 PMID:38009333

    Open questions at the time
    • How recruitment selects capping versus bundling output unclear
    • Direct linear-polymerase activity of EPS8 not biochemically isolated
  16. 2021 High

    Revealed that the stereocilia tip complex functions through liquid-liquid phase separation, with multivalent Whirlin-Myo15-EPS8 condensates promoting actin bundling disrupted by a deafness variant.

    Evidence In vitro phase-separation reconstitution, actin bundling assay, deafness-variant mutagenesis

    PMID:33626355

    Open questions at the time
    • In vivo confirmation of condensate behavior limited
    • Contribution of EPS8 multivalency versus partners not separated
  17. 2022 High

    Established EPS8 as a host target hijacked by pathogens, with influenza virion association licensing RNP nuclear import and bacterial effectors targeting EPS8 to remodel tight junctions and disable its actin activities.

    Evidence Genetic knockout/overexpression and infection assays (influenza); CRISPR KO with organoid and mouse infection (Chlamydia); crystal structure and bundling assay with EPEC NleH kinases

    PMID:31747592 PMID:35976880 PMID:36395759

    Open questions at the time
    • Mechanism of EPS8 contribution to influenza RNP transport undefined
    • Host signaling rewired by effector phosphorylation incompletely mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EPS8's competing capping, bundling, GEF-scaffolding, and adaptor functions are selected and spatially partitioned within a single cell across its many tissue contexts remains unresolved.
  • No unified structural model integrating autoinhibition, phospho-switches, and partner binding
  • Quantitative rules governing partition between signaling and actin pools unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 3 GO:0005829 cytosol 2 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-112316 Neuronal System 2 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-1640170 Cell Cycle 1
Partners
ABI1EGFRIRSP53MYO15ARN-TRESOS1VE-CADHERINWHRN
Complex memberships
EPS8-Abi1-Sos1 Rac-GEF tri-complexMyo15a-whirlin-EPS8 stereocilia tip complexNMDA receptor postsynaptic complexTLR4-MyD88 complex

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Eps8 is a substrate of the EGFR kinase; it is tyrosine-phosphorylated in vivo following EGF stimulation and associates with the EGFR in vivo despite lacking a functional SH2 domain. Overexpression of Eps8 in fibroblasts or hematopoietic cells increases mitogenic response to EGF. cDNA cloning, in vivo tyrosine phosphorylation assay, co-immunoprecipitation, adoptive expression/overexpression mitogenesis assay The EMBO journal High 8404850
1995 Eps8 binds directly to the juxtamembrane domain of EGFR through a non-SH2 domain by a mechanism that does not require phosphotyrosine residues. Direct binding assay with EGFR deletion/point mutants, in vitro binding Oncogene Medium 7532293
1995 EGFR autophosphorylation sites are dispensable for Eps8 phosphorylation; removal of the final 214 COOH-terminal residues of EGFR increases Eps8 phosphorylation ~13-fold, identifying a juxtamembrane region as the structural determinant for efficient phosphorylation of Eps8. EGFR deletion/point mutant phosphorylation assays The Journal of biological chemistry Medium 7608194
1995 Eps8 constitutive tyrosine phosphorylation occurs in tumor cell lines at stoichiometry similar to potent mitogenic response; overexpression of Eps8 transforms NIH 3T3 cells under limiting EGFR activation. Eps8 associates in vivo with Shc, at least partly via the SH3 domain of Eps8. Phosphotyrosine analysis of tumor lines, transformation assay, co-immunoprecipitation Molecular and cellular biology Medium 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 stably associates with Eps8 in vivo. In vitro SH3 domain binding assay with Kd measurement, co-immunoprecipitation Oncogene Medium 8700527
1997 The SH3 domain of Eps8 forms an intertwined dimer via strand interchange (novel fold variant of canonical SH3), and intact Eps8 is multimeric in vivo, suggesting the SH3 domain serves 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 via SH3 library screen; E3B1 associates with Eps8 in vivo and is serine-phosphorylated in a growth-factor-dependent manner. SH3 domain expression library screen, co-immunoprecipitation, phosphoamino acid analysis Oncogene Medium 9010225
1998 Eps8 is recruited to the cell cortex, membrane ruffles, lamellipodia, and dynamic F-actin structures (podosomes) upon cytoskeletal remodeling; a detergent-resistant pool associates with podosomes in v-Src-transformed cells. Immunofluorescence localization, Triton X-100 fractionation, live-cell imaging Experimental cell research Medium 9665816
1999 Eps8, E3b1/Abi-1, and Sos-1 form a tri-complex in vivo that exhibits Rac-specific GEF activity in vitro, mediating signal transduction from Ras to Rac. Co-immunoprecipitation (in vivo tri-complex), in vitro Rac-GEF activity assay, genetic epistasis Nature High 10499589
1999 Eps8 interacts with the PDZ domain of Dvl1 (murine Dishevelled homologue) in vitro and in vivo; Dvl1 is hyperphosphorylated in the presence of Eps8, whereas Dvl1 inhibits EGF-induced tyrosine phosphorylation of Eps8. Yeast two-hybrid screen, in vitro binding confirmation, transfection and phosphorylation analysis Biochemical and biophysical research communications Medium 10581192
2000 Eps8 interacts via its SH3 domain with RN-tre, a Rab5 GAP; this complex inhibits EGFR internalization and attenuates Rac signaling by diverting Eps8 from the Abi1/Sos1 complex. RN-tre activity on Rab5 is regulated by the EGFR. Co-immunoprecipitation, Rab5 GAP activity assay, EGFR endocytosis assay, Rac activation assay Nature High 11099046
2003 PI3K (via p85 subunit) is recruited into the Eps8-Abi1-Sos1 complex through Abi1; both p85 recruitment and the PI3K product PIP3 are required to unmask Rac-GEF activity of the complex in vitro and to activate Rac and actin remodeling in vivo. Co-immunoprecipitation, in vitro Rac-GEF assay, PI3K inhibitor studies, p85 knockout cells The Journal of cell biology High 12515821
2003 Eps8 family members (Eps8L1, Eps8L2, Eps8L3) interact with Abi1 and Sos-1; only Eps8L1 and Eps8L2 activate Rac-GEF activity of Sos-1 and bind actin in vivo, functionally compensating for Eps8 loss in eps8−/− fibroblasts. 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 conserved C-terminal effector domain caps barbed ends with nanomolar affinity. Full-length Eps8 is auto-inhibited, and interaction with Abi1 relieves this inhibition. In vivo, Eps8 removal impairs actin-based propulsion. In vitro actin barbed-end capping assay with isolated domain and full-length protein, Kd measurement, loss-of-function in cells, Abi1 interaction relief-of-inhibition assay Nature cell biology High 15558031
2004 In C. elegans, the EPS-8A isoform (but not EPS-8B) has a C-terminal actin barbed-end capping activity required for proper apical morphogenesis of intestinal cells; the two isoforms differ at their C-termini. C. elegans genetics, isoform rescue experiments, in vitro actin barbed-end capping assay Nature cell biology High 15558032
2004 IRSp53 directly binds Eps8 through the NH2-terminal proline-rich sequence of Eps8 and the IRSp53 SH3 domain; this complex synergistically activates Rac by reinforcing the Eps8/Abi1/Sos1 GEF complex and occurs at the leading edge of motile cells. Co-immunoprecipitation (in vivo), FRET analysis, Rac activation (pull-down assay), cell motility/invasion assays Cancer research Medium 15289329
2006 Eps8 has actin crosslinking (bundling) activity and synergizes with IRSp53 in mediating actin bundling in vitro. Cdc42 binds the IRSp53-Eps8 complex and controls its cellular distribution. Cdc42-induced filopodia require both IRSp53 and Eps8. In vitro actin bundling assay, co-immunoprecipitation, loss-of-function (siRNA), live-cell imaging Nature cell biology High 17115031
2006 Palladin directly binds Eps8 (identified by yeast two-hybrid, confirmed by co-immunoprecipitation); both proteins colocalize in dorsal ruffles; palladin knockdown reduces Rac activation and ruffle formation after PDGF treatment. Yeast two-hybrid, co-immunoprecipitation, colocalization by confocal microscopy, palladin knockdown with functional readout Journal of cell science Medium 16868024
2006 Eps8 is part of the NMDA receptor complex at postsynaptic structures in neurons; Eps8 null mice show abnormal NMDA receptor currents, altered sensitivity to ethanol inhibition, and resistance to NMDA/ethanol-induced actin remodeling. Co-immunoprecipitation (NMDA receptor complex), electrophysiology in knockout neurons, behavioral assay Cell High 17018287
2008 In C. elegans, EPS-8 interacts with the ankyrin repeat protein VAB-19 (central domain of EPS-8 sufficient); both proteins colocalize at cell-matrix attachment structures; eps-8 null mutants are defective in epidermal elongation and epidermal-muscle attachment, dependent on PTB and central domains but independent of C-terminal SH3 and actin-binding domains. Yeast two-hybrid, co-localization, eps-8 null mutant phenotype, domain rescue experiments PloS one Medium 18833327
2009 LanCL1 binds specifically to the SH3 domain of Eps8 in vitro; LanCL1 mutants defective in Eps8 interaction inhibit NGF-induced neurite outgrowth, establishing functional significance of this interaction. In vitro affinity binding, crystal structure of LanCL1, loss-of-function mutagenesis with neurite outgrowth assay Genes & development High 19528316
2009 Eps8 is localized to actin-based cell junctions (blood-testis barrier and apical ectoplasmic specialization) in the seminiferous epithelium; Eps8 knockdown by RNAi causes F-actin disorganization and mislocalization of tight junction proteins occludin and ZO-1; in vivo knockdown causes germ cell sloughing and BTB damage. Immunofluorescence/immunohistochemistry localization, RNAi knockdown with permeability and junction protein assays, in vivo knockdown FASEB journal Medium 19293393
2009 BDNF inhibits the actin barbed-end capping activity of Eps8 through MAPK-dependent phosphorylation at residues S624 and T628; a phosphorylation-defective mutant (S624A/T628A) shows increased actin association and resistance to BDNF-mediated release; a phosphomimetic mutant (S624E/T628E) has opposite effects. This controls axonal filopodia formation. Site-directed mutagenesis, MAPK phosphorylation assay, actin barbed-end capping assay, hippocampal neuron imaging and filopodia quantification PLoS biology High 19564905
2010 The SOS1/EPS8/ABI1 tri-complex facilitates LPA-induced Rac activation specifically in metastatic ovarian cancer cells; re-expression of a missing tri-complex member in non-metastatic cells confers metastatic capability; integrity of the complex is essential for LPA-stimulated cell migration and peritoneal colonization. Co-immunoprecipitation, Rac activation assay, re-expression rescue, in vivo peritoneal metastasis assay Cancer research Medium 21118970
2010 Eps8 in cancer cells localizes to the lysosomal compartment independently of actin polymerization; Eps8 co-immunoprecipitates with Hsc70 and LAMP-2, key elements of chaperone-mediated autophagy (CMA); the region aa 184-535 containing KFERQ-like motifs mediates lysosomal recruitment; Eps8 binds to and is incorporated into lysosomes in vitro, competed by other CMA substrates. Subcellular fractionation, immunofluorescence/confocal colocalization, co-immunoprecipitation, in vitro lysosome binding/incorporation assay, FRAP Experimental cell research Medium 20184880
2011 Eps8 interacts with MyoXVa and whirlin; MyoXVa is required for Eps8 accumulation at stereocilia tips; overexpression of MyoXVa drives elongation and increased Eps8 at tips; exogenous MyoXVa in MyoXVa-deficient cells rescues Eps8 tip localization. Whirlin-deficient mice show reduced Eps8 and MyoXVa at stereocilia tips. MyoXVa-whirlin-Eps8 form a stereocilia tip complex. Co-immunoprecipitation, live imaging, knockout mouse analysis, overexpression rescue Current biology : CB High 21236676
2011 Eps8 is localized at stereocilia tips of cochlear hair cells; Eps8 knockout mice are profoundly deaf and exhibit short stereocilia; inner hair cells (IHCs) fail to mature into functional sensory receptors in Eps8 KO mice, establishing a role for Eps8 in stereocilia elongation and IHC functional maturation. Knockout mouse, immunofluorescence localization, electrophysiology, hearing threshold measurement 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/chemotactic migration in 3D and in reaching draining lymph nodes in vivo, preventing contact hypersensitivity responses. Eps8 is not required for antigen uptake, processing, or presentation. Eps8 knockout mouse, in vitro 3D migration assay, in vivo lymph node migration assay, contact hypersensitivity assay Immunity High 21835647
2012 Eps8 interacts with the clathrin-mediated endocytosis machinery; Src phosphorylates Eps8 downstream of FGFR activation; depletion of Eps8 inhibits FGFR trafficking and immediate Erk signaling. Live-cell imaging, Eps8 depletion (siRNA), co-immunoprecipitation with endocytic machinery, Src phosphorylation assay, Erk signaling assay Journal of cell science Medium 23203811
2012 Ezrin differentially modulates Eps8 and Eps8L1a activities: coexpression of ezrin with Eps8 promotes membrane ruffles and tufts of microvilli via bundling activity; coexpression with Eps8L1a promotes clustering of actin structures via capping activity. Ezrin's effect requires its binding to Eps8/Eps8L1a, and specific actin-bundling/capping activities of these proteins. Overexpression and co-expression studies, domain-mapping mutagenesis, morphological assays Molecular biology of the cell Medium 22262457
2012 Human intersectin 2 (ITSN2) binds Eps8 (interaction domain: aa 260-306 of Eps8 and coiled-coil domain of ITSN2); ITSN2 overexpression induces lysosome-dependent degradation of Eps8. Yeast two-hybrid, co-immunoprecipitation, GST pull-down, domain mapping, protein stability assay with lysosome inhibitor BMB reports Medium 22449706
2012 Eps8 interacts with TLR4 in the cytosol and at the phagosome in LPS-stimulated macrophages; Eps8 facilitates TLR4-MyD88 interaction and downstream Src, FAK, and p38 MAPK activation; Eps8 attenuation reduces LPS-promoted phagocytosis and bacterial killing. Confocal colocalization, co-immunoprecipitation, siRNA knockdown with phagocytosis and signaling readouts, dominant-negative construct 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 in G2 prolongs its localization at the cell cortex, markedly delays cell rounding and prometaphase entry. Eps8 capping activity is required during late mitosis/cytokinesis to prevent membrane blebbing. Biochemical degradation assays, E3 ligase identification (SCFFbxw5), proteasome inhibitor experiments, cell-cycle synchronization, live-cell imaging of Eps8 localization Nature cell biology High 23314863
2013 Eps8 actin-capping activity is required for dendritic spine enlargement during chemically induced LTP; mice lacking Eps8 display immature spines unable to undergo potentiation and are impaired in cognitive functions. Reduced Eps8 levels are found in brains of autism patients. Eps8 KO mouse, chemically induced LTP in culture, spine morphometry, electrophysiology, behavioral cognitive tests The EMBO journal High 23685357
2013 Eps8 forms a biochemical complex with FAK and Src in SCC cells; it controls the spatial distribution of active Src in a FAK-dependent manner and drives Src trafficking to autophagic structures when FAK is absent; when FAK is present, Eps8 is recruited to focal adhesions and required for FAK-dependent polarization and invasion. Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, invasion assay, immunofluorescence Journal of cell science Medium 25359883
2013 Novel Eps8 binding partners identified by phosphoproteomic affinity purification include clathrin, AP-2 (endocytic machinery), NBR1, Vav2, IRS4, and Shp2; 22 Eps8 pTyr and pSer/Thr phosphorylation sites identified, some dependent on Src family kinases and FGFR activity. Differential phosphoproteomics, peptide affinity purification, mass spectrometry PloS one Medium 23626693
2015 Eps8 bundling activity promotes cortex tension and intracellular pressure to drive leader bleb formation during confined migration; Erk phosphorylation inhibits Eps8 capping activity, and Erk activity is concentrated within leader blebs, promoting actin bundling by Eps8 to enhance bleb-based migration. Live-cell imaging, Erk biosensor, cortex tension measurements, loss-of-function/gain-of-function with capping and bundling mutants eLife Medium 26163656
2015 EPS8 is a novel binding partner of VE-cadherin; EPS8 associates with VE-cadherin at remodeling junctions promoting YAP nuclear translocation and transcriptional activation; in stabilized junctions 14-3-3-YAP displaces EPS8. Eps8-null mice show increased vascular permeability and junctional YAP inhibition. Co-immunoprecipitation, live imaging, Eps8 KO mouse, YAP localization and reporter assays The Journal of cell biology High 26668327
2015 Eps8 is a direct interactor of Dvl1 (scaffold for Wnt signaling); gain-of-function of Eps8 mimics Wnt-mediated axon remodeling; Eps8 silencing blocks Wnt3a-induced axon remodeling; blockade of Dvl1-Eps8 interaction abolishes Wnt3a-mediated axonal remodeling. Yeast two-hybrid, functional rescue/silencing in DRG neurons, dominant-negative Dvl1-Eps8 interaction blockade PloS one Medium 26252776
2017 PTK6 (Brk) phosphorylates Eps8 at residues Tyr497, Tyr524, and Tyr534; a phosphorylation-defective 3YF mutant fails to increase proliferation, migration, and ERK/FAK activation mediated by wild-type Eps8 overexpression; EGF-induced Eps8 phosphorylation by endogenous PTK6 enhances ERK and FAK activation, cell adhesion, and anchorage-independent growth. Phosphoproteomics, site-directed mutagenesis (3YF mutant), co-immunoprecipitation, kinase assay, PTK6 knockdown Journal of cellular biochemistry Medium 28214294
2018 IRTKS (BAIAP2L1) recruits EPS8 to microvillar tips via IRTKS SH3 domain to promote epithelial microvillus elongation, as demonstrated by super-resolution microscopy and functional depletion experiments. Super-resolution microscopy, live imaging, co-immunoprecipitation (SH3-dependent interaction), depletion assays Current biology : CB Medium 30197089
2019 FoxO3a directly binds the EPS8 gene promoter (by ChIP assay) and inhibits EPS8 transcription, forming a negative feedback loop in EGFR signaling; FoxO3a and EPS8 play opposing roles in gefitinib resistance, migration, and invasion. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, cell migration/invasion assay EBioMedicine Medium 30738830
2019 EPS8 physically associates with incoming influenza A virion components during uncoating; EPS8 loss does not affect virion attachment, uptake, or fusion, but significantly delays nuclear import of released ribonucleoprotein complexes. EPS8 knockout, overexpression, co-immunoprecipitation with virion components, infection assay measuring uncoating and nuclear import Cell reports Medium 31747592
2021 The Whirlin-Myo15-Eps8 stereocilia tip complex undergoes liquid-liquid phase separation driven by multivalent interactions; the condensates promote actin bundling; a deafness-associated Myo15 mutation disrupts condensate formation and impairs actin bundling. In vitro phase separation reconstitution, actin bundling assay, mutagenesis of deafness-associated variant Cell reports High 33626355
2021 EPS8/EPS-8 regulates general mitochondrial homeostasis and the mitochondrial unfolded protein response (UPRmt) through integrin-mediated remodeling of the actin cytoskeleton, identified by cross-species genetic screening in human stem cells and C. elegans. Cross-species genetic screen, RNAi knockdown, UPRmt reporter assay, actin cytoskeletal imaging Science advances Low 34714674
2021 EPS8 interacts with ALDH7A1 (co-IP); EPS8 knockdown reduces ALDH7A1 protein and increases its poly-ubiquitination; BMI1 mediates ALDH7A1 ubiquitination and degradation, and BMI1 knockdown rescues ALDH7A1 degradation caused by EPS8 loss. Co-immunoprecipitation, ubiquitination assay, double knockdown with functional rescue Experimental cell research Medium 34391775
2022 Chlamydia trachomatis effector TepP alters tyrosine phosphorylation of EPS8; TepP and EPS8 are necessary and sufficient for tight junction remodeling; genetic deletion of EPS8 renders epithelial cells and organoids resistant to TepP-mediated tight junction disruption. Phosphoproteomics, EPS8 genetic knockout (CRISPR), organoid infection model, in vivo mouse infection model Cell host & microbe High 36395759
2022 EPEC effector kinases NleH1 and NleH2 phosphorylate Eps8 at Ser775 via interaction with the Eps8 SH3 domain through noncanonical PxxDY proline-rich motifs; Ser775 phosphorylation hinders Eps8 bundling activity and drives dispersal of Eps8 from AE lesions during infection. Phosphoproteomics, crystal structure of Eps8 SH3 bound to NleH peptide, in vitro bundling assay, bacterial infection imaging Proceedings of the National Academy of Sciences of the United States of America High 35976880
2023 Eps8 and IRSp53 work together to promote linear actin polymerization for tunnelling nanotube (TNT) formation; upon Arp2/3 inhibition, Eps8 shows heightened interaction with IRSp53 and its linear actin polymerase connection, favoring TNT elongation over branched actin structures. Micropatterning, optical tweezers, proteomics of Eps8 interactions, Arp2/3 inhibition, co-immunoprecipitation 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 290 10499589
2000 The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Nature 245 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 206 17115031
2011 Regulation of stereocilia length by myosin XVa and whirlin depends on the actin-regulatory protein Eps8. Current biology : CB 176 21236676
2004 Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nature cell biology 175 15558031
1993 Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals. The EMBO journal 170 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 117 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 113 14565974
2004 IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness. Cancer research 106 15289329
2004 A novel actin barbed-end-capping activity in EPS-8 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans. Nature cell biology 100 15558032
2015 Erk regulation of actin capping and bundling by Eps8 promotes cortex tension and leader bleb-based migration. eLife 98 26163656
2006 Increased ethanol resistance and consumption in Eps8 knockout mice correlates with altered actin dynamics. Cell 98 17018287
2011 Regulation of spermiogenesis, spermiation and blood-testis barrier dynamics: novel insights from studies on Eps8 and Arp3. The Biochemical journal 96 21486226
1997 Isolation and characterization of e3B1, an eps8 binding protein that regulates cell growth. Oncogene 89 9010225
2009 Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF). PLoS biology 85 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 77 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
2018 IRTKS (BAIAP2L1) Elongates Epithelial Microvilli Using EPS8-Dependent and Independent Mechanisms. Current biology : CB 60 30197089
2007 Eps8 is increased in pancreatic cancer and required for dynamic actin-based cell protrusions and intercellular cytoskeletal organization. Cancer letters 60 17537571
2009 Structure of human lanthionine synthetase C-like protein 1 and its interaction with Eps8 and glutathione. Genes & development 55 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
2011 The Eps8/IRSp53/VASP network differentially controls actin capping and bundling in filopodia formation. PLoS computational biology 49 21814501
1995 Direct binding of eps8 to the juxtamembrane domain of EGFR is phosphotyrosine- and SH2-independent. Oncogene 49 7532293
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
2010 Loss of the actin remodeler Eps8 causes intestinal defects and improved metabolic status in mice. PloS one 44 20209148
2011 The signaling adaptor Eps8 is an essential actin capping protein for dendritic cell migration. Immunity 43 21835647
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
2005 Regulation of actin cytoskeleton architecture by Eps8 and Abi1. BMC cell biology 40 16225669
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
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
2023 Tunnelling nanotube formation is driven by Eps8/IRSp53-dependent linear actin polymerization. The EMBO journal 31 38009333
2011 Adjudin disrupts spermatogenesis via the action of some unlikely partners: Eps8, Arp2/3 complex, drebrin E, PAR6 and 14-3-3. Spermatogenesis 31 22332112
1994 Evolutionary conservation of the EPS8 gene and its mapping to human chromosome 12q23-q24. Oncogene 31 8084614
2019 Gene regulation by antitumor miR-130b-5p in pancreatic ductal adenocarcinoma: the clinical significance of oncogenic EPS8. Journal of human genetics 29 30858505
2013 SCFFbxw5 mediates transient degradation of actin remodeller Eps8 to allow proper mitotic progression. Nature cell biology 29 23314863
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
2011 c-Jun N-terminal kinase 2 (JNK2) enhances cell migration through epidermal growth factor substrate 8 (EPS8). The Journal of biological chemistry 27 21357683
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
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
2022 Chlamydia repurposes the actin-binding protein EPS8 to disassemble epithelial tight junctions and promote infection. Cell host & microbe 22 36395759
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
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
2015 Wnt Signalling Promotes Actin Dynamics during Axon Remodelling through the Actin-Binding Protein Eps8. PloS one 19 26252776
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
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
2016 Conditional deletion of Eps8 reduces hippocampal synaptic plasticity and impairs cognitive function. Neuropharmacology 14 27450093
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
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 13 31118055
2015 Silencing of Eps8 inhibits in vitro angiogenesis. Life sciences 13 25896663
2013 Novel binding partners and differentially regulated phosphorylation sites clarify Eps8 as a multi-functional adaptor. PloS one 13 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
2019 EPS8 is a Potential Oncogene in Glioblastoma. OncoTargets and therapy 8 31819533
2018 Hnrnpab regulates neural cell motility through transcription of Eps8. RNA (New York, N.Y.) 8 30314980
2014 The angiopoietin1-Akt pathway regulates barrier function of the cultured spinal cord microvascular endothelial cells through Eps8. Experimental cell research 8 25149679
2011 Eps8 involvement in neuregulin1-ErbB4 mediated migration in the neuronal progenitor cell line ST14A. Experimental cell research 8 21281626
2018 Lack of the Actin Capping Protein, Eps8, Affects NMDA-Type Glutamate Receptor Function and Composition. Frontiers in molecular neuroscience 7 30233314
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

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