Affinage

EVL

Ena/VASP-like protein · UniProt Q9UI08

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EVL is an Ena/VASP-family actin regulatory protein that nucleates actin polymerization and drives the formation of filopodia, lamellipodia, and protrusive structures at the leading edge, focal adhesions, and cell-cell contacts (PMID:10945997, PMID:16336193). Its modular architecture coordinates these activities: the proline-rich core cooperatively binds profilin dimers, while the EVH1/proline-rich region engages SH3-domain partners including Abl, Lyn, and nSrc, with profilin and SH3 domains competing for partially overlapping sites; PKA phosphorylation downregulates EVL actin nucleation and abolishes SH3 binding without affecting profilin engagement (PMID:10945997). A splice-variant insert in the EVH2 domain is phosphorylated by PKD to control filopodial versus lamellipodial localization (PMID:19000756). EVL physically partners with cytoskeletal and membrane-shaping proteins—alphaII-spectrin (via its SH3 domain), Tes at focal adhesions, the I-BAR protein MIM/MTSS1 at dendritic filopodia tips, and the semaphorin SEMA6A-1 (PMID:10993894, PMID:15656790, PMID:16336193, PMID:36828364). Beyond cytoskeletal control, EVL operates in cell-type-specific signaling contexts: it is recruited to the NK cell cytotoxic synapse downstream of NKG2D-DAP10, where it interacts with WASP and VASP and is required for synaptic F-actin, adhesion, and cytotoxicity (PMID:31235500); it controls VEGFR2 internalization and MAPK/ERK signaling to drive sprouting angiogenesis and regulates endothelial focal adhesions and barrier function (PMID:33512764, PMID:34631011). Independently of its cytoskeletal role, the EVH2 domain of EVL binds RAD51 and RAD51B, binds and anneals DNA, and stimulates RAD51-mediated homologous pairing and strand exchange in vitro, with EVL required for RAD51 assembly at damage sites (PMID:19329439, PMID:19725871). EVL mRNA is stabilized by METTL3-mediated m6A modification through IGF2BP2, and the resulting EVL protein binds Smad7 to relieve its suppression of TGF-β1/Smad3 signaling, promoting renal fibrosis (PMID:37537731).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 High

    Establishing whether EVL is an active actin nucleator and how its protein interactions are controlled answered the basic question of how this Ena/VASP member is regulated; the work showed PKA phosphorylation switches off nucleation and SH3 binding while leaving profilin binding intact.

    Evidence In vitro phosphorylation, actin nucleation, GST pulldown and direct binding assays with mutagenesis

    PMID:10945997

    Open questions at the time
    • Cellular consequences of PKA phosphorylation not tested in vivo
    • Identity of the relevant SH3-partner-driven pathway in cells unresolved
  2. 2000 Medium

    Identifying SEMA6A-1 as an EVL partner addressed how semaphorin signaling could couple to the actin machinery, linking the semaphorin and Ena/VASP families via a zyxin-like domain.

    Evidence Yeast two-hybrid, co-localization and binding assay

    PMID:10993894

    Open questions at the time
    • No reciprocal Co-IP reported
    • Functional outcome of the interaction not established
  3. 2005 Medium

    Connecting EVL to alphaII-spectrin and Tes addressed where EVL is anchored within the cytoskeleton, placing it at focal adhesions and spectrin-based membrane scaffolds.

    Evidence Yeast two-hybrid, GST pulldown, reciprocal Co-IP and immunofluorescence co-localization

    PMID:15656790 PMID:16336193

    Open questions at the time
    • Whether spectrin/Tes binding regulates EVL nucleation activity not tested
    • Single-lab findings
  4. 2008 Medium

    Showing that PKD phosphorylates an alternately-included EVH2 insert of the EVL-I splice variant added a second kinase input controlling EVL's choice between filopodial and lamellipodial localization.

    Evidence In vitro kinase assay, Co-IP, siRNA knockdown and immunofluorescence

    PMID:19000756

    Open questions at the time
    • Physiological signal triggering PKD phosphorylation unclear
    • Quantitative effect on actin dynamics not measured
  5. 2009 High

    The discovery that EVL binds RAD51/RAD51B and stimulates homologous pairing revealed an unexpected nuclear DNA-repair function distinct from actin regulation, and domain mapping localized this activity to the EVH2 domain.

    Evidence In vitro recombination reconstitution, pulldown, domain deletion analysis, EVL knockdown with RAD51 foci imaging

    PMID:19329439 PMID:19725871

    Open questions at the time
    • How a cytoskeletal protein accesses chromatin in vivo is unexplained
    • No structural basis for DNA/RAD51 binding
  6. 2010 Medium

    Demonstrating EVL ssDNA-catenation activity with topoisomerase I and direct binding to TOPO IIIα extended its biochemical DNA-processing repertoire beyond RAD51-mediated recombination.

    Evidence In vitro ssDNA catenation, electron microscopy, surface plasmon resonance, cell extract pulldown

    PMID:20639531

    Open questions at the time
    • In vivo relevance of catenation activity unknown
    • Single-study, in vitro reconstitution only
  7. 2011 Medium

    Comparing MENA, VASP and EVL showed all three share RAD51-binding and recombination-stimulating activities and mutually interact, framing the recombination role as a redundant family property rather than EVL-specific.

    Evidence In vitro biochemical assays and surface plasmon resonance

    PMID:21398369

    Open questions at the time
    • Functional redundancy not demonstrated in cells
    • Relative contributions in vivo unresolved
  8. 2019 High

    Placing EVL at the NK cell cytotoxic synapse downstream of NKG2D-DAP10 defined a specific immune context for its actin function, showing it is required for synaptic F-actin, adhesion, WASP/VASP recruitment, and killing.

    Evidence Co-IP, EVL knockdown, F-actin staining, cytotoxicity assays and confocal imaging

    PMID:31235500

    Open questions at the time
    • Direct DAP10-EVL binding interface not mapped
    • Hierarchy among EVL, WASP and VASP at the synapse not resolved
  9. 2021 High

    Endothelial and global knockouts established a non-redundant role for EVL (distinct from VASP) in VEGF-driven sprouting angiogenesis by controlling VEGFR2 internalization and MAPK/ERK signaling, and in regulating focal adhesions and barrier function.

    Evidence Conditional/global mouse knockout, retinal sprouting and VEGFR2 internalization assays, phospho-blots; TIRF imaging, TEER and siRNA knockdown

    PMID:33512764 PMID:34631011

    Open questions at the time
    • Mechanism linking EVL actin activity to receptor internalization unclear
    • Whether DNA-repair functions contribute to vascular phenotypes untested
  10. 2023 High

    Identifying an EVL-MIM/MTSS1 complex at filopodia tips and dendritic protrusions clarified how EVL drives membrane-directed actin polymerization during protrusion morphogenesis in neurons.

    Evidence Genetic and optogenetic manipulation, Co-IP, live imaging and loss-of-function morphological assays

    PMID:36828364

    Open questions at the time
    • Structural basis of the EVL-MTSS1 interaction not defined
    • Role of phosphoregulation in this complex untested
  11. 2023 Medium

    Linking m6A-stabilized EVL to Smad7 sequestration and TGF-β1/Smad3-driven renal fibrosis revealed a post-transcriptional regulatory axis and a profibrotic signaling role for EVL.

    Evidence MeRIP-seq, RNA-seq, METTL3 conditional knockout, RIP, gain/loss-of-function and Co-IP

    PMID:37537731

    Open questions at the time
    • EVL-Smad7 binding interface not mapped
    • Whether actin or DNA-repair functions intersect with the fibrosis role unknown
  12. 2023 Low

    EVL was associated with osteo-/odontogenic differentiation of dental pulp stem cells via JNK activation, extending its functional reach to differentiation programs.

    Evidence EVL overexpression/knockdown, ALP and alizarin red assays, phospho-JNK blots and pharmacological inhibition

    PMID:36684389

    Open questions at the time
    • No direct mechanistic binding linking EVL to JNK pathway components
    • Single-lab gain/loss-of-function only

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EVL's cytoskeletal, DNA-repair, and signaling functions are coordinated within a single cell—and whether they share regulatory inputs—remains unresolved.
  • No structural model integrating EVH1/EVH2 dual functions
  • Mechanism switching EVL between cytoplasmic actin and nuclear recombination roles unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0008092 cytoskeletal protein binding 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-73894 DNA Repair 2 R-HSA-168256 Immune System 1
Partners
MTSS1RAD51RAD51BSEMA6ASPTAN1TESVASPWASP

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 EVL is a substrate for cAMP-dependent protein kinase (PKA), and PKA phosphorylation regulates EVL's interactions with its ligands: phosphorylation decreases actin nucleation activity, abolishes binding to Abl and nSrc SH3 domains, but does not affect profilin binding. EVL directly binds Abl, Lyn, and nSrc SH3 domains; the FE65 WW domain; and profilin via its proline-rich core. Two profilin dimers show strong cooperative binding to the polyproline sequence, and profilin competes with SH3 domains for partially overlapping binding sites. Unlike VASP, EVL nucleates actin polymerization under physiological conditions. In vitro phosphorylation assay, actin nucleation assay, GST pulldown, direct binding assays, mutagenesis The Journal of biological chemistry High 10945997
2000 SEMA6A-1/Sema6A-1 (semaphorin 6A-1) selectively binds EVL via a novel carboxyl-terminal zyxin-like domain, directly linking the semaphorin and Ena/VASP protein families. SEMA6A-1 and EVL are co-localized in cells. Yeast two-hybrid, co-localization, binding assay The Journal of biological chemistry Medium 10993894
2005 AlphaII-spectrin interacts with EVL: EVL binds the SH3 domain within the alpha9 repeat of alphaII-spectrin. EVL also interacts with Tes (a LIM-domain actin-binding protein). Both interactions were confirmed by co-immunoprecipitation and in vitro GST pulldown. EVL and Tes co-localize at focal adhesions. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence co-localization The Biochemical journal Medium 15656790
2006 EVL interacts with the SH3 domain of alphaII-spectrin; co-expression of EVL with the alphaII-spectrin SH3 domain in COS-7 cells causes partial relocalization of the SH3 domain to filopodia and lamellipodia where it co-localizes with EVL. Over-expression of EVL promotes formation of filopodia and lamellipodia, and EVL localizes to filopodial tips and the leading edge. In kidney epithelial cells, spectrin co-localizes with EVL at lateral cell-cell contacts. GST pulldown, co-immunoprecipitation, immunofluorescence, cell over-expression Biology of the cell Medium 16336193
2008 EVL-I (a splice variant of EVL) is a substrate for Protein Kinase D (PKD), which interacts with EVL-I in vitro and in vivo and phosphorylates a 21-amino-acid alternately-included insert in the EVH2 domain. Phosphorylated EVL-I localizes to filopodial tips (following capping protein CPbeta knockdown and laminin spreading) and to lamellipodia; impairment of EVL-I phosphorylation is associated with lamellipodia ruffling upon PDBu stimulation. EVL-I is hyperphosphorylated at cell-cell contacts in certain breast cancer cells and mouse embryo keratinocytes. In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, immunofluorescence, cell biology assays Cellular signalling Medium 19000756
2009 Human EVL directly binds RAD51 and RAD51B proteins, stimulates RAD51-mediated homologous pairing and strand exchange in vitro, promotes single-stranded DNA annealing, and its recombination activities are further enhanced by RAD51B. EVL knockdown impairs RAD51 assembly onto damaged DNA after ionizing radiation or mitomycin C treatment. In vitro recombination assay, pulldown, EVL knockdown with immunofluorescence (RAD51 foci), direct binding The Journal of biological chemistry High 19329439
2009 The EVH2 domain of EVL (fragment EVL(222-418)) is responsible for DNA-binding, RAD51-binding, and stimulation of RAD51-mediated homologous pairing. The EVH1/Pro-rich domain fragment EVL(1-221) does not exhibit these activities. Domain deletion analysis, pulldown (GST), in vitro homologous pairing assay The FEBS journal Medium 19725871
2010 Human EVL forms heat-stable multimers (catenanes) of circular single-stranded DNA (ssDNA) in the presence of a type I topoisomerase in vitro; this activity depends on the ssDNA annealing activity of EVL. EVL physically interacts with TOPO IIIα, as confirmed by pulldown from cell extract and surface plasmon resonance. In vitro ssDNA catenation assay, electron microscopy, surface plasmon resonance, cell extract pulldown Nucleic acids research Medium 20639531
2011 MENA, VASP, and EVL all exhibit RAD51-binding, DNA-binding, DNA-annealing, and stimulation of RAD51-mediated homologous pairing in vitro. All three proteins mutually interact with each other by surface plasmon resonance, supporting functional redundancy in homologous recombination. In vitro biochemical assay, surface plasmon resonance Journal of biochemistry Medium 21398369
2019 EVL is recruited to the NK cell cytotoxic synapse via NKG2D-DAP10 signaling (through a binding site previously implicated in VAV1 and Grb2 recruitment). EVL is required for F-actin generation at the cytotoxic synapse, NK cell-target cell adhesion, antibody-stimulated spreading, and NK cell cytotoxicity. EVL interacts with WASP and VASP, and is required for their localization to the synapse. Co-immunoprecipitation, EVL knockdown, F-actin staining, cytotoxicity assay, confocal imaging Journal of cell science High 31235500
2021 Endothelial-specific deletion of EVL compromises VEGF-induced sprouting angiogenesis, reduces tip cell density and filopodia formation, and impairs VEGF receptor-2 internalization and phosphorylation as well as downstream MAPK/ERK signaling. Global EVL deletion (but not VASP deletion) recapitulates these vascular sprouting defects in postnatal mouse retina. Conditional/global gene knockout (mouse), retinal sprouting assay, VEGFR2 internalization assay, western blot (phospho-VEGFR2, ERK), gene expression profiling EMBO reports High 33512764
2021 EVL is present at endothelial cell focal adhesions and regulates focal adhesion size, distribution, and number in response to sphingosine-1-phosphate (S1P) and thrombin. EVL expression controls endothelial barrier responses (measured by TEER), and focal adhesion kinase (FAK) is a key contributor downstream of S1P-stimulated EVL signaling but has a limited role in thrombin-induced focal adhesion rearrangements. TIRF microscopy, TEER measurement, siRNA knockdown, focal adhesion quantification Pulmonary circulation Medium 34631011
2023 METTL3-mediated m6A modification of EVL mRNA enhances EVL mRNA stability and expression in an IGF2BP2-dependent manner in renal tubular cells. Highly expressed EVL binds to Smad7, abrogating Smad7-mediated suppression of TGF-β1/Smad3 signaling, thereby promoting renal fibrosis progression. MeRIP-seq, RNA-seq, conditional knockout (METTL3), RNA immunoprecipitation, gene silencing/overexpression, western blot, co-immunoprecipitation Clinical and translational medicine Medium 37537731
2023 EVL forms a complex with MIM/MTSS1 (an I-BAR protein) at nascent protrusions and dendritic filopodia tips in neurons, and is uniquely required for morphogenesis and dynamics of dendritic filopodia. EVL promotes protrusive motility through membrane-directed actin polymerization at filopodia tips. Genetic and optogenetic manipulation, co-immunoprecipitation (complex formation), live imaging, loss-of-function with morphological readout The Journal of cell biology High 36828364
2023 EVL promotes osteo-/odontogenic differentiation of human dental pulp stem cells by activating the JNK signaling pathway; EVL overexpression increases ALP activity and mineralized nodule formation, and these effects are suppressed by JNK inhibition but not p38 MAPK inhibition. EVL overexpression/knockdown, ALP staining/activity assay, alizarin red staining, western blot (JNK phosphorylation), pharmacological inhibition Stem cells international Low 36684389

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer. Oncogene 236 18264139
2000 cAMP-dependent protein kinase phosphorylation of EVL, a Mena/VASP relative, regulates its interaction with actin and SH3 domains. The Journal of biological chemistry 159 10945997
2000 The orthologous human and murine semaphorin 6A-1 proteins (SEMA6A-1/Sema6A-1) bind to the enabled/vasodilator-stimulated phosphoprotein-like protein (EVL) via a novel carboxyl-terminal zyxin-like domain. The Journal of biological chemistry 66 10993894
2002 The C. elegans evl-20 gene is a homolog of the small GTPase ARL2 and regulates cytoskeleton dynamics during cytokinesis and morphogenesis. Developmental cell 56 12015966
2003 Caenorhabditis elegans EVL-14/PDS-5 and SCC-3 are essential for sister chromatid cohesion in meiosis and mitosis. Molecular and cellular biology 48 14560015
2023 Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2-dependent mechanism. Clinical and translational medicine 47 37537731
2013 A Pou5f1/Oct4 dependent Klf2a, Klf2b, and Klf17 regulatory sub-network contributes to EVL and ectoderm development during zebrafish embryogenesis. Developmental biology 41 24211655
2005 AlphaII-spectrin interacts with Tes and EVL, two actin-binding proteins located at cell contacts. The Biochemical journal 38 15656790
2006 Spectrin interacts with EVL (Enabled/vasodilator-stimulated phosphoprotein-like protein), a protein involved in actin polymerization. Biology of the cell 30 16336193
2017 Mis-expression of grainyhead-like transcription factors in zebrafish leads to defects in enveloping layer (EVL) integrity, cellular morphogenesis and axial extension. Scientific reports 26 29242584
2021 Estrogen Receptor Beta Prevents Signet Ring Cell Gastric Carcinoma Progression in Young Patients by Inhibiting Pseudopodia Formation via the mTOR-Arpc1b/EVL Signaling Pathway. Frontiers in cell and developmental biology 20 33553141
2019 NKG2D-DAP10 signaling recruits EVL to the cytotoxic synapse to generate F-actin and promote NK cell cytotoxicity. Journal of cell science 20 31235500
2008 Characterization of EVL-I as a protein kinase D substrate. Cellular signalling 19 19000756
2023 EVL and MIM/MTSS1 regulate actin cytoskeletal remodeling to promote dendritic filopodia in neurons. The Journal of cell biology 16 36828364
2009 Recombination activator function of the novel RAD51- and RAD51B-binding protein, human EVL. The Journal of biological chemistry 16 19329439
2021 EVL regulates VEGF receptor-2 internalization and signaling in developmental angiogenesis. EMBO reports 14 33512764
2017 Epigenetic silencing of EVL/miR-342 in multiple myeloma. Translational research : the journal of laboratory and clinical medicine 14 29242101
2021 The balance between the intronic miR-342 and its host gene Evl determines hematopoietic cell fate decision. Leukemia 13 34021250
2012 Heterogeneity across the dorso-ventral axis in zebrafish EVL is regulated by a novel module consisting of sox, snail1a and max genes. Mechanisms of development 11 22522081
1997 Differential display cloning of a novel rat cDNA (RNB6) that shows high expression in the neonatal brain revealed a member of Ena/VASP family. Biochemical and biophysical research communications 9 9268706
2005 Molecular cloning and expression of Ena/Vasp-like (Evl) during Xenopus development. Gene expression patterns : GEP 8 15661649
2007 Regulation of otic vesicle and hair cell stereocilia morphogenesis by Ena/VASP-like (Evl) in Xenopus. Journal of cell science 7 17635997
2021 EVL is a novel focal adhesion protein involved in the regulation of cytoskeletal dynamics and vascular permeability. Pulmonary circulation 6 34631011
2023 EVL Promotes Osteo-/Odontogenic Differentiation of Dental Pulp Stem Cells via Activating JNK Signaling Pathway. Stem cells international 3 36684389
2011 Biochemical analysis of the human ENA/VASP-family proteins, MENA, VASP and EVL, in homologous recombination. Journal of biochemistry 3 21398369
2010 Single-stranded DNA catenation mediated by human EVL and a type I topoisomerase. Nucleic acids research 3 20639531
2021 Exercise effects on DNA methylation in EVL, CDKN2A (p14, ARF), and ESR1 in colon tissue from healthy men and women. Epigenetics 2 34550860
2009 Biochemical analysis of the human EVL domains in homologous recombination. The FEBS journal 2 19725871

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