{"gene":"EVL","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2000,"finding":"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.","method":"In vitro phosphorylation assay, actin nucleation assay, GST pulldown, direct binding assays, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple in vitro biochemical assays with mutagenesis, reconstitution of actin nucleation, direct binding measurements","pmids":["10945997"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Yeast two-hybrid, co-localization, binding assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid and co-localization, single lab, no reciprocal Co-IP reported in abstract","pmids":["10993894"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence co-localization","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and in vitro pulldown, single lab, multiple orthogonal methods","pmids":["15656790"],"is_preprint":false},{"year":2006,"finding":"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.","method":"GST pulldown, co-immunoprecipitation, immunofluorescence, cell over-expression","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed, multiple methods, single lab","pmids":["16336193"],"is_preprint":false},{"year":2008,"finding":"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.","method":"In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, immunofluorescence, cell biology assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus in vivo Co-IP and localization, single lab, multiple orthogonal methods","pmids":["19000756"],"is_preprint":false},{"year":2009,"finding":"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.","method":"In vitro recombination assay, pulldown, EVL knockdown with immunofluorescence (RAD51 foci), direct binding","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution of recombination activity plus loss-of-function cellular validation, single lab with multiple orthogonal assays","pmids":["19329439"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Domain deletion analysis, pulldown (GST), in vitro homologous pairing assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical domain mapping, single lab, single study","pmids":["19725871"],"is_preprint":false},{"year":2010,"finding":"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.","method":"In vitro ssDNA catenation assay, electron microscopy, surface plasmon resonance, cell extract pulldown","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with SPR binding confirmation, single lab, single study","pmids":["20639531"],"is_preprint":false},{"year":2011,"finding":"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.","method":"In vitro biochemical assay, surface plasmon resonance","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution plus SPR, single lab, comparative analysis","pmids":["21398369"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, EVL knockdown, F-actin staining, cytotoxicity assay, confocal imaging","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, genetic knockdown with multiple defined cellular phenotypes, single lab","pmids":["31235500"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Conditional/global gene knockout (mouse), retinal sprouting assay, VEGFR2 internalization assay, western blot (phospho-VEGFR2, ERK), gene expression profiling","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — endothelial-specific and global KO with multiple orthogonal phenotypic and signaling readouts, replicated across genetic models","pmids":["33512764"],"is_preprint":false},{"year":2021,"finding":"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.","method":"TIRF microscopy, TEER measurement, siRNA knockdown, focal adhesion quantification","journal":"Pulmonary circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — live imaging with functional readout, siRNA knockdown, single lab","pmids":["34631011"],"is_preprint":false},{"year":2023,"finding":"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.","method":"MeRIP-seq, RNA-seq, conditional knockout (METTL3), RNA immunoprecipitation, gene silencing/overexpression, western blot, co-immunoprecipitation","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus RIP, genetic KO, and Co-IP for Smad7 interaction, single lab, multiple orthogonal methods","pmids":["37537731"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Genetic and optogenetic manipulation, co-immunoprecipitation (complex formation), live imaging, loss-of-function with morphological readout","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic and optogenetic manipulations with live imaging and co-IP, multiple orthogonal methods, single lab","pmids":["36828364"],"is_preprint":false},{"year":2023,"finding":"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.","method":"EVL overexpression/knockdown, ALP staining/activity assay, alizarin red staining, western blot (JNK phosphorylation), pharmacological inhibition","journal":"Stem cells international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain/loss-of-function with differentiation readout and pathway inhibitor, single lab, no direct mechanistic binding confirmation","pmids":["36684389"],"is_preprint":false}],"current_model":"EVL (Ena/VASP-like protein) is an actin regulatory protein whose EVH1, proline-rich, and EVH2 domains mediate interactions with profilin, SH3-domain proteins (Abl, Lyn, nSrc, alphaII-spectrin), SEMA6A-1, WASP, VASP, MIM/MTSS1, and Smad7; it nucleates actin polymerization at focal adhesions, filopodial tips, lamellipodia, and cytotoxic synapses, and these activities are downregulated by PKA-mediated phosphorylation (or modulated by PKD phosphorylation of its EVH2 insert); through its EVH2 domain EVL additionally binds RAD51/RAD51B and stimulates homologous recombination in vitro; in endothelial cells EVL regulates VEGFR2 internalization and MAPK/ERK signaling to control sprouting angiogenesis; and EVL mRNA stability is post-transcriptionally enhanced by METTL3-mediated m6A modification via IGF2BP2, with the resulting EVL protein binding Smad7 to promote TGF-β/Smad3-driven fibrosis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2000,"claim":"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","pmids":["10945997"],"confidence":"High","gaps":["Cellular consequences of PKA phosphorylation not tested in vivo","Identity of the relevant SH3-partner-driven pathway in cells unresolved"]},{"year":2000,"claim":"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","pmids":["10993894"],"confidence":"Medium","gaps":["No reciprocal Co-IP reported","Functional outcome of the interaction not established"]},{"year":2005,"claim":"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","pmids":["15656790","16336193"],"confidence":"Medium","gaps":["Whether spectrin/Tes binding regulates EVL nucleation activity not tested","Single-lab findings"]},{"year":2008,"claim":"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","pmids":["19000756"],"confidence":"Medium","gaps":["Physiological signal triggering PKD phosphorylation unclear","Quantitative effect on actin dynamics not measured"]},{"year":2009,"claim":"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","pmids":["19329439","19725871"],"confidence":"High","gaps":["How a cytoskeletal protein accesses chromatin in vivo is unexplained","No structural basis for DNA/RAD51 binding"]},{"year":2010,"claim":"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","pmids":["20639531"],"confidence":"Medium","gaps":["In vivo relevance of catenation activity unknown","Single-study, in vitro reconstitution only"]},{"year":2011,"claim":"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","pmids":["21398369"],"confidence":"Medium","gaps":["Functional redundancy not demonstrated in cells","Relative contributions in vivo unresolved"]},{"year":2019,"claim":"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","pmids":["31235500"],"confidence":"High","gaps":["Direct DAP10-EVL binding interface not mapped","Hierarchy among EVL, WASP and VASP at the synapse not resolved"]},{"year":2021,"claim":"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","pmids":["33512764","34631011"],"confidence":"High","gaps":["Mechanism linking EVL actin activity to receptor internalization unclear","Whether DNA-repair functions contribute to vascular phenotypes untested"]},{"year":2023,"claim":"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","pmids":["36828364"],"confidence":"High","gaps":["Structural basis of the EVL-MTSS1 interaction not defined","Role of phosphoregulation in this complex untested"]},{"year":2023,"claim":"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","pmids":["37537731"],"confidence":"Medium","gaps":["EVL-Smad7 binding interface not mapped","Whether actin or DNA-repair functions intersect with the fibrosis role unknown"]},{"year":2023,"claim":"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","pmids":["36684389"],"confidence":"Low","gaps":["No direct mechanistic binding linking EVL to JNK pathway components","Single-lab gain/loss-of-function only"]},{"year":null,"claim":"How EVL's cytoskeletal, DNA-repair, and signaling functions are coordinated within a single cell—and whether they share regulatory inputs—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating EVH1/EVH2 dual functions","Mechanism switching EVL between cytoplasmic actin and nuclear recombination roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3,13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,6,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[9,10]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9]}],"complexes":[],"partners":["VASP","WASP","RAD51","RAD51B","MTSS1","SPTAN1","TES","SEMA6A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UI08","full_name":"Ena/VASP-like protein","aliases":["Ena/vasodilator-stimulated phosphoprotein-like"],"length_aa":416,"mass_kda":44.6,"function":"Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance and lamellipodial and filopodial dynamics in migrating cells. EVL enhances actin nucleation and polymerization","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, stress fiber; Cell projection, lamellipodium","url":"https://www.uniprot.org/uniprotkb/Q9UI08/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EVL","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"VASP","stoichiometry":4.0},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"PFN1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EVL","total_profiled":1310},"omim":[{"mim_id":"616912","title":"ENAH/VASP-LIKE PROTEIN; EVL","url":"https://www.omim.org/entry/616912"},{"mim_id":"609061","title":"ENAH ACTIN REGULATOR; ENAH","url":"https://www.omim.org/entry/609061"},{"mim_id":"605885","title":"SEMAPHORIN 6A; SEMA6A","url":"https://www.omim.org/entry/605885"},{"mim_id":"601703","title":"VASODILATOR-STIMULATED PHOSPHOPROTEIN; VASP","url":"https://www.omim.org/entry/601703"},{"mim_id":"601243","title":"TOPOISOMERASE, DNA, III, ALPHA; TOP3A","url":"https://www.omim.org/entry/601243"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EVL"},"hgnc":{"alias_symbol":["RNB6"],"prev_symbol":[]},"alphafold":{"accession":"Q9UI08","domains":[{"cath_id":"2.30.29.30","chopping":"2-114","consensus_level":"high","plddt":95.538,"start":2,"end":114}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI08","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI08-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI08-F1-predicted_aligned_error_v6.png","plddt_mean":69.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EVL","jax_strain_url":"https://www.jax.org/strain/search?query=EVL"},"sequence":{"accession":"Q9UI08","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UI08.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UI08/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI08"}},"corpus_meta":[{"pmid":"18264139","id":"PMC_18264139","title":"Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18264139","citation_count":236,"is_preprint":false},{"pmid":"10945997","id":"PMC_10945997","title":"cAMP-dependent protein kinase phosphorylation of EVL, a Mena/VASP relative, regulates its interaction with actin and SH3 domains.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10945997","citation_count":159,"is_preprint":false},{"pmid":"10993894","id":"PMC_10993894","title":"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.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10993894","citation_count":66,"is_preprint":false},{"pmid":"12015966","id":"PMC_12015966","title":"The C. elegans evl-20 gene is a homolog of the small GTPase ARL2 and regulates cytoskeleton dynamics during cytokinesis and morphogenesis.","date":"2002","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/12015966","citation_count":56,"is_preprint":false},{"pmid":"14560015","id":"PMC_14560015","title":"Caenorhabditis elegans EVL-14/PDS-5 and SCC-3 are essential for sister chromatid cohesion in meiosis and mitosis.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14560015","citation_count":48,"is_preprint":false},{"pmid":"37537731","id":"PMC_37537731","title":"Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2-dependent mechanism.","date":"2023","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37537731","citation_count":47,"is_preprint":false},{"pmid":"24211655","id":"PMC_24211655","title":"A Pou5f1/Oct4 dependent Klf2a, Klf2b, and Klf17 regulatory sub-network contributes to EVL and ectoderm development during zebrafish embryogenesis.","date":"2013","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/24211655","citation_count":41,"is_preprint":false},{"pmid":"15656790","id":"PMC_15656790","title":"AlphaII-spectrin interacts with Tes and EVL, two actin-binding proteins located at cell contacts.","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15656790","citation_count":38,"is_preprint":false},{"pmid":"16336193","id":"PMC_16336193","title":"Spectrin interacts with EVL (Enabled/vasodilator-stimulated phosphoprotein-like protein), a protein involved in actin polymerization.","date":"2006","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16336193","citation_count":30,"is_preprint":false},{"pmid":"29242584","id":"PMC_29242584","title":"Mis-expression of grainyhead-like transcription factors in zebrafish leads to defects in enveloping layer (EVL) integrity, cellular morphogenesis and axial extension.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29242584","citation_count":26,"is_preprint":false},{"pmid":"31235500","id":"PMC_31235500","title":"NKG2D-DAP10 signaling recruits EVL to the cytotoxic synapse to generate F-actin and promote NK cell cytotoxicity.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31235500","citation_count":20,"is_preprint":false},{"pmid":"33553141","id":"PMC_33553141","title":"Estrogen Receptor Beta Prevents Signet Ring Cell Gastric Carcinoma Progression in Young Patients by Inhibiting Pseudopodia Formation via the mTOR-Arpc1b/EVL Signaling Pathway.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33553141","citation_count":20,"is_preprint":false},{"pmid":"19000756","id":"PMC_19000756","title":"Characterization of EVL-I as a protein kinase D 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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.\",\n      \"method\": \"In vitro phosphorylation assay, actin nucleation assay, GST pulldown, direct binding assays, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple in vitro biochemical assays with mutagenesis, reconstitution of actin nucleation, direct binding measurements\",\n      \"pmids\": [\"10945997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-localization, binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid and co-localization, single lab, no reciprocal Co-IP reported in abstract\",\n      \"pmids\": [\"10993894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence co-localization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and in vitro pulldown, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15656790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, immunofluorescence, cell over-expression\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed, multiple methods, single lab\",\n      \"pmids\": [\"16336193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, immunofluorescence, cell biology assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus in vivo Co-IP and localization, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19000756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro recombination assay, pulldown, EVL knockdown with immunofluorescence (RAD51 foci), direct binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution of recombination activity plus loss-of-function cellular validation, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"19329439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Domain deletion analysis, pulldown (GST), in vitro homologous pairing assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical domain mapping, single lab, single study\",\n      \"pmids\": [\"19725871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro ssDNA catenation assay, electron microscopy, surface plasmon resonance, cell extract pulldown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with SPR binding confirmation, single lab, single study\",\n      \"pmids\": [\"20639531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro biochemical assay, surface plasmon resonance\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution plus SPR, single lab, comparative analysis\",\n      \"pmids\": [\"21398369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, EVL knockdown, F-actin staining, cytotoxicity assay, confocal imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, genetic knockdown with multiple defined cellular phenotypes, single lab\",\n      \"pmids\": [\"31235500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional/global gene knockout (mouse), retinal sprouting assay, VEGFR2 internalization assay, western blot (phospho-VEGFR2, ERK), gene expression profiling\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endothelial-specific and global KO with multiple orthogonal phenotypic and signaling readouts, replicated across genetic models\",\n      \"pmids\": [\"33512764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"TIRF microscopy, TEER measurement, siRNA knockdown, focal adhesion quantification\",\n      \"journal\": \"Pulmonary circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — live imaging with functional readout, siRNA knockdown, single lab\",\n      \"pmids\": [\"34631011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"MeRIP-seq, RNA-seq, conditional knockout (METTL3), RNA immunoprecipitation, gene silencing/overexpression, western blot, co-immunoprecipitation\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus RIP, genetic KO, and Co-IP for Smad7 interaction, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37537731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic and optogenetic manipulation, co-immunoprecipitation (complex formation), live imaging, loss-of-function with morphological readout\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and optogenetic manipulations with live imaging and co-IP, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36828364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"EVL overexpression/knockdown, ALP staining/activity assay, alizarin red staining, western blot (JNK phosphorylation), pharmacological inhibition\",\n      \"journal\": \"Stem cells international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain/loss-of-function with differentiation readout and pathway inhibitor, single lab, no direct mechanistic binding confirmation\",\n      \"pmids\": [\"36684389\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EVL (Ena/VASP-like protein) is an actin regulatory protein whose EVH1, proline-rich, and EVH2 domains mediate interactions with profilin, SH3-domain proteins (Abl, Lyn, nSrc, alphaII-spectrin), SEMA6A-1, WASP, VASP, MIM/MTSS1, and Smad7; it nucleates actin polymerization at focal adhesions, filopodial tips, lamellipodia, and cytotoxic synapses, and these activities are downregulated by PKA-mediated phosphorylation (or modulated by PKD phosphorylation of its EVH2 insert); through its EVH2 domain EVL additionally binds RAD51/RAD51B and stimulates homologous recombination in vitro; in endothelial cells EVL regulates VEGFR2 internalization and MAPK/ERK signaling to control sprouting angiogenesis; and EVL mRNA stability is post-transcriptionally enhanced by METTL3-mediated m6A modification via IGF2BP2, with the resulting EVL protein binding Smad7 to promote TGF-β/Smad3-driven fibrosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #3]. 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 [#0]. A splice-variant insert in the EVH2 domain is phosphorylated by PKD to control filopodial versus lamellipodial localization [#4]. 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 [#1, #2, #3, #13]. 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 [#9]; it controls VEGFR2 internalization and MAPK/ERK signaling to drive sprouting angiogenesis and regulates endothelial focal adhesions and barrier function [#10, #11]. 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 [#5, #6]. 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 [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro phosphorylation, actin nucleation, GST pulldown and direct binding assays with mutagenesis\",\n      \"pmids\": [\"10945997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequences of PKA phosphorylation not tested in vivo\", \"Identity of the relevant SH3-partner-driven pathway in cells unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, co-localization and binding assay\",\n      \"pmids\": [\"10993894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reciprocal Co-IP reported\", \"Functional outcome of the interaction not established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, reciprocal Co-IP and immunofluorescence co-localization\",\n      \"pmids\": [\"15656790\", \"16336193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether spectrin/Tes binding regulates EVL nucleation activity not tested\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP, siRNA knockdown and immunofluorescence\",\n      \"pmids\": [\"19000756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological signal triggering PKD phosphorylation unclear\", \"Quantitative effect on actin dynamics not measured\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro recombination reconstitution, pulldown, domain deletion analysis, EVL knockdown with RAD51 foci imaging\",\n      \"pmids\": [\"19329439\", \"19725871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a cytoskeletal protein accesses chromatin in vivo is unexplained\", \"No structural basis for DNA/RAD51 binding\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating EVL ssDNA-catenation activity with topoisomerase I and direct binding to TOPO IIIα extended its biochemical DNA-processing repertoire beyond RAD51-mediated recombination.\",\n      \"evidence\": \"In vitro ssDNA catenation, electron microscopy, surface plasmon resonance, cell extract pulldown\",\n      \"pmids\": [\"20639531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of catenation activity unknown\", \"Single-study, in vitro reconstitution only\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro biochemical assays and surface plasmon resonance\",\n      \"pmids\": [\"21398369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional redundancy not demonstrated in cells\", \"Relative contributions in vivo unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, EVL knockdown, F-actin staining, cytotoxicity assays and confocal imaging\",\n      \"pmids\": [\"31235500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DAP10-EVL binding interface not mapped\", \"Hierarchy among EVL, WASP and VASP at the synapse not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional/global mouse knockout, retinal sprouting and VEGFR2 internalization assays, phospho-blots; TIRF imaging, TEER and siRNA knockdown\",\n      \"pmids\": [\"33512764\", \"34631011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking EVL actin activity to receptor internalization unclear\", \"Whether DNA-repair functions contribute to vascular phenotypes untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic and optogenetic manipulation, Co-IP, live imaging and loss-of-function morphological assays\",\n      \"pmids\": [\"36828364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the EVL-MTSS1 interaction not defined\", \"Role of phosphoregulation in this complex untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"MeRIP-seq, RNA-seq, METTL3 conditional knockout, RIP, gain/loss-of-function and Co-IP\",\n      \"pmids\": [\"37537731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EVL-Smad7 binding interface not mapped\", \"Whether actin or DNA-repair functions intersect with the fibrosis role unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"EVL was associated with osteo-/odontogenic differentiation of dental pulp stem cells via JNK activation, extending its functional reach to differentiation programs.\",\n      \"evidence\": \"EVL overexpression/knockdown, ALP and alizarin red assays, phospho-JNK blots and pharmacological inhibition\",\n      \"pmids\": [\"36684389\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct mechanistic binding linking EVL to JNK pathway components\", \"Single-lab gain/loss-of-function only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EVL's cytoskeletal, DNA-repair, and signaling functions are coordinated within a single cell—and whether they share regulatory inputs—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating EVH1/EVH2 dual functions\", \"Mechanism switching EVL between cytoplasmic actin and nuclear recombination roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VASP\", \"WASP\", \"RAD51\", \"RAD51B\", \"MTSS1\", \"SPTAN1\", \"TES\", \"SEMA6A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}