{"gene":"EPS8L2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2003,"finding":"EPS8L2 interacts with Abi1 and Sos-1, activates the Rac-GEF activity of Sos-1, and binds to actin in vivo. EPS8L2 localizes to PDGF-induced, F-actin-rich membrane ruffles and can restore receptor tyrosine kinase (RTK)-mediated actin remodeling when expressed in eps8-/- fibroblasts, placing it in the RTK→Rac→actin remodeling pathway.","method":"Co-immunoprecipitation, in vivo actin-binding assay, Rac-GEF activity assay, rescue experiment in eps8-/- fibroblasts, fluorescence localization to PDGF-induced ruffles","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional rescue in knockout cells, GEF activity assay, and localization data in a single study; functionally validated by multiple orthogonal methods","pmids":["14565974"],"is_preprint":false},{"year":2007,"finding":"EPS8L2 SH3 domain binds modestly to the proline-rich PxxDY motif of CD3epsilon; this binding is abolished by phosphorylation of Y166 in CD3epsilon, indicating that EPS8L2 participates in a phosphorylation-regulated switch at the TCR complex.","method":"SH3 domain phage display screen, recombinant protein binding assay, peptide spot filter assay with phosphorylated peptides","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — binding validated with recombinant proteins and peptide arrays in a single lab; EPS8L2 binding was only modest compared to Eps8 and Eps8L1, single study","pmids":["17617578"],"is_preprint":false},{"year":2013,"finding":"EPS8L2 localizes to the tips of stereocilia of cochlear and vestibular hair cells and is required for long-term maintenance of the staircase structure of auditory hair bundles in adult mice. Eps8L2 null mice exhibit progressive, late-onset hearing loss with gradual deterioration of hair bundle morphology; in the absence of both Eps8 and Eps8L2, the ordered staircase structure of the cochlear hair bundle decays completely.","method":"Immunofluorescence/confocal localization, Eps8L2 knockout mouse model, auditory brainstem response testing, electron microscopy of hair bundle morphology, genetic epistasis with Eps8 knockout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse with direct morphological and electrophysiological phenotyping, genetic epistasis with Eps8, multiple orthogonal methods, replicated by subsequent human genetics studies","pmids":["23918390"],"is_preprint":false},{"year":2021,"finding":"EPS8L2 directly interacts with Ctdnep1 (a nuclear envelope phosphatase), and this interaction is required for the formation and thickness of dorsal actin cables that support TAN line engagement during nuclear movement in migrating fibroblasts, thereby regulating nuclear positioning and cell migration.","method":"Co-immunoprecipitation of endogenous proteins, loss-of-function (siRNA/KD) with nuclear positioning assay, live-cell imaging of actin cables and TAN lines, cell migration assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP showing direct interaction, KD with specific nuclear positioning and actin cable phenotype, live-cell imaging; multiple orthogonal methods in a single study","pmids":["33567288"],"is_preprint":false},{"year":2021,"finding":"BAIAP2L2 binds directly to EPS8L2 (as well as TWF2 and CAPZB2) at the tips of shorter-row mechanotransducing stereocilia, and BAIAP2L2 is required for maintenance of these stereocilia; EPS8L2 is identified as a component of the 'row 2 protein complex' at stereociliary tips.","method":"Co-immunoprecipitation, immunofluorescence localization in cochlear hair cells, Baiap2l2 knockout mouse with electrophysiology (MET currents) and FM 1-43FX dye uptake","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating binding, localization data, KO phenotype; single lab but multiple methods","pmids":["34346063"],"is_preprint":false},{"year":2019,"finding":"EPS8L2 protein levels in urinary extracellular vesicles are positively regulated by exocyst complex component EXOC5 and by primary cilia (IFT88): EXOC5 knockdown decreases EPS8L2 in EVs, EXOC5 overexpression increases it, and IFT88 knockout (which ablates cilia) similarly decreases EPS8L2 in EVs.","method":"EXOC5 KD/OE in MDCK cells, IFT88 KO, immunoblotting of isolated extracellular vesicles, proximal-tubule specific EXOC5 KO mouse urine analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunoblotting in KD/KO/OE contexts across multiple genetic perturbations; single lab, no direct functional test of EPS8L2 activity","pmids":["31694916"],"is_preprint":false},{"year":2025,"finding":"In colorectal cancer cells, EPS8L2 increases YBX1 phosphorylation by enhancing the interaction between YBX1 and the kinase S6K1. Phosphorylated YBX1 translocates to the nucleus and activates G3BP2 transcription, leading to activation of the MAPK signaling pathway and promoting CRC cell proliferation and migration.","method":"EPS8L2 overexpression/knockdown in CRC cell lines, Co-IP (EPS8L2-YBX1-S6K1 complex), YBX1 phosphorylation assay, nuclear fractionation, reporter assay for G3BP2 transcription, in vivo AOM/DSS mouse tumor model with Eps8l2 KO, patient-derived organoids","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation assay, nuclear fractionation, transcription reporter, in vivo KO model; single lab, multiple orthogonal methods","pmids":["40783393"],"is_preprint":false}],"current_model":"EPS8L2 is an actin-binding adaptor protein that (1) links RTK signaling to Rac-dependent actin remodeling by interacting with Abi1 and Sos-1 and activating Sos-1's Rac-GEF activity; (2) localizes to and is required for long-term maintenance of the stereocilia staircase structure in cochlear hair cells, with loss causing progressive hearing loss; (3) directly interacts with the nuclear envelope phosphatase Ctdnep1 to organize dorsal actin cables needed for nuclear positioning during cell migration; (4) participates in a 'row 2 protein complex' at mechanotransducing stereociliary tips via binding to BAIAP2L2; and (5) in colorectal cancer cells drives a YBX1-S6K1-G3BP2-MAPK signaling axis promoting proliferation and metastasis."},"narrative":{"mechanistic_narrative":"EPS8L2 is an actin-binding adaptor protein that couples receptor tyrosine kinase signaling to Rac-dependent actin remodeling: it binds F-actin in vivo, interacts with Abi1 and Sos-1, activates the Rac-GEF activity of Sos-1, localizes to PDGF-induced actin-rich membrane ruffles, and restores RTK-mediated actin remodeling in eps8-/- fibroblasts [PMID:14565974]. Consistent with this actin-organizing role, EPS8L2 directly interacts with the nuclear envelope phosphatase Ctdnep1 to build the dorsal actin cables that support TAN line engagement during nuclear movement in migrating fibroblasts, thereby controlling nuclear positioning and cell migration [PMID:33567288]. In the inner ear, EPS8L2 localizes to stereocilia tips and is required for long-term maintenance of the staircase structure of auditory hair bundles, with its loss causing progressive late-onset hearing loss; it is functionally redundant with Eps8, as loss of both collapses the ordered hair bundle [PMID:23918390], and at the tips of shorter-row mechanotransducing stereocilia it is a component of a 'row 2 protein complex' through direct binding to BAIAP2L2 [PMID:34346063]. In colorectal cancer cells, EPS8L2 drives a signaling cascade by enhancing the YBX1-S6K1 interaction to increase YBX1 phosphorylation, promoting nuclear YBX1, G3BP2 transcription, MAPK activation, and tumor cell proliferation and migration [PMID:40783393].","teleology":[{"year":2003,"claim":"Established EPS8L2's core molecular function by placing it in the RTK→Rac→actin remodeling pathway as an actin-binding adaptor that activates a Rac-GEF.","evidence":"Co-IP with Abi1 and Sos-1, in vivo actin-binding assay, Rac-GEF activity assay, and rescue in eps8-/- fibroblasts with localization to PDGF-induced ruffles","pmids":["14565974"],"confidence":"High","gaps":["Structural basis of EPS8L2 binding to Abi1/Sos-1 not resolved","Degree of functional redundancy with Eps8 in fibroblasts not quantified"]},{"year":2007,"claim":"Probed whether the EPS8L2 SH3 domain reads phosphorylation-regulated motifs at receptor complexes, showing it engages a proline-rich PxxDY motif of CD3epsilon in a phospho-switch manner.","evidence":"SH3 phage display screen, recombinant binding assay, and peptide spot filter assay with phosphorylated peptides","pmids":["17617578"],"confidence":"Medium","gaps":["Binding was only modest relative to Eps8/Eps8L1","No cellular validation in T cells","Functional consequence at the TCR not established"]},{"year":2013,"claim":"Defined an in vivo organismal role: EPS8L2 maintains the stereocilia staircase of auditory hair bundles, linking its actin function to hearing.","evidence":"Eps8L2 knockout mouse with auditory brainstem response testing, electron microscopy of hair bundles, and genetic epistasis with Eps8 knockout","pmids":["23918390"],"confidence":"High","gaps":["Molecular mechanism by which EPS8L2 maintains (vs. forms) bundle architecture unresolved","Binding partners at the tip not identified in this study"]},{"year":2019,"claim":"Connected EPS8L2 abundance in extracellular vesicles to exocyst and primary cilia activity, implicating it in ciliary/EV trafficking outputs.","evidence":"EXOC5 KD/OE in MDCK cells, IFT88 KO, and immunoblotting of isolated EVs plus a tubule-specific EXOC5 KO mouse","pmids":["31694916"],"confidence":"Medium","gaps":["No direct test of EPS8L2 function in EVs","Mechanism of EPS8L2 sorting into EVs unknown","Causal versus correlative relationship to cilia not distinguished"]},{"year":2021,"claim":"Identified a direct EPS8L2-Ctdnep1 interaction required for dorsal actin cable formation and nuclear positioning, generalizing EPS8L2's actin-organizing role to nuclear movement during migration.","evidence":"Reciprocal endogenous Co-IP, siRNA knockdown with nuclear positioning assay, live-cell imaging of actin cables/TAN lines, and migration assay","pmids":["33567288"],"confidence":"High","gaps":["How a nuclear envelope phosphatase recruits EPS8L2 to dorsal cables mechanistically unclear","Whether Ctdnep1 phosphatase activity is required not established"]},{"year":2021,"claim":"Placed EPS8L2 within a defined 'row 2 protein complex' at mechanotransducing stereociliary tips via direct binding to BAIAP2L2.","evidence":"Co-IP, immunofluorescence in cochlear hair cells, and Baiap2l2 knockout mouse with MET current recordings and FM 1-43FX uptake","pmids":["34346063"],"confidence":"Medium","gaps":["Stoichiometry and architecture of the row 2 complex unresolved","EPS8L2's specific contribution within this complex not isolated"]},{"year":2025,"claim":"Extended EPS8L2 beyond cytoskeletal roles into oncogenic signaling, showing it scaffolds a YBX1-S6K1-G3BP2-MAPK axis driving colorectal cancer growth.","evidence":"EPS8L2 OE/KD in CRC lines, Co-IP of EPS8L2-YBX1-S6K1, YBX1 phosphorylation and nuclear fractionation, G3BP2 reporter, AOM/DSS Eps8l2 KO mouse, and patient-derived organoids","pmids":["40783393"],"confidence":"Medium","gaps":["How the actin-adaptor function relates to YBX1-S6K1 scaffolding unclear","Direct versus indirect role in promoting the YBX1-S6K1 interaction not dissected","Single lab, not independently replicated"]},{"year":null,"claim":"Whether EPS8L2's actin-remodeling activity and its signaling-scaffold functions reflect a single biochemical mechanism or context-specific partnerships remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model unifying its SH3/actin-binding and scaffolding roles","No reconstitution of EPS8L2-dependent actin cable assembly","Quantitative redundancy with Eps8/Eps8L1 across tissues not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[2,4]}],"complexes":["row 2 protein complex (stereociliary tips)"],"partners":["ABI1","SOS1","CTDNEP1","BAIAP2L2","YBX1","RPS6KB1","CD3E"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H6S3","full_name":"Epidermal growth factor receptor kinase substrate 8-like protein 2","aliases":["Epidermal growth factor receptor pathway substrate 8-related protein 2","EPS8-related protein 2"],"length_aa":715,"mass_kda":80.6,"function":"Stimulates guanine exchange activity of SOS1. May play a role in membrane ruffling and remodeling of the actin cytoskeleton. In the cochlea, is required for stereocilia maintenance in adult hair cells (By similarity)","subcellular_location":"Cytoplasm; Cell projection, stereocilium","url":"https://www.uniprot.org/uniprotkb/Q9H6S3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EPS8L2","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EPS8L2","total_profiled":1310},"omim":[{"mim_id":"617637","title":"DEAFNESS, AUTOSOMAL RECESSIVE 106; DFNB106","url":"https://www.omim.org/entry/617637"},{"mim_id":"614989","title":"EPS8-LIKE PROTEIN 3; EPS8L3","url":"https://www.omim.org/entry/614989"},{"mim_id":"614988","title":"EPS8-LIKE PROTEIN 2; EPS8L2","url":"https://www.omim.org/entry/614988"},{"mim_id":"614987","title":"EPS8-LIKE PROTEIN 1; EPS8L1","url":"https://www.omim.org/entry/614987"},{"mim_id":"600206","title":"EPIDERMAL GROWTH FACTOR RECEPTOR PATHWAY SUBSTRATE 8; EPS8","url":"https://www.omim.org/entry/600206"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":184.2}],"url":"https://www.proteinatlas.org/search/EPS8L2"},"hgnc":{"alias_symbol":["FLJ21935","FLJ22171","MGC3088"],"prev_symbol":[]},"alphafold":{"accession":"Q9H6S3","domains":[{"cath_id":"2.30.29.30","chopping":"41-179","consensus_level":"high","plddt":88.4486,"start":41,"end":179},{"cath_id":"-","chopping":"247-288_297-438","consensus_level":"high","plddt":90.2394,"start":247,"end":438},{"cath_id":"2.30.30.40","chopping":"497-549","consensus_level":"high","plddt":89.0809,"start":497,"end":549},{"cath_id":"1.10.150.50","chopping":"631-713","consensus_level":"high","plddt":77.3875,"start":631,"end":713}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6S3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6S3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6S3-F1-predicted_aligned_error_v6.png","plddt_mean":73.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EPS8L2","jax_strain_url":"https://www.jax.org/strain/search?query=EPS8L2"},"sequence":{"accession":"Q9H6S3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H6S3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H6S3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6S3"}},"corpus_meta":[{"pmid":"14565974","id":"PMC_14565974","title":"The eps8 family of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the Ras/Rac pathway.","date":"2003","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/14565974","citation_count":113,"is_preprint":false},{"pmid":"21207424","id":"PMC_21207424","title":"Molecular markers of endometrial carcinoma detected in uterine aspirates.","date":"2011","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21207424","citation_count":99,"is_preprint":false},{"pmid":"15940259","id":"PMC_15940259","title":"A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embryonal carcinoma.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15940259","citation_count":87,"is_preprint":false},{"pmid":"23918390","id":"PMC_23918390","title":"Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23918390","citation_count":71,"is_preprint":false},{"pmid":"17617578","id":"PMC_17617578","title":"Reciprocal regulation of SH3 and SH2 domain binding via tyrosine phosphorylation of a common site in CD3epsilon.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17617578","citation_count":64,"is_preprint":false},{"pmid":"31694916","id":"PMC_31694916","title":"Primary cilia and the exocyst are linked to urinary extracellular vesicle production and content.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31694916","citation_count":24,"is_preprint":false},{"pmid":"33284140","id":"PMC_33284140","title":"Re-examination of MAGE-A3 as a T-cell Therapeutic Target.","date":"2021","source":"Journal of 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EPS8L2 localizes to PDGF-induced, F-actin-rich membrane ruffles and can restore receptor tyrosine kinase (RTK)-mediated actin remodeling when expressed in eps8-/- fibroblasts, placing it in the RTK→Rac→actin remodeling pathway.\",\n      \"method\": \"Co-immunoprecipitation, in vivo actin-binding assay, Rac-GEF activity assay, rescue experiment in eps8-/- fibroblasts, fluorescence localization to PDGF-induced ruffles\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional rescue in knockout cells, GEF activity assay, and localization data in a single study; functionally validated by multiple orthogonal methods\",\n      \"pmids\": [\"14565974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EPS8L2 SH3 domain binds modestly to the proline-rich PxxDY motif of CD3epsilon; this binding is abolished by phosphorylation of Y166 in CD3epsilon, indicating that EPS8L2 participates in a phosphorylation-regulated switch at the TCR complex.\",\n      \"method\": \"SH3 domain phage display screen, recombinant protein binding assay, peptide spot filter assay with phosphorylated peptides\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — binding validated with recombinant proteins and peptide arrays in a single lab; EPS8L2 binding was only modest compared to Eps8 and Eps8L1, single study\",\n      \"pmids\": [\"17617578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EPS8L2 localizes to the tips of stereocilia of cochlear and vestibular hair cells and is required for long-term maintenance of the staircase structure of auditory hair bundles in adult mice. Eps8L2 null mice exhibit progressive, late-onset hearing loss with gradual deterioration of hair bundle morphology; in the absence of both Eps8 and Eps8L2, the ordered staircase structure of the cochlear hair bundle decays completely.\",\n      \"method\": \"Immunofluorescence/confocal localization, Eps8L2 knockout mouse model, auditory brainstem response testing, electron microscopy of hair bundle morphology, genetic epistasis with Eps8 knockout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse with direct morphological and electrophysiological phenotyping, genetic epistasis with Eps8, multiple orthogonal methods, replicated by subsequent human genetics studies\",\n      \"pmids\": [\"23918390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EPS8L2 directly interacts with Ctdnep1 (a nuclear envelope phosphatase), and this interaction is required for the formation and thickness of dorsal actin cables that support TAN line engagement during nuclear movement in migrating fibroblasts, thereby regulating nuclear positioning and cell migration.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, loss-of-function (siRNA/KD) with nuclear positioning assay, live-cell imaging of actin cables and TAN lines, cell migration assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP showing direct interaction, KD with specific nuclear positioning and actin cable phenotype, live-cell imaging; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"33567288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BAIAP2L2 binds directly to EPS8L2 (as well as TWF2 and CAPZB2) at the tips of shorter-row mechanotransducing stereocilia, and BAIAP2L2 is required for maintenance of these stereocilia; EPS8L2 is identified as a component of the 'row 2 protein complex' at stereociliary tips.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization in cochlear hair cells, Baiap2l2 knockout mouse with electrophysiology (MET currents) and FM 1-43FX dye uptake\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating binding, localization data, KO phenotype; single lab but multiple methods\",\n      \"pmids\": [\"34346063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EPS8L2 protein levels in urinary extracellular vesicles are positively regulated by exocyst complex component EXOC5 and by primary cilia (IFT88): EXOC5 knockdown decreases EPS8L2 in EVs, EXOC5 overexpression increases it, and IFT88 knockout (which ablates cilia) similarly decreases EPS8L2 in EVs.\",\n      \"method\": \"EXOC5 KD/OE in MDCK cells, IFT88 KO, immunoblotting of isolated extracellular vesicles, proximal-tubule specific EXOC5 KO mouse urine analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunoblotting in KD/KO/OE contexts across multiple genetic perturbations; single lab, no direct functional test of EPS8L2 activity\",\n      \"pmids\": [\"31694916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In colorectal cancer cells, EPS8L2 increases YBX1 phosphorylation by enhancing the interaction between YBX1 and the kinase S6K1. Phosphorylated YBX1 translocates to the nucleus and activates G3BP2 transcription, leading to activation of the MAPK signaling pathway and promoting CRC cell proliferation and migration.\",\n      \"method\": \"EPS8L2 overexpression/knockdown in CRC cell lines, Co-IP (EPS8L2-YBX1-S6K1 complex), YBX1 phosphorylation assay, nuclear fractionation, reporter assay for G3BP2 transcription, in vivo AOM/DSS mouse tumor model with Eps8l2 KO, patient-derived organoids\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation assay, nuclear fractionation, transcription reporter, in vivo KO model; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40783393\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EPS8L2 is an actin-binding adaptor protein that (1) links RTK signaling to Rac-dependent actin remodeling by interacting with Abi1 and Sos-1 and activating Sos-1's Rac-GEF activity; (2) localizes to and is required for long-term maintenance of the stereocilia staircase structure in cochlear hair cells, with loss causing progressive hearing loss; (3) directly interacts with the nuclear envelope phosphatase Ctdnep1 to organize dorsal actin cables needed for nuclear positioning during cell migration; (4) participates in a 'row 2 protein complex' at mechanotransducing stereociliary tips via binding to BAIAP2L2; and (5) in colorectal cancer cells drives a YBX1-S6K1-G3BP2-MAPK signaling axis promoting proliferation and metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EPS8L2 is an actin-binding adaptor protein that couples receptor tyrosine kinase signaling to Rac-dependent actin remodeling: it binds F-actin in vivo, interacts with Abi1 and Sos-1, activates the Rac-GEF activity of Sos-1, localizes to PDGF-induced actin-rich membrane ruffles, and restores RTK-mediated actin remodeling in eps8-/- fibroblasts [#0]. Consistent with this actin-organizing role, EPS8L2 directly interacts with the nuclear envelope phosphatase Ctdnep1 to build the dorsal actin cables that support TAN line engagement during nuclear movement in migrating fibroblasts, thereby controlling nuclear positioning and cell migration [#3]. In the inner ear, EPS8L2 localizes to stereocilia tips and is required for long-term maintenance of the staircase structure of auditory hair bundles, with its loss causing progressive late-onset hearing loss; it is functionally redundant with Eps8, as loss of both collapses the ordered hair bundle [#2], and at the tips of shorter-row mechanotransducing stereocilia it is a component of a 'row 2 protein complex' through direct binding to BAIAP2L2 [#4]. In colorectal cancer cells, EPS8L2 drives a signaling cascade by enhancing the YBX1-S6K1 interaction to increase YBX1 phosphorylation, promoting nuclear YBX1, G3BP2 transcription, MAPK activation, and tumor cell proliferation and migration [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established EPS8L2's core molecular function by placing it in the RTK\\u2192Rac\\u2192actin remodeling pathway as an actin-binding adaptor that activates a Rac-GEF.\",\n      \"evidence\": \"Co-IP with Abi1 and Sos-1, in vivo actin-binding assay, Rac-GEF activity assay, and rescue in eps8-/- fibroblasts with localization to PDGF-induced ruffles\",\n      \"pmids\": [\"14565974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of EPS8L2 binding to Abi1/Sos-1 not resolved\", \"Degree of functional redundancy with Eps8 in fibroblasts not quantified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Probed whether the EPS8L2 SH3 domain reads phosphorylation-regulated motifs at receptor complexes, showing it engages a proline-rich PxxDY motif of CD3epsilon in a phospho-switch manner.\",\n      \"evidence\": \"SH3 phage display screen, recombinant binding assay, and peptide spot filter assay with phosphorylated peptides\",\n      \"pmids\": [\"17617578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding was only modest relative to Eps8/Eps8L1\", \"No cellular validation in T cells\", \"Functional consequence at the TCR not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined an in vivo organismal role: EPS8L2 maintains the stereocilia staircase of auditory hair bundles, linking its actin function to hearing.\",\n      \"evidence\": \"Eps8L2 knockout mouse with auditory brainstem response testing, electron microscopy of hair bundles, and genetic epistasis with Eps8 knockout\",\n      \"pmids\": [\"23918390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which EPS8L2 maintains (vs. forms) bundle architecture unresolved\", \"Binding partners at the tip not identified in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected EPS8L2 abundance in extracellular vesicles to exocyst and primary cilia activity, implicating it in ciliary/EV trafficking outputs.\",\n      \"evidence\": \"EXOC5 KD/OE in MDCK cells, IFT88 KO, and immunoblotting of isolated EVs plus a tubule-specific EXOC5 KO mouse\",\n      \"pmids\": [\"31694916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct test of EPS8L2 function in EVs\", \"Mechanism of EPS8L2 sorting into EVs unknown\", \"Causal versus correlative relationship to cilia not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a direct EPS8L2-Ctdnep1 interaction required for dorsal actin cable formation and nuclear positioning, generalizing EPS8L2's actin-organizing role to nuclear movement during migration.\",\n      \"evidence\": \"Reciprocal endogenous Co-IP, siRNA knockdown with nuclear positioning assay, live-cell imaging of actin cables/TAN lines, and migration assay\",\n      \"pmids\": [\"33567288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a nuclear envelope phosphatase recruits EPS8L2 to dorsal cables mechanistically unclear\", \"Whether Ctdnep1 phosphatase activity is required not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed EPS8L2 within a defined 'row 2 protein complex' at mechanotransducing stereociliary tips via direct binding to BAIAP2L2.\",\n      \"evidence\": \"Co-IP, immunofluorescence in cochlear hair cells, and Baiap2l2 knockout mouse with MET current recordings and FM 1-43FX uptake\",\n      \"pmids\": [\"34346063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and architecture of the row 2 complex unresolved\", \"EPS8L2's specific contribution within this complex not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended EPS8L2 beyond cytoskeletal roles into oncogenic signaling, showing it scaffolds a YBX1-S6K1-G3BP2-MAPK axis driving colorectal cancer growth.\",\n      \"evidence\": \"EPS8L2 OE/KD in CRC lines, Co-IP of EPS8L2-YBX1-S6K1, YBX1 phosphorylation and nuclear fractionation, G3BP2 reporter, AOM/DSS Eps8l2 KO mouse, and patient-derived organoids\",\n      \"pmids\": [\"40783393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the actin-adaptor function relates to YBX1-S6K1 scaffolding unclear\", \"Direct versus indirect role in promoting the YBX1-S6K1 interaction not dissected\", \"Single lab, not independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether EPS8L2's actin-remodeling activity and its signaling-scaffold functions reflect a single biochemical mechanism or context-specific partnerships remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model unifying its SH3/actin-binding and scaffolding roles\", \"No reconstitution of EPS8L2-dependent actin cable assembly\", \"Quantitative redundancy with Eps8/Eps8L1 across tissues not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [\"row 2 protein complex (stereociliary tips)\"],\n    \"partners\": [\"ABI1\", \"SOS1\", \"CTDNEP1\", \"BAIAP2L2\", \"YBX1\", \"RPS6KB1\", \"CD3E\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}