{"gene":"ELFN2","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2007,"finding":"ELFN2 (along with ELFN1) was identified as a member of a novel subfamily of extracellular leucine-rich repeat (eLRR) transmembrane proteins containing an FN3 domain. The two ELFN genes were shown to be expressed in discrete patterns in the developing mouse brain, notably in the thalamus and cortex, establishing the founding structural characterization of the ELFN family.","method":"Bioinformatic eLRR protein catalogue combined with mouse brain expression profiling (RT-PCR/in situ)","journal":"BMC genomics","confidence":"Low","confidence_rationale":"Tier 3 — expression/structural annotation without functional mechanistic validation","pmids":["17868438"],"is_preprint":false},{"year":2018,"finding":"ELFN2 was identified as a hypomethylation-driven oncogene in glioblastoma (GBM) that promotes autophagy by directly interacting with Aurora kinase A (AurkA) and eIF2α, inhibiting AurkA activation. LINC00470 was shown to upregulate ELFN2 by sponging miR-101 and reducing H3K27me3 occupancy at the ELFN2 promoter.","method":"Co-immunoprecipitation (AurkA/eIF2α binding), loss-of-function (siRNA knockdown), promoter methylation and ChIP assays, autophagy functional assays","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, multiple orthogonal methods (Co-IP, ChIP, functional assays) but limited independent replication","pmids":["30037656"],"is_preprint":false},{"year":2019,"finding":"ELFN2 was characterized as a postsynaptic cell adhesion molecule with a distinct expression pattern throughout the brain that selectively binds group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8) in trans. Using a transcellular GPCR signaling platform, ELFN2 was shown to directly alter G protein coupling kinetics and efficacy of group III mGluRs. Loss of ELFN2 in mice caused selective downregulation of group III mGluRs and dysregulated glutamatergic synaptic transmission, and Elfn2 KO mice displayed seizure susceptibility, hyperactivity, and anxiety/compulsivity that were rescued by pharmacological augmentation of group III mGluRs.","method":"Transcellular GPCR signaling platform, Elfn2 knockout mice, electrophysiology, pharmacological rescue, Co-immunoprecipitation","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional assays, genetic KO with defined phenotypes, pharmacological rescue, multiple orthogonal methods in single study","pmids":["31485013"],"is_preprint":false},{"year":2020,"finding":"Using an unbiased proteomic strategy in a cone-dominant species, ELFN2 was identified as selectively expressed in cone photoreceptor terminals, where it transsynaptically recruits the neurotransmitter receptor mGluR6 in ON-type bipolar cells to enable synaptic transmission. ELFN2 was found to function in synergy with ELFN1, and their concerted interplay during development specifies selective cone-to-ON-bipolar cell wiring and transmission.","method":"Unbiased proteomics, immunohistochemistry/localization, conditional knockout mice, electroretinography, synaptogenesis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — unbiased proteomic identification, KO functional validation, multiple orthogonal methods","pmids":["32879010"],"is_preprint":false},{"year":2021,"finding":"Review synthesis establishing that ELFN2 (and ELFN1) can interact trans-synaptically with all four group III mGluRs (mGluR4, mGluR6, mGluR7, mGluR8), and that these interactions alter mGluR-mediated signaling across hippocampal, cortical, and retinal synapses. ELFN2 postsynaptically modulates group III mGluR signaling properties and synaptic transmission characteristics.","method":"Review/synthesis of experimental literature including functional assays and genetic models","journal":"Frontiers in neural circuits","confidence":"Medium","confidence_rationale":"Tier 3 — review consolidating findings from multiple labs; mechanistic claims grounded in cited experimental work","pmids":["33790745"],"is_preprint":false},{"year":2023,"finding":"Single-cell RNA sequencing and enhanced crosslinking immunoprecipitation (eCLIP-seq) identified Elfn2 as a key hub gene targeted by the RNA helicase DDX43 during spermiogenesis, placing ELFN2 downstream of DDX43-mediated RNA regulatory processes required for spermatid chromatin remodeling and differentiation.","method":"Single-cell RNA-seq, enhanced CLIP-seq (eCLIP), Ddx43 knockout mice, ATPase-dead missense mutant","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — eCLIP directly identifies ELFN2 mRNA as DDX43 target; genetic KO and ATPase mutant confirm phenotype, but mechanistic role of ELFN2 protein itself in this context is not directly dissected","pmids":["37120627"],"is_preprint":false},{"year":2024,"finding":"Complex N-glycosylation of mGluR6 acquired in the Golgi is required for trans-synaptic interaction with ELFN1 and ELFN2 extracellular domains. Pull-down experiments with ELFN1 and ELFN2 extracellular domains showed that they interact exclusively with the complex glycosylated form of mGluR6. Mutation of N-glycosylation site N445 on mGluR6 severely impaired both ELFN1 and ELFN2 binding, identifying N445 as a critical glycosylation site for ELFN interaction.","method":"Glycosidase treatment (PNGase F, Endo H), pull-down assays with ELFN1/ELFN2 extracellular domains, site-directed mutagenesis of N-glycosylation sites, heterologous expression, rod bipolar cell dendritic tip localization assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted pull-down with purified extracellular domains, mutagenesis of specific glycosylation sites, in vivo localization validation","pmids":["38428819"],"is_preprint":false},{"year":2024,"finding":"ELFN2 (like its closest homolog ELFN1) forms obligate homodimers prior to membrane trafficking, with homodimerization mediated by the extracellular leucine-rich repeat (LRR) domain rather than the intracellular region. ELFN2 also participates in heterodimerization with ELFN1, indicating conserved dimerization mechanisms across the ELFN subfamily. A single membrane-targeting motif in one protomer is sufficient for trafficking of the ELFN homodimer.","method":"Domain deletion/mutagenesis, co-immunoprecipitation, co-expression heterologous cell assays, fluorescence-based membrane trafficking assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and mutagenesis in heterologous cells; ELFN2 properties inferred partly from parallel ELFN1 experiments in same study","pmids":["39675706"],"is_preprint":false},{"year":2026,"finding":"ELFN2 directly interacts with the catalytic subunit alpha of protein phosphatase-1 (PP1A) and inhibits PP1A-mediated dephosphorylation of YAP at Ser127, thereby promoting YAP nuclear export and functional inactivation. Pharmacological inhibition of PP1A abrogated ELFN2-induced YAP inactivation, confirming that PP1A is required in the ELFN2/PP1A/YAP signaling axis. In vivo lymph node metastasis models confirmed that ELFN2 suppresses metastatic dissemination in gastric cancer through this axis.","method":"Co-immunoprecipitation (ELFN2-PP1A direct interaction), PP1A pharmacological inhibition, YAP phosphorylation assays, in vivo lymph node metastasis and peritoneal carcinomatosis models, loss-of-function studies","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP establishes direct interaction, pharmacological rescue confirms pathway placement, in vivo models validate function; single lab","pmids":["41967793"],"is_preprint":false}],"current_model":"ELFN2 is a transmembrane postsynaptic cell adhesion molecule with extracellular LRR and FN3 domains that forms homodimers (and heterodimers with ELFN1) via its LRR domain before trafficking to the membrane; at synapses it transsynaptically recruits and directly modulates G protein coupling kinetics and efficacy of all group III mGluRs (requiring complex N-glycosylation at mGluR6-N445 for binding), specifying cone photoreceptor-to-ON bipolar cell wiring and regulating glutamatergic transmission in the brain; in non-neuronal contexts ELFN2 interacts with AurkA/eIF2α to promote autophagy in glioblastoma, and interacts with PP1A to inhibit YAP dephosphorylation and suppress metastasis in gastric cancer."},"narrative":{"teleology":[{"year":2007,"claim":"Identification of ELFN2 as a member of a novel eLRR transmembrane subfamily with brain-restricted expression established its structural classification and hinted at a neural role, but no function was assigned.","evidence":"Bioinformatic cataloguing of eLRR proteins combined with RT-PCR/in situ hybridization in developing mouse brain","pmids":["17868438"],"confidence":"Low","gaps":["No functional data provided","Expression profiling only, no protein-level validation","No interaction partners identified"]},{"year":2018,"claim":"A cancer biology study revealed that ELFN2 can interact with AurkA and eIF2α to promote autophagy in glioblastoma, providing the first evidence of ELFN2 protein–protein interactions but in a non-neuronal context.","evidence":"Co-immunoprecipitation, siRNA knockdown, ChIP, and autophagy assays in GBM cell lines","pmids":["30037656"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","Relevance of AurkA/eIF2α interaction to normal ELFN2 physiology unclear","No structural basis for the interaction"]},{"year":2019,"claim":"A major functional breakthrough established ELFN2 as a postsynaptic cell adhesion molecule that trans-synaptically binds and modulates G protein coupling of all group III mGluRs, with Elfn2 KO mice showing seizures, hyperactivity, and mGluR downregulation — rescued by group III mGluR agonists — thereby defining ELFN2's core synaptic role.","evidence":"Transcellular GPCR signaling platform, Elfn2 KO mice, electrophysiology, pharmacological rescue, co-immunoprecipitation","pmids":["31485013"],"confidence":"High","gaps":["Structural basis of ELFN2–mGluR interaction not resolved","Relative contributions of ELFN1 vs ELFN2 at specific synapse types unclear","Post-translational requirements for binding not yet explored"]},{"year":2020,"claim":"Unbiased proteomics in a cone-dominant retina revealed that ELFN2 localizes to cone photoreceptor terminals and transsynaptically recruits mGluR6 to specify cone-to-ON-bipolar cell wiring, demonstrating synergy with ELFN1 during circuit development.","evidence":"Proteomics, conditional knockout mice, electroretinography, immunohistochemistry, synaptogenesis assays","pmids":["32879010"],"confidence":"High","gaps":["Mechanism by which ELFN1 and ELFN2 cooperate at molecular level not dissected","Whether ELFN2 instructs or merely maintains cone-ON bipolar synapses unclear"]},{"year":2024,"claim":"Biochemical dissection showed that complex N-glycosylation of mGluR6 — specifically at N445 — is required for ELFN2 trans-synaptic binding, and that ELFN2 forms obligate LRR-mediated homodimers (and ELFN1 heterodimers) before membrane delivery, revealing critical post-translational and quaternary structural requirements.","evidence":"Reconstituted pull-down with purified extracellular domains, glycosidase treatment, site-directed mutagenesis, domain deletion/co-IP, membrane trafficking assays","pmids":["38428819","39675706"],"confidence":"High","gaps":["Crystal or cryo-EM structure of ELFN2–mGluR complex not available","Functional consequences of heterodimerization vs homodimerization on mGluR signaling not tested","Whether glycosylation requirements extend to mGluR4/7/8 binding untested"]},{"year":2026,"claim":"ELFN2 was shown to directly bind PP1A (protein phosphatase 1 catalytic subunit alpha) and inhibit PP1A-mediated YAP dephosphorylation, suppressing metastatic dissemination in gastric cancer — establishing ELFN2 as a bona fide PP1 regulatory subunit outside the nervous system.","evidence":"Co-immunoprecipitation (ELFN2–PP1A), PP1A pharmacological inhibition, YAP phosphorylation assays, in vivo metastasis models","pmids":["41967793"],"confidence":"Medium","gaps":["Single-lab study; independent replication needed","Whether PP1A regulatory activity is relevant in neurons not explored","Structural basis of PP1A binding (RVxF motif usage) not characterized"]},{"year":null,"claim":"No high-resolution structure of ELFN2 alone or in complex with any mGluR exists, and the relative physiological roles of ELFN2 homodimers versus ELFN1–ELFN2 heterodimers at distinct synapse types remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Structural model of ELFN2–mGluR complex needed","Cell-type-resolved functions of homo- vs heterodimers unknown","Whether PP1A regulatory and synaptic adhesion functions are coordinated or context-exclusive is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,7]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[3,6]}],"complexes":[],"partners":["MGLUR6","MGLUR4","MGLUR7","MGLUR8","ELFN1","PPP1CA","AURKA","EIF2S1"],"other_free_text":[]},"mechanistic_narrative":"ELFN2 is a postsynaptic transmembrane leucine-rich repeat (LRR) and fibronectin type III (FN3) domain-containing cell adhesion molecule that trans-synaptically recruits and functionally modulates all four group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8), thereby shaping glutamatergic synaptic transmission and circuit wiring in the brain and retina [PMID:31485013, PMID:32879010]. ELFN2 forms obligate homodimers (and heterodimers with ELFN1) via its LRR domain prior to membrane trafficking, and its trans-synaptic binding to mGluR6 requires complex N-glycosylation at mGluR6-N445 [PMID:39675706, PMID:38428819]. In cone photoreceptor terminals, ELFN2 acts in synergy with ELFN1 to specify cone-to-ON-bipolar cell connectivity and enable synaptic transmission, and Elfn2 knockout mice exhibit seizure susceptibility, hyperactivity, and anxiety-like behaviors that are rescued by group III mGluR agonists [PMID:32879010, PMID:31485013]. ELFN2 also functions as a protein phosphatase 1 (PP1A) regulatory subunit, directly binding PP1A to inhibit YAP dephosphorylation and suppress metastatic dissemination in gastric cancer [PMID:41967793]."},"prefetch_data":{"uniprot":{"accession":"Q5R3F8","full_name":"Protein phosphatase 1 regulatory subunit 29","aliases":["Extracellular leucine-rich repeat and fibronectin type III domain-containing protein 2","Leucine-rich repeat and fibronectin type-III domain-containing protein 6","Leucine-rich repeat-containing protein 62"],"length_aa":820,"mass_kda":89.7,"function":"Inhibits phosphatase activity of protein phosphatase 1 (PP1) complexes","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q5R3F8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ELFN2","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":[],"url":"https://opencell.sf.czbiohub.org/search/ELFN2","total_profiled":1310},"omim":[{"mim_id":"620223","title":"EXTRACELLULAR LEUCINE-RICH REPEAT AND FIBRONECTIN TYPE III DOMAIN-CONTAINING PROTEIN 2; ELFN2","url":"https://www.omim.org/entry/620223"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":17.3},{"tissue":"retina","ntpm":5.6}],"url":"https://www.proteinatlas.org/search/ELFN2"},"hgnc":{"alias_symbol":["dJ63G5.3","KIAA1904"],"prev_symbol":["LRRC62","PPP1R29"]},"alphafold":{"accession":"Q5R3F8","domains":[{"cath_id":"3.80.10.10","chopping":"23-186","consensus_level":"medium","plddt":92.6324,"start":23,"end":186},{"cath_id":"2.60.40.10","chopping":"297-378","consensus_level":"high","plddt":86.9505,"start":297,"end":378}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5R3F8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5R3F8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5R3F8-F1-predicted_aligned_error_v6.png","plddt_mean":60.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELFN2","jax_strain_url":"https://www.jax.org/strain/search?query=ELFN2"},"sequence":{"accession":"Q5R3F8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5R3F8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5R3F8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5R3F8"}},"corpus_meta":[{"pmid":"25025965","id":"PMC_25025965","title":"Unbiased 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XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins.","date":"2001","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/11572484","citation_count":35,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32393512","id":"PMC_32393512","title":"SUMOylation of DDX39A Alters Binding and Export of Antiviral Transcripts to Control Innate Immunity.","date":"2020","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/32393512","citation_count":27,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"39499777","id":"PMC_39499777","title":"Extracellular proximal interaction profiling by cell surface-targeted TurboID reveals LDLR as a partner of liganded EGFR.","date":"2024","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/39499777","citation_count":11,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"37689310","id":"PMC_37689310","title":"Pulse-SILAC and Interactomics Reveal Distinct DDB1-CUL4-Associated Factors, Cellular Functions, and Protein Substrates.","date":"2023","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/37689310","citation_count":8,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35081534","id":"PMC_35081534","title":"Identification of Key Prognostic-Related miRNA-mRNA Pairs in the Progression of Endometrial Carcinoma.","date":"2022","source":"Gynecologic and obstetric investigation","url":"https://pubmed.ncbi.nlm.nih.gov/35081534","citation_count":1,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8804,"output_tokens":2198,"usd":0.029691},"stage2":{"model":"claude-opus-4-6","input_tokens":5481,"output_tokens":2446,"usd":0.132832},"total_usd":0.347357,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":19643,"output_tokens":3505,"usd":0.055752},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6261,"output_tokens":2190,"usd":0.129082}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"ELFN2 is a postsynaptic adhesion molecule that selectively binds group III metabotropic glutamate receptors (mGluRs) in trans, directly altering G protein coupling kinetics and efficacy. Loss of ELFN2 in mice results in selective downregulation of group III mGluRs and dysregulated glutamatergic synaptic transmission, and Elfn2 KO mice show seizure susceptibility, hyperactivity, and anxiety/compulsivity rescuable by pharmacological augmentation of group III mGluRs.\",\n      \"method\": \"Transcellular GPCR signaling platform, reciprocal binding assays, Elfn2 knockout mice with behavioral and electrophysiological readouts, pharmacological rescue\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (in vitro signaling platform, KO mice, pharmacological rescue) in a single study with rigorous controls\",\n      \"pmids\": [\"31485013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ELFN2 is selectively expressed in cone photoreceptors and transsynaptically recruits the postsynaptic neurotransmitter receptor mGluR6 in ON-type bipolar cells to enable synaptic transmission. ELFN2 functions in synergy with ELFN1 in cone terminals to specify selective wiring and transmission of cone signals.\",\n      \"method\": \"Unbiased cone-dominant species proteomics, immunohistochemistry, genetic mouse models (cone-specific markers), electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomic identification plus genetic/functional validation in vivo with defined circuit phenotype\",\n      \"pmids\": [\"32879010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ELFN2 promotes GBM cell autophagy by interacting with Aurora kinase A (AurkA) and eIF2α, inhibiting AurkA activation. Aberrantly high ELFN2 expression in GBM is caused by hypomethylation of its promoter and by LINC00470-mediated adsorption of miR-101 (a negative regulator of ELFN2) as well as LINC00470-mediated reduction of H3K27me3 occupancy at the ELFN2 locus.\",\n      \"method\": \"Co-immunoprecipitation (ELFN2 with AurkA and eIF2α), promoter methylation analysis, miR-101 overexpression/knockdown, LINC00470 manipulation, autophagy assays\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and functional assays in one study, but single lab with cancer cell line context\",\n      \"pmids\": [\"30037656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Complex N-glycosylation of mGluR6 is required for trans-synaptic interaction with ELFN2 (and ELFN1). Pull-down experiments with ELFN2 extracellular domain showed binding exclusively to the complex glycosylated form of mGluR6. Mutation of the N445 glycosylation site severely impaired ELFN2 binding, while the quadruple N-glycosylation mutant completely abolished plasma membrane trafficking.\",\n      \"method\": \"Glycosidase enzyme treatment (PNGase F, Endo H), pull-down assays with ELFN2 extracellular domain, site-directed mutagenesis of N-glycosylation sites, surface expression assays in heterologous cells and rod bipolar cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro pull-down with mutagenesis and cell biological validation with multiple orthogonal methods\",\n      \"pmids\": [\"38428819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ELFN2 exhibits similar membrane trafficking and dimerization properties to ELFN1, including participation in heterodimerization with ELFN1 mediated via the extracellular leucine-rich repeat (LRR) domain. The intracellular domain controls membrane trafficking and post-synaptic localization, while dimerization relies on the extracellular LRR domain.\",\n      \"method\": \"Domain deletion and mutagenesis, co-immunoprecipitation for homodimerization and heterodimerization, live-cell imaging, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and mutagenesis in single study; ELFN2 properties inferred from parallel experiments alongside ELFN1\",\n      \"pmids\": [\"39675706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ELFN2 directly interacts with the catalytic subunit alpha of protein phosphatase-1 (PP1A) and inhibits PP1A-mediated dephosphorylation of YAP at Ser127, thereby promoting YAP nuclear export and functional inactivation to suppress lymph node metastasis in gastric cancer. Pharmacological inhibition of PP1A abrogated ELFN2-induced YAP inactivation.\",\n      \"method\": \"Co-immunoprecipitation (ELFN2 with PP1A), YAP phosphorylation assays, PP1A inhibitor experiments, in vivo mouse models of lymph node metastasis and peritoneal carcinomatosis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus pharmacological validation plus in vivo models, but single lab and single study\",\n      \"pmids\": [\"41967793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELFN2 (and ELFN1) interact trans-synaptically with all group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8), and both can alter mGluR-mediated signaling through trans-interaction. In the retina, ELFN2 is presynaptically expressed in cones and recruits mGluR6 postsynaptically in ON-bipolar cells.\",\n      \"method\": \"Review synthesizing binding and functional data from multiple primary studies using co-IP, transcellular signaling assays, and genetic mouse models\",\n      \"journal\": \"Frontiers in neural circuits\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — synthesis review citing primary experiments; breadth of binding partner evidence supports moderate confidence\",\n      \"pmids\": [\"33790745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In the absence of LRFN2, ELFN2 localization at cone synapses is maintained, demonstrating that ELFN2 synaptic targeting is independent of LRFN2.\",\n      \"method\": \"LRFN2 knockout mice, immunofluorescence localization of ELFN2 at cone synapses\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single immunolocalization result in KO mice, no mechanistic follow-up for ELFN2 itself\",\n      \"pmids\": [\"38408870\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELFN2 is a transmembrane postsynaptic (and in cones, presynaptic) cell-adhesion molecule that transsynaptically recruits and modulates group III metabotropic glutamate receptors (mGluR4/6/7/8) by altering G protein coupling kinetics and efficacy; it heterodimerizes with ELFN1 via extracellular LRR domains, requires complex N-glycosylation on mGluR6 for productive binding, suppresses YAP activity in cancer cells by blocking PP1A-mediated dephosphorylation, and promotes GBM autophagy through interaction with AurkA and eIF2α.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:25025965 — ELFN2 mentioned as one of 11 genes in microarray, no mechanistic finding about ELFN2. EXCLUDE (expression/biomarker only).\n2. PMID:29084944 — CYTH4-ELFN2 locus methylation association study. EXCLUDE (epigenome association, no mechanism).\n3. PMID:30037656 — KEEP: Describes ELFN2 function in GBM, interaction with AurkA and eIF2α, autophagy regulation, epigenetic regulation.\n4. PMID:37120627 — KEEP: Identifies Elfn2 as DDX43-targeted hub gene in spermiogenesis (mechanistic role).\n5. PMID:32879010 — KEEP: ELFN2 role in cone photoreceptor synaptic wiring, recruits mGluR6, works with ELFN1.\n6. PMID:31485013 — KEEP: ELFN2 as postsynaptic adhesion molecule, binds group III mGluRs, alters G protein coupling, KO phenotypes.\n7. PMID:29218251 — KEEP: CST4 promotes gastric cancer via ELFN2 signaling pathway.\n8. PMID:33790745 — KEEP: Review of Elfn-mGluR interactions, trans-synaptic regulation mechanisms.\n9. PMID:25023003 — EXCLUDE: Genetic association/synonymous mutation in ELFN2, no mechanism.\n10. PMID:38428819 — KEEP: Complex N-glycosylation of mGluR6 required for ELFN1/ELFN2 interaction; specific glycosylation site mapping.\n11. PMID:39675706 — KEEP: ELFN1/ELFN2 dimerization, membrane trafficking, heterodimerization.\n12. PMID:38408870 — KEEP: LRFN2 KO study; ELFN2 localization noted, but paper is about LRFN2, not ELFN2. EXCLUDE (ELFN2 mentioned as marker only).\n13. PMID:31301291 — EXCLUDE: About LRRC62, not ELFN2.\n14. PMID:41967793 — KEEP: ELFN2 interacts with PP1A, inhibits YAP dephosphorylation, suppresses LNM in gastric cancer.\n15. PMID:40689847 — KEEP: mGlu7/ELFN1 pharmacology; ELFN2 mentioned as anchoring mGlu7 but paper focuses on ELFN1. Partial KEEP for ELFN2 anchoring role.\n\nGene2pubmed curated papers:\n- Most are large genomics/proteomics studies not specifically about ELFN2 mechanism. The only relevant ones: PMID:17868438 (eLRR superfamily characterization identifying ELFN genes). Others are large-scale studies where ELFN2 may appear incidentally. EXCLUDE most; KEEP PMID:17868438 for initial characterization.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"ELFN2 (along with ELFN1) was identified as a member of a novel subfamily of extracellular leucine-rich repeat (eLRR) transmembrane proteins containing an FN3 domain. The two ELFN genes were shown to be expressed in discrete patterns in the developing mouse brain, notably in the thalamus and cortex, establishing the founding structural characterization of the ELFN family.\",\n      \"method\": \"Bioinformatic eLRR protein catalogue combined with mouse brain expression profiling (RT-PCR/in situ)\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression/structural annotation without functional mechanistic validation\",\n      \"pmids\": [\"17868438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ELFN2 was identified as a hypomethylation-driven oncogene in glioblastoma (GBM) that promotes autophagy by directly interacting with Aurora kinase A (AurkA) and eIF2α, inhibiting AurkA activation. LINC00470 was shown to upregulate ELFN2 by sponging miR-101 and reducing H3K27me3 occupancy at the ELFN2 promoter.\",\n      \"method\": \"Co-immunoprecipitation (AurkA/eIF2α binding), loss-of-function (siRNA knockdown), promoter methylation and ChIP assays, autophagy functional assays\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple orthogonal methods (Co-IP, ChIP, functional assays) but limited independent replication\",\n      \"pmids\": [\"30037656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ELFN2 was characterized as a postsynaptic cell adhesion molecule with a distinct expression pattern throughout the brain that selectively binds group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8) in trans. Using a transcellular GPCR signaling platform, ELFN2 was shown to directly alter G protein coupling kinetics and efficacy of group III mGluRs. Loss of ELFN2 in mice caused selective downregulation of group III mGluRs and dysregulated glutamatergic synaptic transmission, and Elfn2 KO mice displayed seizure susceptibility, hyperactivity, and anxiety/compulsivity that were rescued by pharmacological augmentation of group III mGluRs.\",\n      \"method\": \"Transcellular GPCR signaling platform, Elfn2 knockout mice, electrophysiology, pharmacological rescue, Co-immunoprecipitation\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional assays, genetic KO with defined phenotypes, pharmacological rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"31485013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Using an unbiased proteomic strategy in a cone-dominant species, ELFN2 was identified as selectively expressed in cone photoreceptor terminals, where it transsynaptically recruits the neurotransmitter receptor mGluR6 in ON-type bipolar cells to enable synaptic transmission. ELFN2 was found to function in synergy with ELFN1, and their concerted interplay during development specifies selective cone-to-ON-bipolar cell wiring and transmission.\",\n      \"method\": \"Unbiased proteomics, immunohistochemistry/localization, conditional knockout mice, electroretinography, synaptogenesis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased proteomic identification, KO functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"32879010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Review synthesis establishing that ELFN2 (and ELFN1) can interact trans-synaptically with all four group III mGluRs (mGluR4, mGluR6, mGluR7, mGluR8), and that these interactions alter mGluR-mediated signaling across hippocampal, cortical, and retinal synapses. ELFN2 postsynaptically modulates group III mGluR signaling properties and synaptic transmission characteristics.\",\n      \"method\": \"Review/synthesis of experimental literature including functional assays and genetic models\",\n      \"journal\": \"Frontiers in neural circuits\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review consolidating findings from multiple labs; mechanistic claims grounded in cited experimental work\",\n      \"pmids\": [\"33790745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Single-cell RNA sequencing and enhanced crosslinking immunoprecipitation (eCLIP-seq) identified Elfn2 as a key hub gene targeted by the RNA helicase DDX43 during spermiogenesis, placing ELFN2 downstream of DDX43-mediated RNA regulatory processes required for spermatid chromatin remodeling and differentiation.\",\n      \"method\": \"Single-cell RNA-seq, enhanced CLIP-seq (eCLIP), Ddx43 knockout mice, ATPase-dead missense mutant\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — eCLIP directly identifies ELFN2 mRNA as DDX43 target; genetic KO and ATPase mutant confirm phenotype, but mechanistic role of ELFN2 protein itself in this context is not directly dissected\",\n      \"pmids\": [\"37120627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Complex N-glycosylation of mGluR6 acquired in the Golgi is required for trans-synaptic interaction with ELFN1 and ELFN2 extracellular domains. Pull-down experiments with ELFN1 and ELFN2 extracellular domains showed that they interact exclusively with the complex glycosylated form of mGluR6. Mutation of N-glycosylation site N445 on mGluR6 severely impaired both ELFN1 and ELFN2 binding, identifying N445 as a critical glycosylation site for ELFN interaction.\",\n      \"method\": \"Glycosidase treatment (PNGase F, Endo H), pull-down assays with ELFN1/ELFN2 extracellular domains, site-directed mutagenesis of N-glycosylation sites, heterologous expression, rod bipolar cell dendritic tip localization assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted pull-down with purified extracellular domains, mutagenesis of specific glycosylation sites, in vivo localization validation\",\n      \"pmids\": [\"38428819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ELFN2 (like its closest homolog ELFN1) forms obligate homodimers prior to membrane trafficking, with homodimerization mediated by the extracellular leucine-rich repeat (LRR) domain rather than the intracellular region. ELFN2 also participates in heterodimerization with ELFN1, indicating conserved dimerization mechanisms across the ELFN subfamily. A single membrane-targeting motif in one protomer is sufficient for trafficking of the ELFN homodimer.\",\n      \"method\": \"Domain deletion/mutagenesis, co-immunoprecipitation, co-expression heterologous cell assays, fluorescence-based membrane trafficking assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and mutagenesis in heterologous cells; ELFN2 properties inferred partly from parallel ELFN1 experiments in same study\",\n      \"pmids\": [\"39675706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ELFN2 directly interacts with the catalytic subunit alpha of protein phosphatase-1 (PP1A) and inhibits PP1A-mediated dephosphorylation of YAP at Ser127, thereby promoting YAP nuclear export and functional inactivation. Pharmacological inhibition of PP1A abrogated ELFN2-induced YAP inactivation, confirming that PP1A is required in the ELFN2/PP1A/YAP signaling axis. In vivo lymph node metastasis models confirmed that ELFN2 suppresses metastatic dissemination in gastric cancer through this axis.\",\n      \"method\": \"Co-immunoprecipitation (ELFN2-PP1A direct interaction), PP1A pharmacological inhibition, YAP phosphorylation assays, in vivo lymph node metastasis and peritoneal carcinomatosis models, loss-of-function studies\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP establishes direct interaction, pharmacological rescue confirms pathway placement, in vivo models validate function; single lab\",\n      \"pmids\": [\"41967793\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELFN2 is a transmembrane postsynaptic cell adhesion molecule with extracellular LRR and FN3 domains that forms homodimers (and heterodimers with ELFN1) via its LRR domain before trafficking to the membrane; at synapses it transsynaptically recruits and directly modulates G protein coupling kinetics and efficacy of all group III mGluRs (requiring complex N-glycosylation at mGluR6-N445 for binding), specifying cone photoreceptor-to-ON bipolar cell wiring and regulating glutamatergic transmission in the brain; in non-neuronal contexts ELFN2 interacts with AurkA/eIF2α to promote autophagy in glioblastoma, and interacts with PP1A to inhibit YAP dephosphorylation and suppress metastasis in gastric cancer.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ELFN2 is a leucine-rich repeat (LRR)-containing transmembrane adhesion molecule that functions as a trans-synaptic organizer of glutamatergic signaling by selectively binding and recruiting group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8), directly modulating their G protein coupling kinetics and efficacy [PMID:31485013, PMID:33790745]. In the retina, ELFN2 is expressed presynaptically in cone photoreceptors where it acts in synergy with ELFN1 to recruit postsynaptic mGluR6 on ON-bipolar cells, with productive binding requiring complex N-glycosylation of mGluR6, and ELFN2 heterodimerizes with ELFN1 through its extracellular LRR domain while the intracellular domain governs membrane trafficking and postsynaptic localization [PMID:32879010, PMID:38428819, PMID:39675706]. Loss of ELFN2 in mice causes selective downregulation of group III mGluRs, seizure susceptibility, hyperactivity, and anxiety/compulsivity that are rescued by pharmacological augmentation of group III mGluR signaling [PMID:31485013]. Outside the nervous system, ELFN2 interacts with PP1A to block YAP dephosphorylation, promoting YAP inactivation in gastric cancer cells, and interacts with Aurora kinase A and eIF2α to promote autophagy in glioblastoma [PMID:41967793, PMID:30037656].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"An initial cancer biology context revealed that ELFN2 has functional roles beyond the nervous system, interacting with AurkA and eIF2α to promote autophagy in GBM cells, establishing ELFN2 as a signaling modulator not limited to synaptic function.\",\n      \"evidence\": \"Co-immunoprecipitation of ELFN2 with AurkA and eIF2α, autophagy assays, and epigenetic regulation studies in GBM cell lines\",\n      \"pmids\": [\"30037656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study in cancer cell lines; interaction with AurkA/eIF2α not validated in independent systems\",\n        \"Whether ELFN2-mediated autophagy operates through a mechanism analogous to its synaptic signaling role is unknown\",\n        \"Structural basis of the ELFN2–AurkA interaction is undefined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The central synaptic function of ELFN2 was established: it acts as a postsynaptic adhesion molecule that selectively binds group III mGluRs in trans, directly altering their G protein coupling, thereby explaining how loss of ELFN2 leads to dysregulated glutamatergic transmission and neuropsychiatric-like phenotypes.\",\n      \"evidence\": \"Transcellular GPCR signaling platform, reciprocal binding assays, Elfn2 knockout mice with electrophysiology, behavioral testing, and pharmacological rescue with group III mGluR agonists\",\n      \"pmids\": [\"31485013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the trans-interaction between ELFN2 and group III mGluRs is unresolved\",\n        \"Relative contributions of ELFN2 vs ELFN1 at central synapses remain unclear\",\n        \"Specific synaptic subtypes most affected by ELFN2 loss not fully mapped\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Retinal circuit specificity was resolved: ELFN2 is selectively expressed in cone photoreceptor terminals (presynaptically), where it trans-synaptically recruits mGluR6 to ON-bipolar cell postsynapses, functioning in synergy with ELFN1 to specify cone-bipolar wiring.\",\n      \"evidence\": \"Unbiased proteomics in cone-dominant species, immunohistochemistry, genetic mouse models with electrophysiology\",\n      \"pmids\": [\"32879010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ELFN2 has additional presynaptic partners beyond mGluR6 in cone terminals is unknown\",\n        \"Mechanism of synergy between ELFN1 and ELFN2 at cone synapses is not molecularly defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A critical post-translational requirement for the trans-synaptic interaction was identified: complex N-glycosylation of mGluR6, particularly at N445, is necessary for ELFN2 binding, providing the first glycan-dependent mechanism underlying ELFN2 target recognition.\",\n      \"evidence\": \"Glycosidase treatment, pull-down with ELFN2 extracellular domain, site-directed mutagenesis of mGluR6 N-glycosylation sites, surface expression assays in heterologous cells and rod bipolar cells\",\n      \"pmids\": [\"38428819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether glycosylation similarly gates ELFN2 binding to mGluR4/7/8 is untested\",\n        \"No structural model of the ELFN2–glycosylated mGluR6 interface exists\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The domain architecture governing ELFN2 oligomerization and trafficking was delineated: the extracellular LRR domain mediates both homodimerization and heterodimerization with ELFN1, while the intracellular domain controls membrane trafficking and postsynaptic localization.\",\n      \"evidence\": \"Domain deletion/mutagenesis, co-immunoprecipitation for homo- and heterodimerization, live-cell imaging, subcellular fractionation\",\n      \"pmids\": [\"39675706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"ELFN2-specific experiments were largely inferred from parallel ELFN1 experiments; dedicated ELFN2 mutagenesis data are limited\",\n        \"Stoichiometry of ELFN1–ELFN2 heterodimers at synapses is unknown\",\n        \"How the intracellular domain is recognized by trafficking machinery is undefined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A non-neuronal signaling axis was uncovered: ELFN2 directly binds PP1A and blocks its dephosphorylation of YAP at Ser127, thereby inactivating YAP and suppressing metastasis, establishing ELFN2 as a Hippo pathway modulator in cancer.\",\n      \"evidence\": \"Co-immunoprecipitation of ELFN2 with PP1A, YAP phosphorylation assays, PP1A inhibitor rescue, in vivo mouse metastasis models of gastric cancer\",\n      \"pmids\": [\"41967793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; the ELFN2–PP1A interaction awaits independent replication\",\n        \"Whether the PP1A-binding function operates in normal neuronal or retinal physiology is unknown\",\n        \"Domain on ELFN2 responsible for PP1A binding is not mapped\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structural model of ELFN2 or its complexes with mGluR partners exists, and the mechanisms by which ELFN2 allosterically modulates G protein coupling kinetics remain unresolved at the molecular level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-level structure of ELFN2 alone or in complex with any mGluR is lacking\",\n        \"Allosteric mechanism by which ELFN2 trans-binding changes mGluR G protein coupling is unknown\",\n        \"Relative in vivo contributions of ELFN2 homodimers vs ELFN1–ELFN2 heterodimers are undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"ELFN1-ELFN2 heterodimer\"\n    ],\n    \"partners\": [\n      \"ELFN1\",\n      \"GRM6\",\n      \"GRM7\",\n      \"GRM4\",\n      \"GRM8\",\n      \"PPP1CA\",\n      \"AURKA\",\n      \"EIF2S1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ELFN2 is a postsynaptic transmembrane leucine-rich repeat (LRR) and fibronectin type III (FN3) domain-containing cell adhesion molecule that trans-synaptically recruits and functionally modulates all four group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8), thereby shaping glutamatergic synaptic transmission and circuit wiring in the brain and retina [PMID:31485013, PMID:32879010]. ELFN2 forms obligate homodimers (and heterodimers with ELFN1) via its LRR domain prior to membrane trafficking, and its trans-synaptic binding to mGluR6 requires complex N-glycosylation at mGluR6-N445 [PMID:39675706, PMID:38428819]. In cone photoreceptor terminals, ELFN2 acts in synergy with ELFN1 to specify cone-to-ON-bipolar cell connectivity and enable synaptic transmission, and Elfn2 knockout mice exhibit seizure susceptibility, hyperactivity, and anxiety-like behaviors that are rescued by group III mGluR agonists [PMID:32879010, PMID:31485013]. ELFN2 also functions as a protein phosphatase 1 (PP1A) regulatory subunit, directly binding PP1A to inhibit YAP dephosphorylation and suppress metastatic dissemination in gastric cancer [PMID:41967793].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of ELFN2 as a member of a novel eLRR transmembrane subfamily with brain-restricted expression established its structural classification and hinted at a neural role, but no function was assigned.\",\n      \"evidence\": \"Bioinformatic cataloguing of eLRR proteins combined with RT-PCR/in situ hybridization in developing mouse brain\",\n      \"pmids\": [\"17868438\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional data provided\", \"Expression profiling only, no protein-level validation\", \"No interaction partners identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A cancer biology study revealed that ELFN2 can interact with AurkA and eIF2α to promote autophagy in glioblastoma, providing the first evidence of ELFN2 protein–protein interactions but in a non-neuronal context.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, ChIP, and autophagy assays in GBM cell lines\",\n      \"pmids\": [\"30037656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent replication\", \"Relevance of AurkA/eIF2α interaction to normal ELFN2 physiology unclear\", \"No structural basis for the interaction\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A major functional breakthrough established ELFN2 as a postsynaptic cell adhesion molecule that trans-synaptically binds and modulates G protein coupling of all group III mGluRs, with Elfn2 KO mice showing seizures, hyperactivity, and mGluR downregulation — rescued by group III mGluR agonists — thereby defining ELFN2's core synaptic role.\",\n      \"evidence\": \"Transcellular GPCR signaling platform, Elfn2 KO mice, electrophysiology, pharmacological rescue, co-immunoprecipitation\",\n      \"pmids\": [\"31485013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ELFN2–mGluR interaction not resolved\", \"Relative contributions of ELFN1 vs ELFN2 at specific synapse types unclear\", \"Post-translational requirements for binding not yet explored\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Unbiased proteomics in a cone-dominant retina revealed that ELFN2 localizes to cone photoreceptor terminals and transsynaptically recruits mGluR6 to specify cone-to-ON-bipolar cell wiring, demonstrating synergy with ELFN1 during circuit development.\",\n      \"evidence\": \"Proteomics, conditional knockout mice, electroretinography, immunohistochemistry, synaptogenesis assays\",\n      \"pmids\": [\"32879010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ELFN1 and ELFN2 cooperate at molecular level not dissected\", \"Whether ELFN2 instructs or merely maintains cone-ON bipolar synapses unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Biochemical dissection showed that complex N-glycosylation of mGluR6 — specifically at N445 — is required for ELFN2 trans-synaptic binding, and that ELFN2 forms obligate LRR-mediated homodimers (and ELFN1 heterodimers) before membrane delivery, revealing critical post-translational and quaternary structural requirements.\",\n      \"evidence\": \"Reconstituted pull-down with purified extracellular domains, glycosidase treatment, site-directed mutagenesis, domain deletion/co-IP, membrane trafficking assays\",\n      \"pmids\": [\"38428819\", \"39675706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal or cryo-EM structure of ELFN2–mGluR complex not available\", \"Functional consequences of heterodimerization vs homodimerization on mGluR signaling not tested\", \"Whether glycosylation requirements extend to mGluR4/7/8 binding untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"ELFN2 was shown to directly bind PP1A (protein phosphatase 1 catalytic subunit alpha) and inhibit PP1A-mediated YAP dephosphorylation, suppressing metastatic dissemination in gastric cancer — establishing ELFN2 as a bona fide PP1 regulatory subunit outside the nervous system.\",\n      \"evidence\": \"Co-immunoprecipitation (ELFN2–PP1A), PP1A pharmacological inhibition, YAP phosphorylation assays, in vivo metastasis models\",\n      \"pmids\": [\"41967793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study; independent replication needed\", \"Whether PP1A regulatory activity is relevant in neurons not explored\", \"Structural basis of PP1A binding (RVxF motif usage) not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structure of ELFN2 alone or in complex with any mGluR exists, and the relative physiological roles of ELFN2 homodimers versus ELFN1–ELFN2 heterodimers at distinct synapse types remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Structural model of ELFN2–mGluR complex needed\", \"Cell-type-resolved functions of homo- vs heterodimers unknown\", \"Whether PP1A regulatory and synaptic adhesion functions are coordinated or context-exclusive is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MGLUR6\",\n      \"MGLUR4\",\n      \"MGLUR7\",\n      \"MGLUR8\",\n      \"ELFN1\",\n      \"PPP1CA\",\n      \"AURKA\",\n      \"EIF2S1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}