{"gene":"ELFN2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2019,"finding":"ELFN2 is a postsynaptic adhesion molecule that selectively binds group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8) in trans across the synapse, directly alters G protein coupling kinetics and efficacy of group III mGluRs, and its loss results in selective downregulation of group III mGluRs and dysregulated glutamatergic synaptic transmission. Elfn2 KO mice display seizure susceptibility, hyperactivity, and anxiety/compulsivity rescued by pharmacological augmentation of group III mGluRs.","method":"Transcellular GPCR signaling platform, Elfn2 knockout mice, electrophysiology, behavioral assays, pharmacological rescue","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including transcellular signaling assay, KO mice with defined synaptic and behavioral phenotypes, and pharmacological rescue in a single rigorous study","pmids":["31485013"],"is_preprint":false},{"year":2020,"finding":"ELFN2 is selectively expressed in cone photoreceptors (not rods) and transsynaptically recruits mGluR6 in ON-bipolar cells to enable cone synaptic transmission. ELFN2 functions in synergy with ELFN1 during development to specify selective wiring and transmission of cone signals to ON-type bipolar cells.","method":"Unbiased proteomics in cone-dominant species, conditional knockout mice, immunolocalization, electrophysiology (ERG), and genetic interaction (ELFN1/ELFN2 double mutants)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic identification, KO mouse models with defined synaptic phenotypes, genetic interaction experiments, and functional electrophysiology in a single study","pmids":["32879010"],"is_preprint":false},{"year":2018,"finding":"In GBM cells, ELFN2 promotes autophagy by interacting with Aurora kinase A (AurkA) and eIF2α and inhibiting AurkA activation. ELFN2 expression is epigenetically regulated by promoter hypomethylation, miR-101 downregulation, and the lncRNA LINC00470 (which adsorbs miR-101 and decreases H3K27me3 occupancy at the ELFN2 promoter).","method":"Co-immunoprecipitation, overexpression/knockdown in GBM cell lines, autophagy assays, methylation analysis, chromatin immunoprecipitation","journal":"Molecular therapy : the journal of the American Society of Gene Therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and functional cell-based assays in a single lab; some orthogonal methods but abstract-level description limits mechanistic detail","pmids":["30037656"],"is_preprint":false},{"year":2019,"finding":"LRRC62 (ELFN2 alias) functions as an adaptor protein that recruits the deubiquitinase CYLD to TAK1, thereby promoting K63-linked deubiquitination and inactivation of TAK1, resulting in negative regulation of TLR-induced NF-κB and MAPK signaling and reduced pro-inflammatory cytokine production.","method":"Co-immunoprecipitation, overexpression and knockdown in cell lines, cytokine production assays, ubiquitination assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional assays in a single lab with multiple orthogonal readouts; LRRC62 is a confirmed alias for ELFN2 (PPP1R29/LRRC62)","pmids":["31301291"],"is_preprint":false},{"year":2024,"finding":"Complex N-glycosylation of mGluR6 is required for its trans-synaptic interaction with ELFN2 (and ELFN1). Pull-down experiments with ELFN2 extracellular domains showed interaction exclusively with complex-glycosylated mGluR6. Mutation at N445 of mGluR6 severely impaired ELFN2 binding. N-glycosylation at N445 is sufficient but not necessary for dendritic tip localization of mGluR6.","method":"Glycosidase treatment (PNGase F, Endo H), pulldown assays with ELFN2 extracellular domain, site-directed mutagenesis of N-glycosylation sites, surface expression and localization assays in heterologous cells and rod bipolar cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution (pulldown with recombinant extracellular domains), mutagenesis, and multiple orthogonal assays establishing glycosylation requirement for ELFN2 binding","pmids":["38428819"],"is_preprint":false},{"year":2024,"finding":"ELFN2 forms homodimers prior to membrane trafficking, utilizing the extracellular leucine-rich repeat (LRR) domain for dimerization. ELFN2 also participates in heterodimerization with ELFN1. The intracellular domain controls membrane targeting and postsynaptic localization, with a ~30 amino acid juxtamembranous region required for membrane-targeting, and a single membrane-targeting motif in one protomer is sufficient for trafficking of the homodimer.","method":"Domain deletion/mutagenesis, co-immunoprecipitation for dimerization, subcellular fractionation, live-cell imaging, postsynaptic localization assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis and co-IP for dimerization, localization assays; single lab but multiple orthogonal methods","pmids":["39675706"],"is_preprint":false},{"year":2026,"finding":"ELFN2 interacts directly 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, suppressing lymph node metastasis in gastric cancer. Pharmacological inhibition of PP1A abrogated ELFN2-induced YAP inactivation.","method":"Co-immunoprecipitation, phosphorylation assays, PP1A inhibitor pharmacology, in vivo metastasis models (lymph node and peritoneal carcinomatosis)","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and pharmacological rescue with in vivo validation; single lab, single publication, abstract-level description","pmids":["41967793"],"is_preprint":false},{"year":2021,"finding":"ELFN2 (and ELFN1) can interact in trans with all group III mGluRs (mGluR4, mGluR6, mGluR7, mGluR8) and alter mGluR-mediated signaling through these trans-interactions. Postsynaptic ELFN2 in the brain mediates regulation of excitatory input through recruitment of presynaptic group III mGluRs.","method":"Review synthesizing results from multiple studies including transcellular signaling assays and KO models (mechanistic synthesis/review article citing primary data)","journal":"Frontiers in neural circuits","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — finding is corroborated by multiple primary studies; this is a review, but the underlying mechanistic data are replicated across labs","pmids":["33790745"],"is_preprint":false},{"year":2026,"finding":"ELFN2 is mislocalized at cone pedicles when mGluR6 is ablated prior to synaptogenesis during human retinal development (in iPSC-derived organoids), indicating that mGluR6 is required for proper ELFN2 localization during circuit assembly.","method":"CRISPR-based genetic ablation in human iPSC-derived retinal organoids, immunofluorescence localization","journal":"bioRxiv : the preprint server for biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, immunolocalization only without functional follow-up for ELFN2 specifically","pmids":["42094404"],"is_preprint":true}],"current_model":"ELFN2 is a postsynaptic leucine-rich repeat and fibronectin type III domain-containing transmembrane adhesion molecule that transsynaptically recruits and modulates all group III metabotropic glutamate receptors (mGluR4/6/7/8) by altering G protein coupling kinetics, is selectively expressed in cone photoreceptors where it orchestrates ON-bipolar cell wiring by recruiting mGluR6, forms homodimers (via its extracellular LRR domain) and heterodimers with ELFN1 prior to membrane trafficking, requires complex N-glycosylation of mGluR6 at N445 for trans-synaptic binding, interacts with PP1A to block YAP dephosphorylation and suppress metastasis in gastric cancer, and in immune cells (as LRRC62) acts as an adaptor recruiting deubiquitinase CYLD to TAK1 to attenuate TLR-driven NF-κB signaling."},"narrative":{"mechanistic_narrative":"ELFN2 is a postsynaptic transmembrane adhesion molecule that organizes glutamatergic synapses by selectively binding all group III metabotropic glutamate receptors (mGluR4/6/7/8) in trans across the synaptic cleft and directly altering their G protein coupling kinetics and signaling efficacy [PMID:31485013, PMID:33790745]. Its loss downregulates group III mGluRs and dysregulates synaptic transmission, producing seizure susceptibility, hyperactivity, and anxiety/compulsivity phenotypes in knockout mice that are reversed by pharmacological augmentation of group III mGluRs [PMID:31485013]. In the retina, ELFN2 is selectively expressed in cone photoreceptors, where together with ELFN1 it transsynaptically recruits mGluR6 in ON-bipolar cells to specify cone-to-bipolar wiring and transmission [PMID:32879010]. The trans-synaptic interaction depends on complex N-glycosylation of mGluR6 at N445, which is required for binding by the ELFN2 extracellular domain [PMID:38428819], and ELFN2 itself dimerizes through its extracellular leucine-rich repeat domain—forming homodimers and ELFN1 heterodimers prior to trafficking—while its intracellular juxtamembranous region directs membrane targeting and postsynaptic localization [PMID:39675706]. Beyond the synapse, ELFN2 has been assigned roles as an adaptor that recruits the deubiquitinase CYLD to TAK1 to attenuate TLR-driven NF-κB and MAPK signaling (as LRRC62) [PMID:31301291] and as a binding partner of protein phosphatase-1 catalytic subunit alpha (PP1A) that blocks YAP Ser127 dephosphorylation to suppress gastric cancer metastasis [PMID:41967793].","teleology":[{"year":2019,"claim":"Established ELFN2's core function: it was unknown how postsynaptic cues selectively shape group III mGluR signaling, and this work showed ELFN2 binds group III mGluRs in trans and tunes their G protein coupling, with loss causing defined synaptic and behavioral phenotypes.","evidence":"Transcellular GPCR signaling platform, Elfn2 KO mice, electrophysiology, behavioral assays, and pharmacological rescue","pmids":["31485013"],"confidence":"High","gaps":["Structural basis of selective group III mGluR recognition not defined","Mechanism by which trans-binding alters G protein coupling kinetics unresolved"]},{"year":2020,"claim":"Resolved the cell-type-specific role in vision: it was unclear which adhesion molecule wires cone photoreceptors to ON-bipolar cells, and this work showed ELFN2 is cone-selective and acts with ELFN1 to recruit mGluR6 and enable cone synaptic transmission.","evidence":"Unbiased proteomics in cone-dominant species, conditional KO mice, immunolocalization, ERG, and ELFN1/ELFN2 genetic interaction","pmids":["32879010"],"confidence":"High","gaps":["Division of labor between ELFN1 and ELFN2 at cone synapses incompletely defined","Developmental timing of ELFN2 recruitment not detailed"]},{"year":2021,"claim":"Consolidated cross-study evidence that postsynaptic ELFN2 regulates excitatory input broadly by recruiting presynaptic group III mGluRs across multiple brain circuits, generalizing the synaptic-organizer model.","evidence":"Review synthesizing transcellular signaling assays and KO models from multiple labs","pmids":["33790745"],"confidence":"Medium","gaps":["Review-level synthesis rather than new primary data","Circuit-specific contributions of ELFN2 versus ELFN1 not delineated"]},{"year":2024,"claim":"Defined the molecular determinants of the trans-synaptic bond: it was unknown what makes the ELFN2-mGluR6 interaction specific, and this work showed complex N-glycosylation of mGluR6 at N445 is required for binding by the ELFN2 extracellular domain.","evidence":"Glycosidase treatment, pulldown with recombinant ELFN2 extracellular domain, site-directed mutagenesis, and localization assays in heterologous and bipolar cells","pmids":["38428819"],"confidence":"High","gaps":["Structure of the glycan-dependent interface not solved","Whether other group III mGluRs require analogous glycosylation untested"]},{"year":2024,"claim":"Clarified how ELFN2 is built and trafficked: it was unknown how ELFN2 oligomerizes and reaches the postsynapse, and this work showed LRR-domain-mediated homo- and ELFN1-heterodimerization precedes trafficking, with a juxtamembranous intracellular motif controlling membrane targeting.","evidence":"Domain deletion/mutagenesis, co-IP, subcellular fractionation, live-cell imaging, and postsynaptic localization assays","pmids":["39675706"],"confidence":"Medium","gaps":["Single-lab structural inference without crystallographic confirmation","Functional consequence of homo- versus heterodimer composition at synapses unknown"]},{"year":2018,"claim":"Implicated ELFN2 in a non-synaptic role: in glioblastoma cells it interacts with Aurora kinase A and eIF2α to promote autophagy, with expression controlled by promoter hypomethylation, miR-101, and lncRNA LINC00470.","evidence":"Co-IP, overexpression/knockdown in GBM lines, autophagy assays, methylation analysis, and ChIP","pmids":["30037656"],"confidence":"Medium","gaps":["Mechanism linking AurkA inhibition to autophagy not detailed","Relationship to ELFN2's synaptic adhesion function unclear"]},{"year":2019,"claim":"Identified an immune signaling role: as LRRC62, ELFN2 acts as an adaptor recruiting the deubiquitinase CYLD to TAK1, promoting K63 deubiquitination and dampening TLR-driven NF-κB and MAPK signaling.","evidence":"Co-IP, overexpression/knockdown, cytokine assays, and ubiquitination assays","pmids":["31301291"],"confidence":"Medium","gaps":["Single-lab characterization without in vivo immune validation","How a transmembrane adhesion protein engages cytosolic TAK1/CYLD not reconciled"]},{"year":2026,"claim":"Linked ELFN2 to cancer signaling: it binds PP1A and blocks dephosphorylation of YAP at Ser127, driving YAP nuclear export and suppressing gastric cancer lymph node metastasis.","evidence":"Co-IP, phosphorylation assays, PP1A inhibitor pharmacology, and in vivo metastasis models","pmids":["41967793"],"confidence":"Medium","gaps":["Single-lab, abstract-level mechanistic detail","Whether PP1A inhibition is direct competition or allosteric not resolved"]},{"year":2026,"claim":"Probed the developmental interdependence of the synaptic partners: ablating mGluR6 before synaptogenesis mislocalizes ELFN2 at cone pedicles, indicating mGluR6 is needed for proper ELFN2 positioning during human retinal circuit assembly.","evidence":"CRISPR ablation in human iPSC-derived retinal organoids with immunofluorescence localization (preprint)","pmids":["42094404"],"confidence":"Low","gaps":["Preprint, immunolocalization only without functional follow-up for ELFN2","Whether mislocalization reflects loss of trans-binding or upstream defect untested"]},{"year":null,"claim":"How ELFN2's disparate roles—synaptic group III mGluR organization versus cytosolic regulation of TAK1, PP1A, and AurkA—are reconciled mechanistically and whether they reflect distinct contexts of a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ELFN2 or its complexes","No unifying account of how a transmembrane adhesion molecule accesses intracellular signaling partners"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7]}],"complexes":[],"partners":["GRM4","GRM6","GRM7","GRM8","ELFN1","CYLD","PPP1CA"],"other_free_text":[]}},"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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Elfn2 KO mice display seizure susceptibility, hyperactivity, and anxiety/compulsivity rescued by pharmacological augmentation of group III mGluRs.\",\n      \"method\": \"Transcellular GPCR signaling platform, Elfn2 knockout mice, electrophysiology, behavioral assays, pharmacological rescue\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including transcellular signaling assay, KO mice with defined synaptic and behavioral phenotypes, and pharmacological rescue in a single rigorous study\",\n      \"pmids\": [\"31485013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ELFN2 is selectively expressed in cone photoreceptors (not rods) and transsynaptically recruits mGluR6 in ON-bipolar cells to enable cone synaptic transmission. ELFN2 functions in synergy with ELFN1 during development to specify selective wiring and transmission of cone signals to ON-type bipolar cells.\",\n      \"method\": \"Unbiased proteomics in cone-dominant species, conditional knockout mice, immunolocalization, electrophysiology (ERG), and genetic interaction (ELFN1/ELFN2 double mutants)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic identification, KO mouse models with defined synaptic phenotypes, genetic interaction experiments, and functional electrophysiology in a single study\",\n      \"pmids\": [\"32879010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In GBM cells, ELFN2 promotes autophagy by interacting with Aurora kinase A (AurkA) and eIF2α and inhibiting AurkA activation. ELFN2 expression is epigenetically regulated by promoter hypomethylation, miR-101 downregulation, and the lncRNA LINC00470 (which adsorbs miR-101 and decreases H3K27me3 occupancy at the ELFN2 promoter).\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown in GBM cell lines, autophagy assays, methylation analysis, chromatin immunoprecipitation\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and functional cell-based assays in a single lab; some orthogonal methods but abstract-level description limits mechanistic detail\",\n      \"pmids\": [\"30037656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LRRC62 (ELFN2 alias) functions as an adaptor protein that recruits the deubiquitinase CYLD to TAK1, thereby promoting K63-linked deubiquitination and inactivation of TAK1, resulting in negative regulation of TLR-induced NF-κB and MAPK signaling and reduced pro-inflammatory cytokine production.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown in cell lines, cytokine production assays, ubiquitination assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional assays in a single lab with multiple orthogonal readouts; LRRC62 is a confirmed alias for ELFN2 (PPP1R29/LRRC62)\",\n      \"pmids\": [\"31301291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Complex N-glycosylation of mGluR6 is required for its trans-synaptic interaction with ELFN2 (and ELFN1). Pull-down experiments with ELFN2 extracellular domains showed interaction exclusively with complex-glycosylated mGluR6. Mutation at N445 of mGluR6 severely impaired ELFN2 binding. N-glycosylation at N445 is sufficient but not necessary for dendritic tip localization of mGluR6.\",\n      \"method\": \"Glycosidase treatment (PNGase F, Endo H), pulldown assays with ELFN2 extracellular domain, site-directed mutagenesis of N-glycosylation sites, surface expression and localization assays in heterologous cells and rod bipolar cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution (pulldown with recombinant extracellular domains), mutagenesis, and multiple orthogonal assays establishing glycosylation requirement for ELFN2 binding\",\n      \"pmids\": [\"38428819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ELFN2 forms homodimers prior to membrane trafficking, utilizing the extracellular leucine-rich repeat (LRR) domain for dimerization. ELFN2 also participates in heterodimerization with ELFN1. The intracellular domain controls membrane targeting and postsynaptic localization, with a ~30 amino acid juxtamembranous region required for membrane-targeting, and a single membrane-targeting motif in one protomer is sufficient for trafficking of the homodimer.\",\n      \"method\": \"Domain deletion/mutagenesis, co-immunoprecipitation for dimerization, subcellular fractionation, live-cell imaging, postsynaptic localization assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis and co-IP for dimerization, localization assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39675706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ELFN2 interacts directly 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, suppressing lymph node metastasis in gastric cancer. Pharmacological inhibition of PP1A abrogated ELFN2-induced YAP inactivation.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, PP1A inhibitor pharmacology, in vivo metastasis models (lymph node and peritoneal carcinomatosis)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and pharmacological rescue with in vivo validation; single lab, single publication, abstract-level description\",\n      \"pmids\": [\"41967793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELFN2 (and ELFN1) can interact in trans with all group III mGluRs (mGluR4, mGluR6, mGluR7, mGluR8) and alter mGluR-mediated signaling through these trans-interactions. Postsynaptic ELFN2 in the brain mediates regulation of excitatory input through recruitment of presynaptic group III mGluRs.\",\n      \"method\": \"Review synthesizing results from multiple studies including transcellular signaling assays and KO models (mechanistic synthesis/review article citing primary data)\",\n      \"journal\": \"Frontiers in neural circuits\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — finding is corroborated by multiple primary studies; this is a review, but the underlying mechanistic data are replicated across labs\",\n      \"pmids\": [\"33790745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ELFN2 is mislocalized at cone pedicles when mGluR6 is ablated prior to synaptogenesis during human retinal development (in iPSC-derived organoids), indicating that mGluR6 is required for proper ELFN2 localization during circuit assembly.\",\n      \"method\": \"CRISPR-based genetic ablation in human iPSC-derived retinal organoids, immunofluorescence localization\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, immunolocalization only without functional follow-up for ELFN2 specifically\",\n      \"pmids\": [\"42094404\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ELFN2 is a postsynaptic leucine-rich repeat and fibronectin type III domain-containing transmembrane adhesion molecule that transsynaptically recruits and modulates all group III metabotropic glutamate receptors (mGluR4/6/7/8) by altering G protein coupling kinetics, is selectively expressed in cone photoreceptors where it orchestrates ON-bipolar cell wiring by recruiting mGluR6, forms homodimers (via its extracellular LRR domain) and heterodimers with ELFN1 prior to membrane trafficking, requires complex N-glycosylation of mGluR6 at N445 for trans-synaptic binding, interacts with PP1A to block YAP dephosphorylation and suppress metastasis in gastric cancer, and in immune cells (as LRRC62) acts as an adaptor recruiting deubiquitinase CYLD to TAK1 to attenuate TLR-driven NF-κB signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ELFN2 is a postsynaptic transmembrane adhesion molecule that organizes glutamatergic synapses by selectively binding all group III metabotropic glutamate receptors (mGluR4/6/7/8) in trans across the synaptic cleft and directly altering their G protein coupling kinetics and signaling efficacy [#0, #7]. Its loss downregulates group III mGluRs and dysregulates synaptic transmission, producing seizure susceptibility, hyperactivity, and anxiety/compulsivity phenotypes in knockout mice that are reversed by pharmacological augmentation of group III mGluRs [#0]. In the retina, ELFN2 is selectively expressed in cone photoreceptors, where together with ELFN1 it transsynaptically recruits mGluR6 in ON-bipolar cells to specify cone-to-bipolar wiring and transmission [#1]. The trans-synaptic interaction depends on complex N-glycosylation of mGluR6 at N445, which is required for binding by the ELFN2 extracellular domain [#4], and ELFN2 itself dimerizes through its extracellular leucine-rich repeat domain—forming homodimers and ELFN1 heterodimers prior to trafficking—while its intracellular juxtamembranous region directs membrane targeting and postsynaptic localization [#5]. Beyond the synapse, ELFN2 has been assigned roles as an adaptor that recruits the deubiquitinase CYLD to TAK1 to attenuate TLR-driven NF-\\u03baB and MAPK signaling (as LRRC62) [#3] and as a binding partner of protein phosphatase-1 catalytic subunit alpha (PP1A) that blocks YAP Ser127 dephosphorylation to suppress gastric cancer metastasis [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established ELFN2's core function: it was unknown how postsynaptic cues selectively shape group III mGluR signaling, and this work showed ELFN2 binds group III mGluRs in trans and tunes their G protein coupling, with loss causing defined synaptic and behavioral phenotypes.\",\n      \"evidence\": \"Transcellular GPCR signaling platform, Elfn2 KO mice, electrophysiology, behavioral assays, and pharmacological rescue\",\n      \"pmids\": [\"31485013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of selective group III mGluR recognition not defined\", \"Mechanism by which trans-binding alters G protein coupling kinetics unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the cell-type-specific role in vision: it was unclear which adhesion molecule wires cone photoreceptors to ON-bipolar cells, and this work showed ELFN2 is cone-selective and acts with ELFN1 to recruit mGluR6 and enable cone synaptic transmission.\",\n      \"evidence\": \"Unbiased proteomics in cone-dominant species, conditional KO mice, immunolocalization, ERG, and ELFN1/ELFN2 genetic interaction\",\n      \"pmids\": [\"32879010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Division of labor between ELFN1 and ELFN2 at cone synapses incompletely defined\", \"Developmental timing of ELFN2 recruitment not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidated cross-study evidence that postsynaptic ELFN2 regulates excitatory input broadly by recruiting presynaptic group III mGluRs across multiple brain circuits, generalizing the synaptic-organizer model.\",\n      \"evidence\": \"Review synthesizing transcellular signaling assays and KO models from multiple labs\",\n      \"pmids\": [\"33790745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis rather than new primary data\", \"Circuit-specific contributions of ELFN2 versus ELFN1 not delineated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the molecular determinants of the trans-synaptic bond: it was unknown what makes the ELFN2-mGluR6 interaction specific, and this work showed complex N-glycosylation of mGluR6 at N445 is required for binding by the ELFN2 extracellular domain.\",\n      \"evidence\": \"Glycosidase treatment, pulldown with recombinant ELFN2 extracellular domain, site-directed mutagenesis, and localization assays in heterologous and bipolar cells\",\n      \"pmids\": [\"38428819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the glycan-dependent interface not solved\", \"Whether other group III mGluRs require analogous glycosylation untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Clarified how ELFN2 is built and trafficked: it was unknown how ELFN2 oligomerizes and reaches the postsynapse, and this work showed LRR-domain-mediated homo- and ELFN1-heterodimerization precedes trafficking, with a juxtamembranous intracellular motif controlling membrane targeting.\",\n      \"evidence\": \"Domain deletion/mutagenesis, co-IP, subcellular fractionation, live-cell imaging, and postsynaptic localization assays\",\n      \"pmids\": [\"39675706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab structural inference without crystallographic confirmation\", \"Functional consequence of homo- versus heterodimer composition at synapses unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated ELFN2 in a non-synaptic role: in glioblastoma cells it interacts with Aurora kinase A and eIF2\\u03b1 to promote autophagy, with expression controlled by promoter hypomethylation, miR-101, and lncRNA LINC00470.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown in GBM lines, autophagy assays, methylation analysis, and ChIP\",\n      \"pmids\": [\"30037656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking AurkA inhibition to autophagy not detailed\", \"Relationship to ELFN2's synaptic adhesion function unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified an immune signaling role: as LRRC62, ELFN2 acts as an adaptor recruiting the deubiquitinase CYLD to TAK1, promoting K63 deubiquitination and dampening TLR-driven NF-\\u03baB and MAPK signaling.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown, cytokine assays, and ubiquitination assays\",\n      \"pmids\": [\"31301291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab characterization without in vivo immune validation\", \"How a transmembrane adhesion protein engages cytosolic TAK1/CYLD not reconciled\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked ELFN2 to cancer signaling: it binds PP1A and blocks dephosphorylation of YAP at Ser127, driving YAP nuclear export and suppressing gastric cancer lymph node metastasis.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, PP1A inhibitor pharmacology, and in vivo metastasis models\",\n      \"pmids\": [\"41967793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab, abstract-level mechanistic detail\", \"Whether PP1A inhibition is direct competition or allosteric not resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Probed the developmental interdependence of the synaptic partners: ablating mGluR6 before synaptogenesis mislocalizes ELFN2 at cone pedicles, indicating mGluR6 is needed for proper ELFN2 positioning during human retinal circuit assembly.\",\n      \"evidence\": \"CRISPR ablation in human iPSC-derived retinal organoids with immunofluorescence localization (preprint)\",\n      \"pmids\": [\"42094404\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, immunolocalization only without functional follow-up for ELFN2\", \"Whether mislocalization reflects loss of trans-binding or upstream defect untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ELFN2's disparate roles—synaptic group III mGluR organization versus cytosolic regulation of TAK1, PP1A, and AurkA—are reconciled mechanistically and whether they reflect distinct contexts of a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ELFN2 or its complexes\", \"No unifying account of how a transmembrane adhesion molecule accesses intracellular signaling partners\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GRM4\", \"GRM6\", \"GRM7\", \"GRM8\", \"ELFN1\", \"CYLD\", \"PPP1CA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}