{"gene":"LRFN1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2006,"finding":"LRFN1 (Lrfn1) C-terminus binds PDZ domains of the postsynaptic scaffolding protein PSD-95, redistributing PSD-95 to the cell periphery where LRFN1 is detected, indicating a direct physical interaction between LRFN1 and PSD-95.","method":"Co-expression/redistribution assay in cells; PDZ domain binding assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding assay showing functional redistribution of PSD-95, single lab","pmids":["16828986"],"is_preprint":false},{"year":2006,"finding":"LRFN1 (as part of the SALM/Lrfn family) is a neuronal transmembrane glycoprotein with LRR-Ig-Fn domain structure, N-terminus extracellular and C-terminus intracellular, expressed predominantly in the brain and starting from immature neural cells during development.","method":"Structural/domain analysis, expression profiling, glycoprotein characterization","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical characterization of domain structure and glycosylation, single lab","pmids":["16828986"],"is_preprint":false},{"year":2011,"finding":"LRFN1 (SALM1) directly interacts with NMDA receptors but not AMPA receptors, and SALMs 1-3 (including LRFN1) form homo- and heteromeric cis complexes with each other; the C-terminal PDZ-binding motif of LRFN1 interacts with PSD-95.","method":"Co-immunoprecipitation, complex formation assays","journal":"Seminars in cell & developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 — review summarizing co-IP and binding data from multiple labs; NMDA receptor interaction is a key mechanistic finding","pmids":["21736948"],"is_preprint":false},{"year":2008,"finding":"SALM family proteins including LRFN1 promote neurite outgrowth; the C-terminal PDZ binding domain of SALMs 1-3 is required for most aspects of neurite outgrowth, and the N-terminus also contributes, as demonstrated by deletion constructs and chimeric SALM2/4 proteins.","method":"Overexpression of deletion constructs and chimeric proteins in cultured hippocampal neurons; RNAi knockdown; antibody blocking of extracellular domain","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function (RNAi + antibody) and domain-deletion experiments with defined neurite outgrowth readout","pmids":["18585462"],"is_preprint":false},{"year":2018,"finding":"Crystal structures of PTPδ-SALM2 and PTPδ-SALM5 complexes reveal that the LRR domains of SALMs interact with the second Ig domain of PTPδ, while the Ig domains of SALMs interact with both the second and third Ig domains of PTPδ, forming a 2:2 LRR-mediated trans-synaptic complex; SALM2 (LRFN1) can bind PTPδ in this structural context.","method":"X-ray crystallography of PTPδ-SALM2 complex; site-directed mutagenesis; synaptogenic co-culture assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of SALM2-PTPδ complex with mutagenesis validation","pmids":["29348429"],"is_preprint":false},{"year":2022,"finding":"miR-187-3p directly targets the 3'-UTR of LRFN1 and negatively regulates LRFN1 expression; LRFN1 rescues proliferation and invasion capacities suppressed by miR-187-3p overexpression in ccRCC cells in vitro and in xenograft models.","method":"Luciferase reporter assay for 3'-UTR targeting; miR-187-3p mimic transfection; rescue experiments in A498 and 786O cells; subcutaneous xenograft models","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter (Tier 1 method for miRNA targeting) plus rescue experiments, single lab in cancer context","pmids":["35799072"],"is_preprint":false}],"current_model":"LRFN1 is a neuronal transmembrane glycoprotein (LRR-Ig-Fn domain architecture) that localizes to excitatory postsynaptic sites, where its C-terminal PDZ-binding motif directly engages PSD-95, its extracellular LRR and Ig domains form a 2:2 trans-synaptic complex with presynaptic PTPδ (as revealed by crystal structure), and its intracellular interactions with NMDA receptors and cis-complexes with other SALM family members collectively regulate excitatory synapse differentiation and neurite outgrowth; additionally, miR-187-3p post-transcriptionally represses LRFN1 via its 3'-UTR."},"narrative":{"teleology":[{"year":2006,"claim":"Identifying LRFN1 as a neuronal transmembrane glycoprotein that directly binds PSD-95 via its C-terminal PDZ-binding motif established the first molecular link between the SALM family and postsynaptic scaffolding.","evidence":"Co-expression/redistribution assay and PDZ domain binding assay in heterologous cells","pmids":["16828986"],"confidence":"Medium","gaps":["Interaction demonstrated in overexpression system, not confirmed at endogenous levels in neurons","Functional consequence of PSD-95 binding at synapses not tested","Extracellular ligand unknown"]},{"year":2008,"claim":"Demonstrating that LRFN1 promotes neurite outgrowth through both its PDZ-binding C-terminus and its extracellular N-terminus resolved that synapse-organizing SALMs also regulate neuronal morphogenesis through separable domains.","evidence":"Overexpression of deletion/chimeric constructs, RNAi knockdown, and antibody blocking in cultured hippocampal neurons","pmids":["18585462"],"confidence":"Medium","gaps":["In vivo validation of neurite outgrowth phenotype lacking","Specific extracellular binding partner mediating outgrowth not identified","Relative contribution of LRFN1 versus other SALMs in outgrowth not separated"]},{"year":2011,"claim":"Establishing that LRFN1 selectively interacts with NMDA receptors (not AMPA receptors) and forms homo- and heteromeric cis-complexes with other SALMs revealed a combinatorial logic for postsynaptic receptor organization.","evidence":"Co-immunoprecipitation and complex formation assays","pmids":["21736948"],"confidence":"Medium","gaps":["NMDA receptor interaction based on co-IP; direct binding domain not mapped","Functional impact on NMDA receptor trafficking or gating not tested","Stoichiometry of SALM cis-complexes undefined"]},{"year":2018,"claim":"Solving the crystal structure of the PTPδ–SALM complex at atomic resolution established the structural basis for a 2:2 trans-synaptic bridging mechanism mediated by the LRR and Ig domains, explaining how LRFN1 organizes synaptic contacts.","evidence":"X-ray crystallography of PTPδ-SALM2 complex with site-directed mutagenesis and synaptogenic co-culture validation","pmids":["29348429"],"confidence":"High","gaps":["Crystal structure solved for SALM2 (LRFN4); direct structural data for LRFN1–PTPδ complex not yet available","In vivo relevance of PTPδ interaction for LRFN1-specific synaptogenesis not demonstrated","Whether other LAR-RPTP family members bind LRFN1 comparably is untested"]},{"year":2022,"claim":"Identifying miR-187-3p as a direct post-transcriptional repressor of LRFN1 via its 3′-UTR extended LRFN1 regulation beyond synaptic biology into a cancer-relevant context.","evidence":"Luciferase reporter assay, miRNA mimic transfection, rescue experiments in ccRCC cell lines and xenograft models","pmids":["35799072"],"confidence":"Medium","gaps":["Mechanism by which LRFN1 promotes proliferation/invasion in non-neuronal cells is unknown","Relevance of miR-187-3p regulation to LRFN1 function in the brain not addressed","Single-lab finding in cancer context without independent replication"]},{"year":null,"claim":"The in vivo synaptic phenotype of LRFN1 loss-of-function and the precise mechanism by which LRFN1 coordinates NMDA receptor function, PSD-95 scaffolding, and PTPδ trans-synaptic signaling remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No Lrfn1 knockout mouse phenotype reported","No electrophysiological characterization of LRFN1-dependent synaptic transmission","Structural basis for LRFN1-specific (versus other SALM) functions not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2,3,4]}],"complexes":[],"partners":["DLG4","PTPRD","LRFN2","LRFN3"],"other_free_text":[]},"mechanistic_narrative":"LRFN1 (SALM1) is a brain-enriched transmembrane glycoprotein with an extracellular LRR-Ig-Fn domain architecture whose C-terminal PDZ-binding motif directly engages the postsynaptic scaffold PSD-95 and whose intracellular domain selectively interacts with NMDA receptors but not AMPA receptors [PMID:16828986, PMID:21736948]. The extracellular LRR and Ig domains mediate a 2:2 trans-synaptic complex with presynaptic receptor-type tyrosine phosphatase PTPδ, as demonstrated by crystal structure analysis, positioning LRFN1 as a synaptic organizer bridging pre- and postsynaptic compartments [PMID:29348429]. Both the C-terminal PDZ-binding domain and the N-terminal extracellular domains are required for LRFN1-driven neurite outgrowth in hippocampal neurons, and LRFN1 forms homo- and heteromeric cis-complexes with other SALM family members [PMID:18585462, PMID:21736948]."},"prefetch_data":{"uniprot":{"accession":"Q9P244","full_name":"Leucine-rich repeat and fibronectin type III domain-containing protein 1","aliases":["Synaptic adhesion-like molecule 2"],"length_aa":771,"mass_kda":82.3,"function":"Promotes neurite outgrowth in hippocampal neurons. Involved in the regulation and maintenance of excitatory synapses. Induces the clustering of excitatory postsynaptic proteins, including DLG4, DLGAP1, GRIA1 and GRIN1 (By similarity)","subcellular_location":"Membrane; Synapse; Postsynaptic density membrane","url":"https://www.uniprot.org/uniprotkb/Q9P244/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRFN1","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRFN1","total_profiled":1310},"omim":[{"mim_id":"612811","title":"LEUCINE-RICH REPEAT AND FIBRONECTIN TYPE III DOMAIN-CONTAINING PROTEIN 5; LRFN5","url":"https://www.omim.org/entry/612811"},{"mim_id":"612809","title":"LEUCINE-RICH REPEAT AND FIBRONECTIN TYPE III DOMAIN-CONTAINING PROTEIN 3; LRFN3","url":"https://www.omim.org/entry/612809"},{"mim_id":"612807","title":"LEUCINE-RICH REPEAT AND FIBRONECTIN TYPE III DOMAIN-CONTAINING PROTEIN 1; LRFN1","url":"https://www.omim.org/entry/612807"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":14.3}],"url":"https://www.proteinatlas.org/search/LRFN1"},"hgnc":{"alias_symbol":["KIAA1484","SALM2"],"prev_symbol":[]},"alphafold":{"accession":"Q9P244","domains":[{"cath_id":"2.60.40.10","chopping":"299-389","consensus_level":"high","plddt":91.5604,"start":299,"end":389},{"cath_id":"2.60.40.10","chopping":"430-518","consensus_level":"high","plddt":82.3892,"start":430,"end":518}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P244","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P244-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P244-F1-predicted_aligned_error_v6.png","plddt_mean":69.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRFN1","jax_strain_url":"https://www.jax.org/strain/search?query=LRFN1"},"sequence":{"accession":"Q9P244","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P244.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P244/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P244"}},"corpus_meta":[{"pmid":"16630835","id":"PMC_16630835","title":"SALM synaptic cell adhesion-like molecules regulate the differentiation of excitatory synapses.","date":"2006","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/16630835","citation_count":122,"is_preprint":false},{"pmid":"16828986","id":"PMC_16828986","title":"Comparative analysis of structure, expression and PSD95-binding capacity of Lrfn, a novel family of neuronal transmembrane proteins.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/16828986","citation_count":67,"is_preprint":false},{"pmid":"21736948","id":"PMC_21736948","title":"The SALM/Lrfn family of leucine-rich repeat-containing cell adhesion molecules.","date":"2011","source":"Seminars in cell & developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/21736948","citation_count":56,"is_preprint":false},{"pmid":"27887572","id":"PMC_27887572","title":"Maternal smoking impacts key biological pathways in newborns through epigenetic modification in Utero.","date":"2016","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/27887572","citation_count":43,"is_preprint":false},{"pmid":"18585462","id":"PMC_18585462","title":"Synaptic adhesion-like molecules (SALMs) promote neurite outgrowth.","date":"2008","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/18585462","citation_count":37,"is_preprint":false},{"pmid":"29348429","id":"PMC_29348429","title":"Structural basis of trans-synaptic interactions between PTPδ and SALMs for inducing synapse formation.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29348429","citation_count":36,"is_preprint":false},{"pmid":"32060041","id":"PMC_32060041","title":"RNA sequencing profiles and diagnostic signatures linked with response to ramucirumab in gastric cancer.","date":"2020","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/32060041","citation_count":30,"is_preprint":false},{"pmid":"34011559","id":"PMC_34011559","title":"Whole-Genome Sequencing of Common Salivary Gland Carcinomas: Subtype-Restricted and Shared Genetic Alterations.","date":"2021","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/34011559","citation_count":21,"is_preprint":false},{"pmid":"31956794","id":"PMC_31956794","title":"Whole Exome and Transcriptome RNA-Sequencing Model for the Diagnosis of Prostate Cancer.","date":"2019","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/31956794","citation_count":12,"is_preprint":false},{"pmid":"33110456","id":"PMC_33110456","title":"Identification of a Set of Genes Improving Survival Prediction in Kidney Renal Clear Cell Carcinoma through Integrative Reanalysis of Transcriptomic Data.","date":"2020","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/33110456","citation_count":11,"is_preprint":false},{"pmid":"35799072","id":"PMC_35799072","title":"Deciphering the role of miR-187-3p/LRFN1 axis in modulating progression, aerobic glycolysis and immune microenvironment of clear cell renal cell carcinoma.","date":"2022","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35799072","citation_count":10,"is_preprint":false},{"pmid":"24579982","id":"PMC_24579982","title":"Autosomal dominant partial epilepsy with auditory features: a new locus on chromosome 19q13.11-q13.31.","date":"2014","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/24579982","citation_count":7,"is_preprint":false},{"pmid":"41789476","id":"PMC_41789476","title":"Transcriptomic signature of frontotemporal lobar degeneration with TDP-43 type C pathology.","date":"2026","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/41789476","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8405,"output_tokens":1521,"usd":0.024015},"stage2":{"model":"claude-opus-4-6","input_tokens":4785,"output_tokens":1744,"usd":0.101288},"total_usd":0.125303,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"LRFN1 (Lrfn1) C-terminus binds PDZ domains of the postsynaptic scaffolding protein PSD-95, redistributing PSD-95 to the cell periphery where LRFN1 is detected, indicating a direct physical interaction between LRFN1 and PSD-95.\",\n      \"method\": \"Co-expression/redistribution assay in cells; PDZ domain binding assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay showing functional redistribution of PSD-95, single lab\",\n      \"pmids\": [\"16828986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LRFN1 (as part of the SALM/Lrfn family) is a neuronal transmembrane glycoprotein with LRR-Ig-Fn domain structure, N-terminus extracellular and C-terminus intracellular, expressed predominantly in the brain and starting from immature neural cells during development.\",\n      \"method\": \"Structural/domain analysis, expression profiling, glycoprotein characterization\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical characterization of domain structure and glycosylation, single lab\",\n      \"pmids\": [\"16828986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LRFN1 (SALM1) directly interacts with NMDA receptors but not AMPA receptors, and SALMs 1-3 (including LRFN1) form homo- and heteromeric cis complexes with each other; the C-terminal PDZ-binding motif of LRFN1 interacts with PSD-95.\",\n      \"method\": \"Co-immunoprecipitation, complex formation assays\",\n      \"journal\": \"Seminars in cell & developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review summarizing co-IP and binding data from multiple labs; NMDA receptor interaction is a key mechanistic finding\",\n      \"pmids\": [\"21736948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SALM family proteins including LRFN1 promote neurite outgrowth; the C-terminal PDZ binding domain of SALMs 1-3 is required for most aspects of neurite outgrowth, and the N-terminus also contributes, as demonstrated by deletion constructs and chimeric SALM2/4 proteins.\",\n      \"method\": \"Overexpression of deletion constructs and chimeric proteins in cultured hippocampal neurons; RNAi knockdown; antibody blocking of extracellular domain\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function (RNAi + antibody) and domain-deletion experiments with defined neurite outgrowth readout\",\n      \"pmids\": [\"18585462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structures of PTPδ-SALM2 and PTPδ-SALM5 complexes reveal that the LRR domains of SALMs interact with the second Ig domain of PTPδ, while the Ig domains of SALMs interact with both the second and third Ig domains of PTPδ, forming a 2:2 LRR-mediated trans-synaptic complex; SALM2 (LRFN1) can bind PTPδ in this structural context.\",\n      \"method\": \"X-ray crystallography of PTPδ-SALM2 complex; site-directed mutagenesis; synaptogenic co-culture assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of SALM2-PTPδ complex with mutagenesis validation\",\n      \"pmids\": [\"29348429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-187-3p directly targets the 3'-UTR of LRFN1 and negatively regulates LRFN1 expression; LRFN1 rescues proliferation and invasion capacities suppressed by miR-187-3p overexpression in ccRCC cells in vitro and in xenograft models.\",\n      \"method\": \"Luciferase reporter assay for 3'-UTR targeting; miR-187-3p mimic transfection; rescue experiments in A498 and 786O cells; subcutaneous xenograft models\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter (Tier 1 method for miRNA targeting) plus rescue experiments, single lab in cancer context\",\n      \"pmids\": [\"35799072\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRFN1 is a neuronal transmembrane glycoprotein (LRR-Ig-Fn domain architecture) that localizes to excitatory postsynaptic sites, where its C-terminal PDZ-binding motif directly engages PSD-95, its extracellular LRR and Ig domains form a 2:2 trans-synaptic complex with presynaptic PTPδ (as revealed by crystal structure), and its intracellular interactions with NMDA receptors and cis-complexes with other SALM family members collectively regulate excitatory synapse differentiation and neurite outgrowth; additionally, miR-187-3p post-transcriptionally represses LRFN1 via its 3'-UTR.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LRFN1 (SALM1) is a brain-enriched transmembrane glycoprotein with an extracellular LRR-Ig-Fn domain architecture whose C-terminal PDZ-binding motif directly engages the postsynaptic scaffold PSD-95 and whose intracellular domain selectively interacts with NMDA receptors but not AMPA receptors [PMID:16828986, PMID:21736948]. The extracellular LRR and Ig domains mediate a 2:2 trans-synaptic complex with presynaptic receptor-type tyrosine phosphatase PTPδ, as demonstrated by crystal structure analysis, positioning LRFN1 as a synaptic organizer bridging pre- and postsynaptic compartments [PMID:29348429]. Both the C-terminal PDZ-binding domain and the N-terminal extracellular domains are required for LRFN1-driven neurite outgrowth in hippocampal neurons, and LRFN1 forms homo- and heteromeric cis-complexes with other SALM family members [PMID:18585462, PMID:21736948].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying LRFN1 as a neuronal transmembrane glycoprotein that directly binds PSD-95 via its C-terminal PDZ-binding motif established the first molecular link between the SALM family and postsynaptic scaffolding.\",\n      \"evidence\": \"Co-expression/redistribution assay and PDZ domain binding assay in heterologous cells\",\n      \"pmids\": [\"16828986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction demonstrated in overexpression system, not confirmed at endogenous levels in neurons\",\n        \"Functional consequence of PSD-95 binding at synapses not tested\",\n        \"Extracellular ligand unknown\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that LRFN1 promotes neurite outgrowth through both its PDZ-binding C-terminus and its extracellular N-terminus resolved that synapse-organizing SALMs also regulate neuronal morphogenesis through separable domains.\",\n      \"evidence\": \"Overexpression of deletion/chimeric constructs, RNAi knockdown, and antibody blocking in cultured hippocampal neurons\",\n      \"pmids\": [\"18585462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo validation of neurite outgrowth phenotype lacking\",\n        \"Specific extracellular binding partner mediating outgrowth not identified\",\n        \"Relative contribution of LRFN1 versus other SALMs in outgrowth not separated\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that LRFN1 selectively interacts with NMDA receptors (not AMPA receptors) and forms homo- and heteromeric cis-complexes with other SALMs revealed a combinatorial logic for postsynaptic receptor organization.\",\n      \"evidence\": \"Co-immunoprecipitation and complex formation assays\",\n      \"pmids\": [\"21736948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"NMDA receptor interaction based on co-IP; direct binding domain not mapped\",\n        \"Functional impact on NMDA receptor trafficking or gating not tested\",\n        \"Stoichiometry of SALM cis-complexes undefined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Solving the crystal structure of the PTPδ–SALM complex at atomic resolution established the structural basis for a 2:2 trans-synaptic bridging mechanism mediated by the LRR and Ig domains, explaining how LRFN1 organizes synaptic contacts.\",\n      \"evidence\": \"X-ray crystallography of PTPδ-SALM2 complex with site-directed mutagenesis and synaptogenic co-culture validation\",\n      \"pmids\": [\"29348429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Crystal structure solved for SALM2 (LRFN4); direct structural data for LRFN1–PTPδ complex not yet available\",\n        \"In vivo relevance of PTPδ interaction for LRFN1-specific synaptogenesis not demonstrated\",\n        \"Whether other LAR-RPTP family members bind LRFN1 comparably is untested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying miR-187-3p as a direct post-transcriptional repressor of LRFN1 via its 3′-UTR extended LRFN1 regulation beyond synaptic biology into a cancer-relevant context.\",\n      \"evidence\": \"Luciferase reporter assay, miRNA mimic transfection, rescue experiments in ccRCC cell lines and xenograft models\",\n      \"pmids\": [\"35799072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which LRFN1 promotes proliferation/invasion in non-neuronal cells is unknown\",\n        \"Relevance of miR-187-3p regulation to LRFN1 function in the brain not addressed\",\n        \"Single-lab finding in cancer context without independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo synaptic phenotype of LRFN1 loss-of-function and the precise mechanism by which LRFN1 coordinates NMDA receptor function, PSD-95 scaffolding, and PTPδ trans-synaptic signaling remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No Lrfn1 knockout mouse phenotype reported\",\n        \"No electrophysiological characterization of LRFN1-dependent synaptic transmission\",\n        \"Structural basis for LRFN1-specific (versus other SALM) functions not determined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2, 3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DLG4\",\n      \"PTPRD\",\n      \"LRFN2\",\n      \"LRFN3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}