{"gene":"ADGRL1","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2012,"finding":"The olfactomedin-like domain of CIRL1/latrophilin-1 (ADGRL1) mediates direct, high-affinity (nanomolar) binding to neurexins lacking an insert at splice site 4 (SS4); neurexins with an SS4 insert cannot bind. This interaction is trans-cellular and forms a stable intercellular adhesion complex. ADGRL1 competes with neuroligin-1 for neurexin binding.","method":"Saturation binding assays, deletion mapping of extracellular domains, cell adhesion assays (co-culture of neurexin- and ADGRL1-expressing cells)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (saturation binding, domain deletion mapping, cell adhesion assay) in a rigorous single study establishing binding domain and splice-site regulation","pmids":["22262843"],"is_preprint":false},{"year":2010,"finding":"ADGRL1/CIRL-1 undergoes constitutive autoproteolytic cleavage at its GPS domain in the endoplasmic reticulum, producing a heterodimeric two-subunit receptor complex (NTF + CTF). Protein kinase C activators (PMA and ionomycin) inhibit GPS cleavage and downregulate trafficking to the cell surface, causing accumulation of the uncleaved precursor intracellularly. A non-cleavable mutant showed that downregulation of trafficking is independent of cleavage, suggesting that GPS proteolysis is not purely autocatalytic and may require auxiliary factors.","method":"Transfection of wild-type and mutant CIRL-1 in cells, treatment with PKC activators PMA and ionomycin, trafficking/surface expression assays, non-cleavable soluble mutant analysis","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — cell-based mechanistic experiments with mutants and pharmacological tools in a single lab, two orthogonal approaches (cleavage assay + trafficking assay)","pmids":["20100540"],"is_preprint":false},{"year":2018,"finding":"Comprehensive mutagenesis of the transmembrane domain (TMD) of ADGRL1/latrophilin-1 identified specific TMD residues essential for basal constitutive activity and for agonist peptide (endogenous tethered agonist peptide) response. A cancer-associated TMD mutation showed increased basal activity and failed to rescue embryonic developmental phenotype in transgenic C. elegans, linking TMD residues to receptor activation mechanism.","method":"Comprehensive mutagenesis screen of TMD residues, functional assays for basal activity and agonist peptide response, transgenic C. elegans rescue experiments","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic mutagenesis with functional assays and in vivo validation in two orthogonal systems (cell-based + C. elegans transgenic rescue)","pmids":["30428326"],"is_preprint":false},{"year":2019,"finding":"Alternative splicing of ADGRL1/latrophilin-1 at the cytoplasmic SSB site confers dual cAMP signaling: SSB-containing variants show both constitutive Gαi/o coupling (constitutive cAMP production) and ligand-dependent Gαs activation (cAMP increase upon neurexin or FLRT binding), whereas SSB-deficient variants show only ligand-dependent cAMP decrease. Neither variant increased intracellular Ca2+ or activated MAP kinase upon ligand binding.","method":"cAMP competitive binding assays, pertussis toxin treatment (Gαi/o inhibition), expression of SSB-containing vs SSB-deficient LPHN1 variants, Ca2+ and MAPK assays","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple pharmacological and biochemical assays in a single lab establishing splice-dependent G-protein coupling bias","pmids":["31339586"],"is_preprint":false},{"year":2019,"finding":"The C-terminal fragment (CTF) of latrophilin-1/ADGRL1 in synapses is phosphorylated on multiple sites. Phosphorylated CTF has high affinity for the N-terminal fragment (NTF) and co-purifies with it. Dephosphorylated CTF has lower affinity for NTF and can behave as a separate protein. α-Latrotoxin binding to NTF brings it together with receptor-like protein tyrosine phosphatase σ (RPTPσ), leading to CTF dephosphorylation and CTF release from the NTF–CTF complex.","method":"Affinity column co-purification, sucrose density gradient fractionation, phosphorylation analysis of synaptic preparations, α-latrotoxin binding experiments","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — biochemical fractionation and co-purification from synaptic preparations with pharmacological intervention, single lab","pmids":["31553068"],"is_preprint":false},{"year":2022,"finding":"ADGRL1 haploinsufficiency impairs ligand-induced regulation of intracellular Ca2+ influx (shown by in vitro expression of human variants in neuroblastoma cells). In Adgrl1 knockout mice, loss of ADGRL1 causes increased spontaneous exocytosis of dopamine, acetylcholine, and glutamate from synaptic preparations, and Adgrl1-null neurons form synapses poorly in vitro, demonstrating that ADGRL1 regulates neurotransmitter release and synapse formation.","method":"In vitro Ca2+ influx assays in neuroblastoma cells expressing human ADGRL1 variants; ex vivo synaptic preparations measuring spontaneous exocytosis; in vitro synapse formation assay in Adgrl1-/- neurons; mouse knockout on two genetic backgrounds","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Ca2+ signaling, exocytosis assay, synapse formation in vitro) combined with genetic knockout in two backgrounds","pmids":["35907405"],"is_preprint":false},{"year":2023,"finding":"TAFA2 (a CNS-specific cytokine) directly binds to the lectin-like domain (Lec domain) of ADGRL1. This interaction activates the cAMP/PKA/CREB/BCL2 signaling pathway to suppress apoptosis. Overexpression of ADGRL1 lacking the Lec domain (ADGRL1ΔLec) failed to mediate TAFA2's anti-apoptotic effects, and ADGRL1-/- cells were unresponsive to recombinant TAFA2.","method":"Co-immunoprecipitation, quantitative mass spectrometry proteomics, pull-down assays, ADGRL1 knockout and Lec-deletion mutant overexpression, cAMP/p-PKA/p-CREB/BCL2 signaling measurements, apoptosis assays","journal":"Life sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, pulldown, MS, loss-of-function KO, domain deletion mutant, pathway readout) establishing binding domain and downstream signaling","pmids":["37944639"],"is_preprint":false},{"year":2023,"finding":"ADGRL1 binds glucose and functions as a glucose receptor in hypothalamic neurons. Validated by ligand-receptor binding assays in CHO cells stably expressing human ADGRL1. Adgrl1-deficient mice showed impaired glucose sensing by VMH neurons (electrophysiology), fasting hyperinsulinemia, enhanced glucose-stimulated insulin secretion, insulin resistance, and impaired feeding responses, demonstrating a role for ADGRL1 in energy and glucose homeostasis.","method":"Cell-based affinity chromatography to enrich glucose-bound neurons, proteomics identification, ligand-receptor binding assays in ADGRL1-expressing CHO cells, global and hypothalamus-specific Adgrl1 knockout mice, electrophysiology of VMH neurons, metabolic phenotyping","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (binding assay, two genetic KO models, electrophysiology, metabolic phenotyping) establishing glucose binding and downstream physiology","pmids":["37712955"],"is_preprint":false},{"year":2024,"finding":"ADGRL1/LPHN1 deficiency in mice causes increased food consumption and severe obesity with dysregulated glucose homeostasis, and a partially inactivating human ADGRL1 mutation was identified in an obese patient, establishing ADGRL1 as a regulator of energy balance.","method":"Adgrl1-deficient mouse metabolic phenotyping (food intake, body weight, glucose homeostasis); human genetic variant functional characterization","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — mouse KO with defined metabolic phenotype plus human variant identification, single study","pmids":["38664368"],"is_preprint":false},{"year":2026,"finding":"ADGRL1 ablation activates type I interferon signaling and promotes JAK/STAT1-dependent Decorin secretion by disrupting the GSK3β/β-catenin pathway, which facilitates cDC1–CD8+ T cell hub formation and anti-tumor immunity. An ADGRL1-targeting small molecule identified by virtual screening and DARTS showed antitumor efficacy in vivo.","method":"RNAi screening in Drosophila tumor model, single-cell transcriptomics, genetic KO in mice, pathway analysis (IFN/JAK/STAT1, GSK3β/β-catenin), Decorin secretion assays, PD-1 blockade combination, DARTS-based compound identification, in vivo tumor models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (scRNA-seq, genetic KO, pathway assays, in vivo) in a single study, but primarily single lab","pmids":["42172123"],"is_preprint":false},{"year":2026,"finding":"ADGRL1/Latrophilin-1 recruits β-arrestins (βarr) constitutively at the plasma membrane and early endosomes. βarr recruitment is prerequisite for G-protein activation (all four G-protein families: Gs, Gi/o, Gq, G13); βarr or dynamin depletion suppressed G-protein biosensor activation, indicating endosomal priming of G-protein signaling. Splice-variant SSB determines differential trafficking kinetics and distinct βarr/G-protein complex assemblies (shared for Gs, divergent for Gq and G13) upon neurexin-1β stimulation.","method":"G-protein BRET biosensors, β-arrestin knockdown and knockout in HEK293 cells, dynamin inhibition, endosome-targeted biosensors, splice variant overexpression, receptor internalization imaging","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biosensor, genetic KO/KD, pharmacological, and compartment-specific approaches establishing mechanism of β-arrestin-dependent endosomal G-protein signaling","pmids":["41819453"],"is_preprint":false},{"year":2024,"finding":"ADGRL1 acts as a functional receptor for hevin/SPARCL1 in nucleus accumbens neurons. Hevin interacts with membrane-expressed ADGRL1, induces its internalization, stabilizes the uncleaved receptor fraction, and alters ADGRL1/Neurexin-1-mediated intercellular adhesion contacts. Hevin stimulation selectively modulates ADGRL1 G-protein coupling with bias toward Gi3, Gs, and G13. Pan-neuronal Adgrl1 deficiency in the nucleus accumbens impairs cocaine-induced reinforcement and reward.","method":"Co-IP, receptor internalization assays, cell adhesion assays, G-protein coupling BRET assays, mouse Adgrl1 knockdown in NAc, cocaine conditioned place preference and self-administration","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple biochemical and in vivo assays, preprint (not yet peer-reviewed)","pmids":["bio_10.1101_2024.07.03.601736"],"is_preprint":true},{"year":2025,"finding":"Teneurin-4 (Ten4) switches between homophilic (Ten4–Ten4) and heterophilic (Ten4–ADGRL1/Latrophilin) interactions to direct cortical neuron migration along radial glial cells: in the intermediate zone, Ten4–Latrophilin/ADGRL1 interactions promote neuron–radial glial cell association, while in the cortical plate, Ten4–Ten4 dimerization reduces radial glial cell attachment. Cryo-EM of Ten2 showed that canonical Latrophilin binding is sterically incompatible with Teneurin dimerization, making the two interactions mutually exclusive.","method":"Single-particle cryo-EM (Ten2 structure), engineered surface mutations disrupting Ten-Ten or Ten-Latrophilin interactions, in vivo gene editing, super-resolution microscopy, proteomics","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — cryo-EM structure plus mutagenesis plus in vivo gene editing, but preprint and findings primarily on Teneurin side; ADGRL1 role inferred from the interaction","pmids":["bio_10.1101_2025.09.09.671438"],"is_preprint":true}],"current_model":"ADGRL1/Latrophilin-1 is an adhesion GPCR that undergoes GPS-domain autoproteolysis to form a non-covalent NTF–CTF heterodimer; its extracellular olfactomedin-like domain mediates high-affinity, SS4-splice-regulated trans-synaptic binding to neurexins (and also to teneurins, FLRT3, TAFA2, and glucose), while its transmembrane domain residues and cytoplasmic alternative splicing (SSB) control constitutive and ligand-dependent coupling to multiple G-protein families (Gs, Gi/o, Gq, G13) as well as β-arrestin–dependent endosomal signaling; phosphorylation of the CTF modulates NTF–CTF association and α-latrotoxin-induced neurotransmitter release, and loss of ADGRL1 impairs synapse formation, increases spontaneous exocytosis of dopamine/acetylcholine/glutamate, disrupts hypothalamic glucose sensing and energy homeostasis, and activates anti-tumor immune signaling via JAK/STAT1-Decorin and GSK3β/β-catenin pathways."},"narrative":{"mechanistic_narrative":"ADGRL1 (Latrophilin-1) is an adhesion G-protein-coupled receptor that bridges trans-synaptic adhesion to intracellular signaling and governs synapse formation, neurotransmitter release, and systemic energy homeostasis [PMID:35907405, PMID:37712955]. The receptor matures by constitutive autoproteolytic cleavage at its GPS domain in the endoplasmic reticulum, generating a non-covalent N-terminal/C-terminal fragment (NTF–CTF) heterodimer whose surface trafficking is suppressed by PKC activation [PMID:20100540]. Its extracellular olfactomedin/lectin-like region mediates high-affinity, splice-site-4-regulated adhesion to neurexins lacking the SS4 insert, competing with neuroligin-1 for neurexin binding [PMID:22262843], and also engages the cytokine TAFA2 through its lectin-like domain to drive cAMP/PKA/CREB/BCL2 anti-apoptotic signaling [PMID:37944639]. Specific transmembrane-domain residues control basal constitutive activity and the response to the endogenous tethered agonist peptide, with a cancer-associated TMD mutation increasing basal activity [PMID:30428326]. Downstream coupling is shaped by cytoplasmic SSB alternative splicing, which dictates constitutive Gαi/o versus ligand-dependent Gαs cAMP output [PMID:31339586], and by constitutive β-arrestin recruitment at the plasma membrane and early endosomes that primes activation of all four G-protein families [PMID:41819453]. Phosphorylation of the CTF stabilizes its association with the NTF, while α-latrotoxin binding recruits RPTPσ to dephosphorylate and release the CTF [PMID:31553068]. ADGRL1 additionally binds glucose to mediate hypothalamic VMH glucose sensing and energy balance, with loss causing obesity and dysregulated glucose homeostasis [PMID:37712955, PMID:38664368], and its ablation activates JAK/STAT1-Decorin and disrupts GSK3β/β-catenin signaling to promote anti-tumor immunity [PMID:42172123].","teleology":[{"year":2010,"claim":"Established how ADGRL1 matures into a functional two-subunit receptor, addressing whether the receptor is processed and how its surface delivery is controlled.","evidence":"Transfection of wild-type and non-cleavable CIRL-1 mutants with PKC activator treatment and surface trafficking assays","pmids":["20100540"],"confidence":"Medium","gaps":["Identity of any auxiliary factor required for GPS cleavage not defined","Physiological trigger linking PKC signaling to receptor downregulation unresolved"]},{"year":2012,"claim":"Defined the extracellular adhesion partner and the structural basis of partner selection, showing ADGRL1 forms a splice-regulated trans-cellular complex with neurexins.","evidence":"Saturation binding, extracellular domain deletion mapping, and co-culture cell adhesion assays","pmids":["22262843"],"confidence":"High","gaps":["Downstream signaling consequence of neurexin adhesion not addressed in this study","In vivo relevance of the competition with neuroligin-1 untested"]},{"year":2018,"claim":"Mapped the transmembrane determinants of receptor activation, linking specific TMD residues to constitutive activity and tethered-agonist response.","evidence":"Comprehensive TMD mutagenesis with cell-based functional assays and transgenic C. elegans rescue","pmids":["30428326"],"confidence":"High","gaps":["Structural mechanism by which the tethered agonist engages the TMD not resolved","Which G-protein outputs each residue controls not delineated"]},{"year":2019,"claim":"Showed that cytoplasmic SSB splicing creates signaling bias, answering how a single receptor produces divergent cAMP responses.","evidence":"cAMP competitive binding assays with pertussis toxin and SSB-containing versus SSB-deficient variants, plus Ca2+ and MAPK readouts","pmids":["31339586"],"confidence":"Medium","gaps":["Structural basis of splice-dependent coupling bias unknown","In vivo distribution and function of the two variants not established"]},{"year":2019,"claim":"Connected CTF phosphorylation state to NTF–CTF heterodimer stability and to α-latrotoxin-triggered subunit dissociation, defining a regulatable activation switch.","evidence":"Affinity co-purification, sucrose gradient fractionation, and phosphorylation/α-latrotoxin analysis of synaptic preparations","pmids":["31553068"],"confidence":"Medium","gaps":["Kinase responsible for CTF phosphorylation not identified","Functional consequence of CTF release for downstream signaling not directly measured"]},{"year":2022,"claim":"Demonstrated the in vivo neuronal role of ADGRL1, establishing it as a regulator of synapse formation and neurotransmitter release with human variant relevance.","evidence":"Human variant expression with Ca2+ assays in neuroblastoma cells, ex vivo exocytosis assays, in vitro synapse formation, and Adgrl1 knockout mice on two backgrounds","pmids":["35907405"],"confidence":"High","gaps":["Molecular link between adhesion/coupling and exocytosis control not mechanistically resolved","Specific synaptic G-protein effectors not identified"]},{"year":2023,"claim":"Identified TAFA2 as a lectin-domain ligand coupling ADGRL1 to an anti-apoptotic cAMP/PKA/CREB/BCL2 program.","evidence":"Co-IP, mass spectrometry, pulldowns, KO and Lec-deletion mutants, and pathway/apoptosis readouts","pmids":["37944639"],"confidence":"High","gaps":["G-protein identity downstream of TAFA2 not specified","Tissue context of TAFA2–ADGRL1 signaling beyond cell models limited"]},{"year":2023,"claim":"Revealed an unexpected metabolic function by showing ADGRL1 binds glucose and is required for hypothalamic glucose sensing and energy homeostasis.","evidence":"Glucose-binding affinity assays in CHO cells, global and hypothalamus-specific knockouts, VMH electrophysiology, and metabolic phenotyping","pmids":["37712955"],"confidence":"High","gaps":["Structural site of glucose binding not defined","Signal transduction from glucose binding to VMH neuron firing not mapped"]},{"year":2024,"claim":"Reinforced ADGRL1 as an energy-balance regulator, linking deficiency to obesity and a partially inactivating human mutation.","evidence":"Adgrl1-deficient mouse metabolic phenotyping and human variant functional characterization","pmids":["38664368"],"confidence":"Medium","gaps":["Causal chain from receptor loss to hyperphagia not resolved","Single human variant limits genetic generalization"]},{"year":2024,"claim":"Identified hevin/SPARCL1 as a ligand that biases ADGRL1 coupling and modulates adhesion and reward behavior.","evidence":"Co-IP, internalization and adhesion assays, BRET coupling assays, and NAc Adgrl1 knockdown with cocaine reward paradigms (preprint)","pmids":["bio_10.1101_2024.07.03.601736"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Direct binding domain on ADGRL1 not mapped","Mechanism linking coupling bias to reward behavior unresolved"]},{"year":2026,"claim":"Resolved the order of signaling events, showing β-arrestin recruitment and endosomal localization prime activation of all four G-protein families.","evidence":"G-protein BRET biosensors, β-arrestin knockdown/knockout, dynamin inhibition, endosome-targeted biosensors, and splice-variant analysis in HEK293 cells","pmids":["41819453"],"confidence":"High","gaps":["Whether endosomal priming operates in neurons in vivo not tested","Structural basis of distinct βarr/G-protein complex assemblies unresolved"]},{"year":2026,"claim":"Connected ADGRL1 loss to anti-tumor immunity via interferon, JAK/STAT1-Decorin, and GSK3β/β-catenin pathways, opening a therapeutic avenue.","evidence":"Drosophila RNAi screen, single-cell transcriptomics, mouse KO, pathway and Decorin secretion assays, PD-1 combination, and DARTS-based compound identification","pmids":["42172123"],"confidence":"Medium","gaps":["Direct molecular link between ADGRL1 and GSK3β/β-catenin not defined","Receptor signaling state driving the immune phenotype unclear"]},{"year":null,"claim":"How ADGRL1's distinct ligands (neurexins, teneurins, TAFA2, hevin, glucose) are integrated into selective G-protein and β-arrestin outputs across synaptic, metabolic, and immune contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking ligand identity to coupling bias","Tissue-specific signaling outputs not reconciled","In vivo significance of endosomal G-protein priming untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,10]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,10]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[10]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,8]}],"complexes":["NTF–CTF heterodimer"],"partners":["NRXN1","TAFA2","RPTPΣ","FLRT3","SPARCL1","TENM4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94910","full_name":"Adhesion G protein-coupled receptor L1","aliases":["Calcium-independent alpha-latrotoxin receptor 1","CIRL-1","Latrophilin-1","Lectomedin-2"],"length_aa":1474,"mass_kda":162.7,"function":"Calcium-independent receptor of high affinity for alpha-latrotoxin, an excitatory neurotoxin present in black widow spider venom which triggers massive exocytosis from neurons and neuroendocrine cells (PubMed:35907405). Receptor for TENM2 that mediates heterophilic synaptic cell-cell contact and postsynaptic specialization. Receptor probably implicated in the regulation of exocytosis (By similarity)","subcellular_location":"Cell membrane; Cell projection, axon; Cell projection, growth cone; Synapse; Presynaptic cell membrane; Synapse, synaptosome","url":"https://www.uniprot.org/uniprotkb/O94910/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADGRL1","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/ADGRL1","total_profiled":1310},"omim":[{"mim_id":"620065","title":"DEVELOPMENTAL DELAY, BEHAVIORAL ABNORMALITIES, AND NEUROPSYCHIATRIC DISORDERS; DEDBANP","url":"https://www.omim.org/entry/620065"},{"mim_id":"616417","title":"ADHESION G PROTEIN-COUPLED RECEPTOR L3; ADGRL3","url":"https://www.omim.org/entry/616417"},{"mim_id":"616416","title":"ADHESION G PROTEIN-COUPLED RECEPTOR L1; ADGRL1","url":"https://www.omim.org/entry/616416"},{"mim_id":"610119","title":"TENEURIN TRANSMEMBRANE PROTEIN 2; TENM2","url":"https://www.omim.org/entry/610119"},{"mim_id":"610084","title":"TENEURIN TRANSMEMBRANE PROTEIN 4; TENM4","url":"https://www.omim.org/entry/610084"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":70.4}],"url":"https://www.proteinatlas.org/search/ADGRL1"},"hgnc":{"alias_symbol":["KIAA0821","CIRL1","LEC2"],"prev_symbol":["LPHN1"]},"alphafold":{"accession":"O94910","domains":[{"cath_id":"2.60.120.740","chopping":"37-130","consensus_level":"high","plddt":88.9346,"start":37,"end":130},{"cath_id":"2.120.10,2.120.10","chopping":"136-398","consensus_level":"medium","plddt":89.7696,"start":136,"end":398},{"cath_id":"1.25.40.610","chopping":"495-640","consensus_level":"medium","plddt":90.4569,"start":495,"end":640},{"cath_id":"2.60.220.50","chopping":"668-748_760-850","consensus_level":"medium","plddt":85.9792,"start":668,"end":850},{"cath_id":"1.20.1070.10","chopping":"854-1112","consensus_level":"high","plddt":80.5375,"start":854,"end":1112}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94910","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94910-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94910-F1-predicted_aligned_error_v6.png","plddt_mean":69.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADGRL1","jax_strain_url":"https://www.jax.org/strain/search?query=ADGRL1"},"sequence":{"accession":"O94910","fasta_url":"https://rest.uniprot.org/uniprotkb/O94910.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94910/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94910"}},"corpus_meta":[{"pmid":"28830937","id":"PMC_28830937","title":"The BABY BOOM Transcription Factor Activates the LEC1-ABI3-FUS3-LEC2 Network to Induce Somatic Embryogenesis.","date":"2017","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28830937","citation_count":209,"is_preprint":false},{"pmid":"22262843","id":"PMC_22262843","title":"High affinity neurexin binding to cell adhesion G-protein-coupled receptor CIRL1/latrophilin-1 produces an intercellular adhesion complex.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22262843","citation_count":149,"is_preprint":false},{"pmid":"9685366","id":"PMC_9685366","title":"Mutants of the CMP-sialic acid transporter causing the Lec2 phenotype.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9685366","citation_count":96,"is_preprint":false},{"pmid":"28979275","id":"PMC_28979275","title":"Soybean LEC2 Regulates Subsets of Genes Involved in Controlling the Biosynthesis and Catabolism of Seed Storage Substances and Seed Development.","date":"2017","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/28979275","citation_count":88,"is_preprint":false},{"pmid":"25790072","id":"PMC_25790072","title":"Senescence-inducible LEC2 enhances triacylglycerol accumulation in leaves without negatively affecting plant growth.","date":"2015","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/25790072","citation_count":56,"is_preprint":false},{"pmid":"30428326","id":"PMC_30428326","title":"A Comprehensive Mutagenesis Screen of the Adhesion GPCR Latrophilin-1/ADGRL1.","date":"2018","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/30428326","citation_count":52,"is_preprint":false},{"pmid":"31439805","id":"PMC_31439805","title":"Variation in Expression of the HECT E3 Ligase UPL3 Modulates LEC2 Levels, Seed Size, and Crop Yields in Brassica napus.","date":"2019","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/31439805","citation_count":49,"is_preprint":false},{"pmid":"35907405","id":"PMC_35907405","title":"ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model.","date":"2022","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35907405","citation_count":35,"is_preprint":false},{"pmid":"30150851","id":"PMC_30150851","title":"Expression and DNA methylation of SERK, BBM, LEC2 and WUS genes in in vitro cultures of Boesenbergia rotunda (L.) 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This interaction is trans-cellular and forms a stable intercellular adhesion complex. ADGRL1 competes with neuroligin-1 for neurexin binding.\",\n      \"method\": \"Saturation binding assays, deletion mapping of extracellular domains, cell adhesion assays (co-culture of neurexin- and ADGRL1-expressing cells)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (saturation binding, domain deletion mapping, cell adhesion assay) in a rigorous single study establishing binding domain and splice-site regulation\",\n      \"pmids\": [\"22262843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADGRL1/CIRL-1 undergoes constitutive autoproteolytic cleavage at its GPS domain in the endoplasmic reticulum, producing a heterodimeric two-subunit receptor complex (NTF + CTF). Protein kinase C activators (PMA and ionomycin) inhibit GPS cleavage and downregulate trafficking to the cell surface, causing accumulation of the uncleaved precursor intracellularly. A non-cleavable mutant showed that downregulation of trafficking is independent of cleavage, suggesting that GPS proteolysis is not purely autocatalytic and may require auxiliary factors.\",\n      \"method\": \"Transfection of wild-type and mutant CIRL-1 in cells, treatment with PKC activators PMA and ionomycin, trafficking/surface expression assays, non-cleavable soluble mutant analysis\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — cell-based mechanistic experiments with mutants and pharmacological tools in a single lab, two orthogonal approaches (cleavage assay + trafficking assay)\",\n      \"pmids\": [\"20100540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Comprehensive mutagenesis of the transmembrane domain (TMD) of ADGRL1/latrophilin-1 identified specific TMD residues essential for basal constitutive activity and for agonist peptide (endogenous tethered agonist peptide) response. A cancer-associated TMD mutation showed increased basal activity and failed to rescue embryonic developmental phenotype in transgenic C. elegans, linking TMD residues to receptor activation mechanism.\",\n      \"method\": \"Comprehensive mutagenesis screen of TMD residues, functional assays for basal activity and agonist peptide response, transgenic C. elegans rescue experiments\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic mutagenesis with functional assays and in vivo validation in two orthogonal systems (cell-based + C. elegans transgenic rescue)\",\n      \"pmids\": [\"30428326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Alternative splicing of ADGRL1/latrophilin-1 at the cytoplasmic SSB site confers dual cAMP signaling: SSB-containing variants show both constitutive Gαi/o coupling (constitutive cAMP production) and ligand-dependent Gαs activation (cAMP increase upon neurexin or FLRT binding), whereas SSB-deficient variants show only ligand-dependent cAMP decrease. Neither variant increased intracellular Ca2+ or activated MAP kinase upon ligand binding.\",\n      \"method\": \"cAMP competitive binding assays, pertussis toxin treatment (Gαi/o inhibition), expression of SSB-containing vs SSB-deficient LPHN1 variants, Ca2+ and MAPK assays\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple pharmacological and biochemical assays in a single lab establishing splice-dependent G-protein coupling bias\",\n      \"pmids\": [\"31339586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The C-terminal fragment (CTF) of latrophilin-1/ADGRL1 in synapses is phosphorylated on multiple sites. Phosphorylated CTF has high affinity for the N-terminal fragment (NTF) and co-purifies with it. Dephosphorylated CTF has lower affinity for NTF and can behave as a separate protein. α-Latrotoxin binding to NTF brings it together with receptor-like protein tyrosine phosphatase σ (RPTPσ), leading to CTF dephosphorylation and CTF release from the NTF–CTF complex.\",\n      \"method\": \"Affinity column co-purification, sucrose density gradient fractionation, phosphorylation analysis of synaptic preparations, α-latrotoxin binding experiments\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — biochemical fractionation and co-purification from synaptic preparations with pharmacological intervention, single lab\",\n      \"pmids\": [\"31553068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADGRL1 haploinsufficiency impairs ligand-induced regulation of intracellular Ca2+ influx (shown by in vitro expression of human variants in neuroblastoma cells). In Adgrl1 knockout mice, loss of ADGRL1 causes increased spontaneous exocytosis of dopamine, acetylcholine, and glutamate from synaptic preparations, and Adgrl1-null neurons form synapses poorly in vitro, demonstrating that ADGRL1 regulates neurotransmitter release and synapse formation.\",\n      \"method\": \"In vitro Ca2+ influx assays in neuroblastoma cells expressing human ADGRL1 variants; ex vivo synaptic preparations measuring spontaneous exocytosis; in vitro synapse formation assay in Adgrl1-/- neurons; mouse knockout on two genetic backgrounds\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Ca2+ signaling, exocytosis assay, synapse formation in vitro) combined with genetic knockout in two backgrounds\",\n      \"pmids\": [\"35907405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TAFA2 (a CNS-specific cytokine) directly binds to the lectin-like domain (Lec domain) of ADGRL1. This interaction activates the cAMP/PKA/CREB/BCL2 signaling pathway to suppress apoptosis. Overexpression of ADGRL1 lacking the Lec domain (ADGRL1ΔLec) failed to mediate TAFA2's anti-apoptotic effects, and ADGRL1-/- cells were unresponsive to recombinant TAFA2.\",\n      \"method\": \"Co-immunoprecipitation, quantitative mass spectrometry proteomics, pull-down assays, ADGRL1 knockout and Lec-deletion mutant overexpression, cAMP/p-PKA/p-CREB/BCL2 signaling measurements, apoptosis assays\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, pulldown, MS, loss-of-function KO, domain deletion mutant, pathway readout) establishing binding domain and downstream signaling\",\n      \"pmids\": [\"37944639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADGRL1 binds glucose and functions as a glucose receptor in hypothalamic neurons. Validated by ligand-receptor binding assays in CHO cells stably expressing human ADGRL1. Adgrl1-deficient mice showed impaired glucose sensing by VMH neurons (electrophysiology), fasting hyperinsulinemia, enhanced glucose-stimulated insulin secretion, insulin resistance, and impaired feeding responses, demonstrating a role for ADGRL1 in energy and glucose homeostasis.\",\n      \"method\": \"Cell-based affinity chromatography to enrich glucose-bound neurons, proteomics identification, ligand-receptor binding assays in ADGRL1-expressing CHO cells, global and hypothalamus-specific Adgrl1 knockout mice, electrophysiology of VMH neurons, metabolic phenotyping\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (binding assay, two genetic KO models, electrophysiology, metabolic phenotyping) establishing glucose binding and downstream physiology\",\n      \"pmids\": [\"37712955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADGRL1/LPHN1 deficiency in mice causes increased food consumption and severe obesity with dysregulated glucose homeostasis, and a partially inactivating human ADGRL1 mutation was identified in an obese patient, establishing ADGRL1 as a regulator of energy balance.\",\n      \"method\": \"Adgrl1-deficient mouse metabolic phenotyping (food intake, body weight, glucose homeostasis); human genetic variant functional characterization\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — mouse KO with defined metabolic phenotype plus human variant identification, single study\",\n      \"pmids\": [\"38664368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ADGRL1 ablation activates type I interferon signaling and promotes JAK/STAT1-dependent Decorin secretion by disrupting the GSK3β/β-catenin pathway, which facilitates cDC1–CD8+ T cell hub formation and anti-tumor immunity. An ADGRL1-targeting small molecule identified by virtual screening and DARTS showed antitumor efficacy in vivo.\",\n      \"method\": \"RNAi screening in Drosophila tumor model, single-cell transcriptomics, genetic KO in mice, pathway analysis (IFN/JAK/STAT1, GSK3β/β-catenin), Decorin secretion assays, PD-1 blockade combination, DARTS-based compound identification, in vivo tumor models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (scRNA-seq, genetic KO, pathway assays, in vivo) in a single study, but primarily single lab\",\n      \"pmids\": [\"42172123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ADGRL1/Latrophilin-1 recruits β-arrestins (βarr) constitutively at the plasma membrane and early endosomes. βarr recruitment is prerequisite for G-protein activation (all four G-protein families: Gs, Gi/o, Gq, G13); βarr or dynamin depletion suppressed G-protein biosensor activation, indicating endosomal priming of G-protein signaling. Splice-variant SSB determines differential trafficking kinetics and distinct βarr/G-protein complex assemblies (shared for Gs, divergent for Gq and G13) upon neurexin-1β stimulation.\",\n      \"method\": \"G-protein BRET biosensors, β-arrestin knockdown and knockout in HEK293 cells, dynamin inhibition, endosome-targeted biosensors, splice variant overexpression, receptor internalization imaging\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biosensor, genetic KO/KD, pharmacological, and compartment-specific approaches establishing mechanism of β-arrestin-dependent endosomal G-protein signaling\",\n      \"pmids\": [\"41819453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADGRL1 acts as a functional receptor for hevin/SPARCL1 in nucleus accumbens neurons. Hevin interacts with membrane-expressed ADGRL1, induces its internalization, stabilizes the uncleaved receptor fraction, and alters ADGRL1/Neurexin-1-mediated intercellular adhesion contacts. Hevin stimulation selectively modulates ADGRL1 G-protein coupling with bias toward Gi3, Gs, and G13. Pan-neuronal Adgrl1 deficiency in the nucleus accumbens impairs cocaine-induced reinforcement and reward.\",\n      \"method\": \"Co-IP, receptor internalization assays, cell adhesion assays, G-protein coupling BRET assays, mouse Adgrl1 knockdown in NAc, cocaine conditioned place preference and self-administration\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple biochemical and in vivo assays, preprint (not yet peer-reviewed)\",\n      \"pmids\": [\"bio_10.1101_2024.07.03.601736\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Teneurin-4 (Ten4) switches between homophilic (Ten4–Ten4) and heterophilic (Ten4–ADGRL1/Latrophilin) interactions to direct cortical neuron migration along radial glial cells: in the intermediate zone, Ten4–Latrophilin/ADGRL1 interactions promote neuron–radial glial cell association, while in the cortical plate, Ten4–Ten4 dimerization reduces radial glial cell attachment. Cryo-EM of Ten2 showed that canonical Latrophilin binding is sterically incompatible with Teneurin dimerization, making the two interactions mutually exclusive.\",\n      \"method\": \"Single-particle cryo-EM (Ten2 structure), engineered surface mutations disrupting Ten-Ten or Ten-Latrophilin interactions, in vivo gene editing, super-resolution microscopy, proteomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — cryo-EM structure plus mutagenesis plus in vivo gene editing, but preprint and findings primarily on Teneurin side; ADGRL1 role inferred from the interaction\",\n      \"pmids\": [\"bio_10.1101_2025.09.09.671438\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ADGRL1/Latrophilin-1 is an adhesion GPCR that undergoes GPS-domain autoproteolysis to form a non-covalent NTF–CTF heterodimer; its extracellular olfactomedin-like domain mediates high-affinity, SS4-splice-regulated trans-synaptic binding to neurexins (and also to teneurins, FLRT3, TAFA2, and glucose), while its transmembrane domain residues and cytoplasmic alternative splicing (SSB) control constitutive and ligand-dependent coupling to multiple G-protein families (Gs, Gi/o, Gq, G13) as well as β-arrestin–dependent endosomal signaling; phosphorylation of the CTF modulates NTF–CTF association and α-latrotoxin-induced neurotransmitter release, and loss of ADGRL1 impairs synapse formation, increases spontaneous exocytosis of dopamine/acetylcholine/glutamate, disrupts hypothalamic glucose sensing and energy homeostasis, and activates anti-tumor immune signaling via JAK/STAT1-Decorin and GSK3β/β-catenin pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADGRL1 (Latrophilin-1) is an adhesion G-protein-coupled receptor that bridges trans-synaptic adhesion to intracellular signaling and governs synapse formation, neurotransmitter release, and systemic energy homeostasis [#5, #7]. The receptor matures by constitutive autoproteolytic cleavage at its GPS domain in the endoplasmic reticulum, generating a non-covalent N-terminal/C-terminal fragment (NTF–CTF) heterodimer whose surface trafficking is suppressed by PKC activation [#1]. Its extracellular olfactomedin/lectin-like region mediates high-affinity, splice-site-4-regulated adhesion to neurexins lacking the SS4 insert, competing with neuroligin-1 for neurexin binding [#0], and also engages the cytokine TAFA2 through its lectin-like domain to drive cAMP/PKA/CREB/BCL2 anti-apoptotic signaling [#6]. Specific transmembrane-domain residues control basal constitutive activity and the response to the endogenous tethered agonist peptide, with a cancer-associated TMD mutation increasing basal activity [#2]. Downstream coupling is shaped by cytoplasmic SSB alternative splicing, which dictates constitutive Gαi/o versus ligand-dependent Gαs cAMP output [#3], and by constitutive β-arrestin recruitment at the plasma membrane and early endosomes that primes activation of all four G-protein families [#10]. Phosphorylation of the CTF stabilizes its association with the NTF, while α-latrotoxin binding recruits RPTPσ to dephosphorylate and release the CTF [#4]. ADGRL1 additionally binds glucose to mediate hypothalamic VMH glucose sensing and energy balance, with loss causing obesity and dysregulated glucose homeostasis [#7, #8], and its ablation activates JAK/STAT1-Decorin and disrupts GSK3β/β-catenin signaling to promote anti-tumor immunity [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established how ADGRL1 matures into a functional two-subunit receptor, addressing whether the receptor is processed and how its surface delivery is controlled.\",\n      \"evidence\": \"Transfection of wild-type and non-cleavable CIRL-1 mutants with PKC activator treatment and surface trafficking assays\",\n      \"pmids\": [\"20100540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of any auxiliary factor required for GPS cleavage not defined\", \"Physiological trigger linking PKC signaling to receptor downregulation unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the extracellular adhesion partner and the structural basis of partner selection, showing ADGRL1 forms a splice-regulated trans-cellular complex with neurexins.\",\n      \"evidence\": \"Saturation binding, extracellular domain deletion mapping, and co-culture cell adhesion assays\",\n      \"pmids\": [\"22262843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling consequence of neurexin adhesion not addressed in this study\", \"In vivo relevance of the competition with neuroligin-1 untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped the transmembrane determinants of receptor activation, linking specific TMD residues to constitutive activity and tethered-agonist response.\",\n      \"evidence\": \"Comprehensive TMD mutagenesis with cell-based functional assays and transgenic C. elegans rescue\",\n      \"pmids\": [\"30428326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism by which the tethered agonist engages the TMD not resolved\", \"Which G-protein outputs each residue controls not delineated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that cytoplasmic SSB splicing creates signaling bias, answering how a single receptor produces divergent cAMP responses.\",\n      \"evidence\": \"cAMP competitive binding assays with pertussis toxin and SSB-containing versus SSB-deficient variants, plus Ca2+ and MAPK readouts\",\n      \"pmids\": [\"31339586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of splice-dependent coupling bias unknown\", \"In vivo distribution and function of the two variants not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected CTF phosphorylation state to NTF–CTF heterodimer stability and to α-latrotoxin-triggered subunit dissociation, defining a regulatable activation switch.\",\n      \"evidence\": \"Affinity co-purification, sucrose gradient fractionation, and phosphorylation/α-latrotoxin analysis of synaptic preparations\",\n      \"pmids\": [\"31553068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for CTF phosphorylation not identified\", \"Functional consequence of CTF release for downstream signaling not directly measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated the in vivo neuronal role of ADGRL1, establishing it as a regulator of synapse formation and neurotransmitter release with human variant relevance.\",\n      \"evidence\": \"Human variant expression with Ca2+ assays in neuroblastoma cells, ex vivo exocytosis assays, in vitro synapse formation, and Adgrl1 knockout mice on two backgrounds\",\n      \"pmids\": [\"35907405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between adhesion/coupling and exocytosis control not mechanistically resolved\", \"Specific synaptic G-protein effectors not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified TAFA2 as a lectin-domain ligand coupling ADGRL1 to an anti-apoptotic cAMP/PKA/CREB/BCL2 program.\",\n      \"evidence\": \"Co-IP, mass spectrometry, pulldowns, KO and Lec-deletion mutants, and pathway/apoptosis readouts\",\n      \"pmids\": [\"37944639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"G-protein identity downstream of TAFA2 not specified\", \"Tissue context of TAFA2–ADGRL1 signaling beyond cell models limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an unexpected metabolic function by showing ADGRL1 binds glucose and is required for hypothalamic glucose sensing and energy homeostasis.\",\n      \"evidence\": \"Glucose-binding affinity assays in CHO cells, global and hypothalamus-specific knockouts, VMH electrophysiology, and metabolic phenotyping\",\n      \"pmids\": [\"37712955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural site of glucose binding not defined\", \"Signal transduction from glucose binding to VMH neuron firing not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reinforced ADGRL1 as an energy-balance regulator, linking deficiency to obesity and a partially inactivating human mutation.\",\n      \"evidence\": \"Adgrl1-deficient mouse metabolic phenotyping and human variant functional characterization\",\n      \"pmids\": [\"38664368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from receptor loss to hyperphagia not resolved\", \"Single human variant limits genetic generalization\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified hevin/SPARCL1 as a ligand that biases ADGRL1 coupling and modulates adhesion and reward behavior.\",\n      \"evidence\": \"Co-IP, internalization and adhesion assays, BRET coupling assays, and NAc Adgrl1 knockdown with cocaine reward paradigms (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.03.601736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Direct binding domain on ADGRL1 not mapped\", \"Mechanism linking coupling bias to reward behavior unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved the order of signaling events, showing β-arrestin recruitment and endosomal localization prime activation of all four G-protein families.\",\n      \"evidence\": \"G-protein BRET biosensors, β-arrestin knockdown/knockout, dynamin inhibition, endosome-targeted biosensors, and splice-variant analysis in HEK293 cells\",\n      \"pmids\": [\"41819453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endosomal priming operates in neurons in vivo not tested\", \"Structural basis of distinct βarr/G-protein complex assemblies unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected ADGRL1 loss to anti-tumor immunity via interferon, JAK/STAT1-Decorin, and GSK3β/β-catenin pathways, opening a therapeutic avenue.\",\n      \"evidence\": \"Drosophila RNAi screen, single-cell transcriptomics, mouse KO, pathway and Decorin secretion assays, PD-1 combination, and DARTS-based compound identification\",\n      \"pmids\": [\"42172123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between ADGRL1 and GSK3β/β-catenin not defined\", \"Receptor signaling state driving the immune phenotype unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ADGRL1's distinct ligands (neurexins, teneurins, TAFA2, hevin, glucose) are integrated into selective G-protein and β-arrestin outputs across synaptic, metabolic, and immune contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking ligand identity to coupling bias\", \"Tissue-specific signaling outputs not reconciled\", \"In vivo significance of endosomal G-protein priming untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\"NTF–CTF heterodimer\"],\n    \"partners\": [\"NRXN1\", \"TAFA2\", \"RPTPσ\", \"FLRT3\", \"SPARCL1\", \"TENM4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}