{"gene":"ADGRB1","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":2007,"finding":"BAI1 functions as a phosphatidylserine recognition receptor on apoptotic cells: its thrombospondin type 1 repeats in the extracellular region directly bind phosphatidylserine, and BAI1 forms a trimeric complex with ELMO and Dock180 to activate Rac GTPase and promote apoptotic cell engulfment.","method":"Co-immunoprecipitation, pulldown assays, phosphatidylserine-binding assays, loss-of-function (knockdown/interference), in vivo engulfment assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, direct binding assays, in vivo functional studies), replicated across multiple experimental systems (ex vivo and in vivo)","pmids":["17960134"],"is_preprint":false},{"year":1997,"finding":"BAI1 is a p53-target gene; its extracellular thrombospondin type 1 repeats mediate inhibition of angiogenesis, as demonstrated by a recombinant TSP-repeat protein inhibiting bFGF-induced neovascularization in the rat cornea.","method":"Recombinant protein in vivo angiogenesis assay (rat cornea model), gene cloning and characterization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vivo reconstitution with recombinant domain, single lab, single method for functional assay","pmids":["9393972"],"is_preprint":false},{"year":1998,"finding":"BAI1 interacts with BAP1 (a MAGUK family PDZ domain-containing protein) via a QTEV motif in the C-terminal region of BAI1 and PDZ domains of BAP1; both proteins co-localize at the cytoplasmic membrane and cell-cell junctions, and BAI1 expression induces filopodia-like extensions.","method":"Yeast two-hybrid, co-immunoprecipitation, immunocytochemistry in COS-7 cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus co-localization, single lab, two methods","pmids":["9647739"],"is_preprint":false},{"year":1999,"finding":"BAI1 interacts via its proline-rich cytoplasmic region with the SH3 domain of BAIAP2 (IRSp53 homologue); BAIAP2 localizes to the plasma membrane only when co-expressed with BAI1, and BAI1 protein is predominantly found in growth cone-enriched fractions.","method":"Yeast two-hybrid, in vitro binding assay, double-color immunofluorescence, subcellular fractionation","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid confirmed by in vitro binding, co-localization and fractionation, single lab","pmids":["10343108"],"is_preprint":false},{"year":1998,"finding":"BAI1 interacts with BAP3, a C2 domain-containing protein homologous to Munc13, through a region distinct from the C2 domains; interaction was mapped by deletion-mutant analysis in the yeast two-hybrid system.","method":"Yeast two-hybrid, deletion-mutant analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid only, single lab, single method","pmids":["9790924"],"is_preprint":false},{"year":2001,"finding":"BAI1 interacts with PAHX-AP1 (BAP4) via its cytoplasmic region, confirmed by GST-pulldown and co-immunoprecipitation from brain lysate; BAI1 is predominantly expressed in neurons of cortex and hippocampus and its expression is decreased in the ischemic hemisphere after focal cerebral ischemia.","method":"GST-pulldown, co-immunoprecipitation from brain lysate, in situ hybridization, Western blot","journal":"Brain research. Molecular brain research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal pulldown and Co-IP from native brain tissue, two orthogonal methods, single lab","pmids":["11245925"],"is_preprint":false},{"year":2011,"finding":"BAI1 acts as a pattern recognition receptor on macrophages that recognizes Gram-negative bacterial lipopolysaccharide via its thrombospondin repeats, and promotes non-opsonic phagocytosis through ELMO/Dock-dependent Rac1 activation; inhibition of the BAI1/ELMO1 interaction prevents Rac activation and bacterial uptake. BAI1 does not recognize Gram-positive bacteria.","method":"Recombinant ectodomain competition, BAI1 knockdown and overexpression in macrophages and non-phagocytic cells, Rac activation assay, peritoneal infection model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (recombinant competition, KD, OE, Rac GTPase assays, in vivo infection), consistent results across systems","pmids":["21245295"],"is_preprint":false},{"year":2012,"finding":"The N terminus of BAI1 is proteolytically cleaved extracellularly by a two-step cascade: proprotein convertases (primarily furin) activate latent MMP-14, which then directly cleaves BAI1 to release a bioactive 40 kDa fragment (Vasculostatin-40) that inhibits angiogenesis.","method":"Biochemical proteolysis assays, protease inhibition, cell-based cleavage assays, in vitro angiogenesis assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic cascade demonstrated with protease inhibitors and reconstitution, single lab with multiple orthogonal methods","pmids":["22330140"],"is_preprint":false},{"year":2013,"finding":"BAI1 interacts with the Par3/Tiam1 polarity complex and recruits these proteins to dendritic spines to promote spinogenesis and synaptogenesis via local Rac1 activation; a BAI1 mutant that cannot interact with ELMO/DOCK180 still rescues spine defects (ELMO interaction is dispensable for this function), while a mutant lacking Par3/Tiam1 interaction fails to rescue spine or Par3 localization defects.","method":"Co-immunoprecipitation, BAI1 knockdown in hippocampal neurons, rescue experiments with BAI1 mutants, immunofluorescence of Rac1 and F-actin","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis via domain-specific mutants, Co-IP, and cellular rescue experiments; multiple orthogonal approaches in single lab","pmids":["23595754"],"is_preprint":false},{"year":2013,"finding":"BAI1 acts as a phosphatidylserine receptor on myoblasts that promotes myoblast fusion through the ELMO/Dock180/Rac1 signaling axis; apoptotic myoblasts expose phosphatidylserine and signal in a contact-dependent manner through BAI1 on neighboring healthy myoblasts to promote fusion. In vivo, Bai1−/− mice have smaller myofibers and impaired muscle regeneration after injury.","method":"BAI1 overexpression and knockout, apoptosis blockade, addition of exogenous apoptotic myoblasts, in vivo muscle injury model (Bai1−/− mice)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (OE, KO mice, rescue with apoptotic cells, in vivo injury), replicated in primary human myoblasts","pmids":["23615608"],"is_preprint":false},{"year":2014,"finding":"In zebrafish microglia, BAI1 specifically controls phagosome formation around dying neurons and intracellular cargo transport during neuronal engulfment, whereas TIM-4 is required for phagosome stabilization; combined activity of both receptors is needed for complete clearance of dying neurons.","method":"Live imaging in zebrafish, genetic knockdown of BAI1 and TIM-4, quantitative phagocytosis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — live single-cell resolution imaging with genetic KD, ortholog in zebrafish with consistent molecular context","pmids":["24898390"],"is_preprint":false},{"year":2015,"finding":"BAI1 prevents MDM2-mediated polyubiquitination and proteasomal degradation of PSD-95 through a direct interaction with MDM2; loss of BAI1 in mice leads to reduced PSD-95 protein levels, thinning of the postsynaptic density, enhanced LTP, impaired LTD, and hippocampus-dependent spatial learning deficits that are rescued by viral restoration of PSD-95.","method":"BAI1 knockout mice, co-immunoprecipitation of BAI1-MDM2 complex, ubiquitination assay, viral gene delivery rescue, electrophysiology (LTP/LTD)","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, in vivo KO, ubiquitination assay, and functional rescue by gene therapy; multiple orthogonal methods","pmids":["25751059"],"is_preprint":false},{"year":2015,"finding":"BAI1 constitutive signaling activity does not require the membrane-proximal stalk peptide revealed by GAIN domain cleavage; a stalkless BAI1 mutant (B1-SL) retains robust signaling activity across multiple assays, supporting stalk-independent activation of BAI1.","method":"Engineered stalkless mutant receptors, battery of signaling assays (TGFα shedding, NFAT-luciferase, β-arrestin recruitment, SRF-luciferase)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling assays with engineered mutants, single lab","pmids":["26710850"],"is_preprint":false},{"year":2016,"finding":"BAI1 mediates phagosomal ROS production in macrophages challenged with Gram-negative bacteria by activating Rac1 GTPase, which stimulates NADPH oxidase; BAI1-deficient macrophages show attenuated Rac activity, reduced ROS, and impaired bacterial killing, and BAI1-deficient mice show increased susceptibility to Gram-negative peritoneal infection.","method":"Primary BAI1-deficient macrophages, Rac GTPase activation assay, ROS measurement, bacterial killing assays, in vivo peritoneal infection model","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO primary cells plus in vivo model, multiple mechanistic readouts (Rac activity, ROS, microbicidal killing), consistent results","pmids":["26838550"],"is_preprint":false},{"year":2018,"finding":"BAI1 prevents MDM2-mediated p53 polyubiquitination and degradation; loss of BAI1 (ADGRB1) in mice increases proliferation of cerebellar granule neuron precursors and accelerates tumor growth in the Ptch1+/− medulloblastoma model; ADGRB1 is epigenetically silenced in medulloblastomas by MBD2 binding to the hypermethylated promoter.","method":"Adgrb1 knockout mice crossed with Ptch1+/− tumor model, p53 ubiquitination assay, chromatin immunoprecipitation for MBD2, in vivo tumor growth assays, MBD2 pathway inhibitor treatment","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo tumor model, biochemical ubiquitination assay, ChIP, pharmacological rescue; multiple orthogonal methods in one study","pmids":["29894688"],"is_preprint":false},{"year":2018,"finding":"BAI1 promotes excitatory synaptogenesis via three distinct mechanisms: (1) Stachel peptide-dependent activation drives synaptic Rac1 activation and spinogenesis; (2) BAI1 acts trans-synaptically to induce clustering of presynaptic vGluT1 in contacting axons; (3) BAI1 forms a receptor complex with Neuroligin-1 (NRLN1) to mediate NRLN1-dependent spine growth and synapse development. The N-terminal extracellular segment is required for both prospinogenic and prosynaptogenic functions.","method":"In utero electroporation knockdown, Stachel peptide activation, mixed-culture trans-synaptic assay, co-immunoprecipitation of BAI1-NRLN1, in vivo hippocampal spine analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vivo KD, peptide activation, Co-IP, trans-synaptic assay) in single study with consistent results","pmids":["30120207"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of the ELMO2 RAE supramodule (RBD-ARR-ELMO) in complex with a conserved fragment of the BAI1 C-terminal cytoplasmic tail reveals the molecular basis of BAI/ELMO interaction; disease-causing mutations in BAI and ELMO map to this interface and disrupt complex formation.","method":"X-ray crystallography, co-immunoprecipitation, mutagenesis of interface residues","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis and biochemical validation of the complex","pmids":["30604775"],"is_preprint":false},{"year":2019,"finding":"BAI1 regulates dendritic arbor growth arrest by coupling to the RhoA pathway: BAI1 associates with Bcr late in development and stimulates its cryptic RhoA-GEF activity (together with Bcr's Rac1-GAP activity) to terminate arborization; BAI1 loss lowers RhoA activation and causes dendritic hypertrophy. This function is independent of BAI1's Rac1-dependent synaptogenic pathway.","method":"BAI1 loss-of-function and overexpression in hippocampal neurons, RhoA activation assay, co-immunoprecipitation of BAI1-Bcr, domain mutant rescue experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, GTPase activation assay, multiple mutants, and loss-of-function with specific phenotypic readout; multiple orthogonal methods","pmids":["31461398"],"is_preprint":false},{"year":2022,"finding":"Extracellular phosphatidylserine (PS) exposure modulates BAI1 G protein-dependent signaling: reducing PS in the outer leaflet (via co-expression of the PS flippase ATP11A or deletion of the scramblase ANO6) markedly reduces BAI1 signaling activity; ATP11A also forms a protein complex with BAI1 detected by co-immunoprecipitation. A truncated BAI1 lacking the TSP repeats is insensitive to PS reduction, demonstrating the TSP repeats mediate PS-dependent signaling.","method":"Co-expression of PS flippase ATP11A, ANO6 knockout cells, co-immunoprecipitation, G protein signaling assays, truncation mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent PS-reduction methods (ATP11A co-expression and ANO6 KO) with consistent results, Co-IP, domain mapping; multiple orthogonal methods single lab","pmids":["36370845"],"is_preprint":false},{"year":2024,"finding":"BAI1 is required for clustering of AMPA receptor subunits GluR2-4 at the postsynaptic density of spiral ganglion neuron (SGN) afferent synapses in the cochlea; Bai1-deficient mice have normal inner hair cells but fail to transmit auditory information to SGNs, indicating BAI1 is essential for trafficking or anchoring AMPA receptors at cochlear ribbon synapses.","method":"Bai1 knockout mice, immunostaining for AMPA receptor subunits, auditory brainstem response and hearing threshold measurement, confocal and electron microscopy of synapses","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with specific molecular (AMPA receptor clustering) and functional (hearing threshold) phenotypic readouts, multiple imaging modalities","pmids":["38564333"],"is_preprint":false},{"year":2025,"finding":"C1q acts through BAI1 to drive neural stem cell (NSC) quiescence via two parallel BAI1-dependent mechanisms: (1) BAI1-dependent negative regulation of MDM2 causing cell cycle suppression through p53; (2) endocytic internalization of the C1q-BAI1 complex driving regulation of p32 (C1qBP) and metabolic reprogramming toward aerobic glycolysis. These functions were validated in human NSCs and in a mouse spinal cord injury model.","method":"BAI1 loss-of-function, MDM2/p53 pathway assay, endocytosis assay, metabolic profiling, in vivo spinal cord injury model with hNSC transplant","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic readouts and in vivo validation, but mechanistic details rely heavily on loss-of-function without full reconstitution; single lab","pmids":["41381494"],"is_preprint":false},{"year":2025,"finding":"ADGRB1/BAI1 is required for astrocyte-mediated phagocytosis of excitatory presynaptic elements; Adgrb1-knockout astrocytes show reduced phagocytic capacity, less engulfment of presynaptic material, and a higher density of excitatory synapses in vivo, indicating BAI1 mediates synaptic pruning by astrocytes.","method":"Adgrb1 knockout mice, cultured astrocyte phagocytosis assay, immunostaining of pre- and post-synaptic markers, RNA-seq of KO astrocytes","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with specific molecular and cellular phenotypic readouts, in vitro and in vivo consistency, single lab","pmids":["40930306"],"is_preprint":false}],"current_model":"BAI1 (ADGRB1) is a multi-functional adhesion GPCR whose extracellular thrombospondin type 1 repeats directly bind phosphatidylserine on apoptotic cells and bacterial LPS, coupling these ligands to intracellular ELMO/Dock180/Rac1-dependent actin remodeling for phagocytosis and myoblast fusion; in neurons it recruits the Par3/Tiam1 complex to dendritic spines for Rac1-dependent synaptogenesis, signals through Bcr-mediated RhoA activation to terminate dendrite growth, interacts with Neuroligin-1 for bidirectional trans-synaptic organization, stabilizes PSD-95 by protecting it from MDM2-mediated ubiquitination, and localizes AMPA receptors at cochlear ribbon synapse PSDs; its N terminus is proteolytically released by a furin/MMP-14 cascade to generate an anti-angiogenic Vasculostatin-40 fragment, and extracellular PS exposure itself modulates BAI1 G-protein signaling through the TSP repeat domain."},"narrative":{"mechanistic_narrative":"ADGRB1 (BAI1) is an adhesion GPCR that functions as an engulfment and synaptic-organizing receptor, coupling extracellular ligand recognition to Rho-family GTPase signaling [PMID:17960134, PMID:23595754]. Its extracellular thrombospondin type 1 repeats directly bind phosphatidylserine displayed on apoptotic cells and lipopolysaccharide on Gram-negative bacteria, and these ligands are transduced through a cytoplasmic ELMO/Dock180 module that activates Rac1 to drive non-opsonic phagocytosis, apoptotic cell clearance, and phagosomal NADPH-oxidase-dependent ROS production for bacterial killing [PMID:17960134, PMID:21245295, PMID:26838550]; the same PS-recognition/Rac1 axis promotes contact-dependent myoblast fusion and muscle regeneration in vivo [PMID:23615608], and the structural basis of BAI1 engagement of the ELMO RAE supramodule has been resolved by crystallography [PMID:30604775]. PS exposure on the outer membrane leaflet additionally modulates BAI1 G-protein signaling through the TSP repeats, and BAI1 forms a complex with the PS flippase ATP11A [PMID:36370845]. In neurons BAI1 organizes excitatory synapses through multiple parallel routes: Stachel/Par3-Tiam1-dependent local Rac1 activation drives spinogenesis and synaptogenesis, BAI1 acts trans-synaptically and forms a receptor complex with Neuroligin-1 to coordinate pre- and post-synaptic assembly, and it is required for AMPA receptor clustering at cochlear ribbon synapses [PMID:23595754, PMID:30120207, PMID:38564333]. BAI1 also stabilizes PSD-95 by sequestering MDM2 to block its ubiquitination, supporting postsynaptic density integrity, synaptic plasticity, and spatial learning [PMID:25751059], while a developmentally late association with Bcr couples BAI1 to RhoA activation to terminate dendritic arbor growth, independently of its Rac1 synaptogenic function [PMID:31461398]. Through MDM2 antagonism BAI1 stabilizes p53 to restrain cerebellar precursor proliferation, and ADGRB1 is epigenetically silenced in medulloblastoma [PMID:29894688]. The N terminus is proteolytically released by a furin-activated MMP-14 cascade to generate the anti-angiogenic Vasculostatin-40 fragment, consistent with BAI1's identification as a p53-target anti-angiogenic gene [PMID:9393972, PMID:22330140].","teleology":[{"year":1997,"claim":"Established BAI1's founding identity as a p53-inducible gene whose extracellular TSP repeats carry anti-angiogenic activity, framing it as a tumor-suppressor-associated receptor.","evidence":"Gene cloning plus recombinant TSP-repeat protein in a rat corneal neovascularization assay","pmids":["9393972"],"confidence":"Medium","gaps":["Did not identify the receptor's ligand or signaling output","Single functional assay for the anti-angiogenic effect"]},{"year":1998,"claim":"First mapped cytoplasmic binding partners (BAP1/MAGUK, BAP3/Munc13-homolog), indicating BAI1 couples to scaffolding and membrane-associated machinery.","evidence":"Yeast two-hybrid, co-IP, and co-localization in COS-7 cells; deletion-mutant mapping","pmids":["9647739","9790924"],"confidence":"Medium","gaps":["BAP3 interaction rests on yeast two-hybrid alone","Functional consequence of the scaffolding interactions undefined"]},{"year":1999,"claim":"Linked BAI1 to actin-based membrane remodeling via its proline-rich tail binding the SH3 domain of BAIAP2/IRSp53 and enriched localization in growth cones.","evidence":"Yeast two-hybrid, in vitro binding, immunofluorescence, and subcellular fractionation","pmids":["10343108"],"confidence":"Medium","gaps":["No demonstration of in vivo cytoskeletal phenotype","Did not connect to a defined signaling pathway"]},{"year":2001,"claim":"Showed BAI1 is a neuronal protein (cortex, hippocampus) with an additional cytoplasmic partner (PAHX-AP1/BAP4) and is downregulated after cerebral ischemia, placing it in a brain-injury context.","evidence":"GST-pulldown and co-IP from brain lysate, in situ hybridization, Western blot","pmids":["11245925"],"confidence":"Medium","gaps":["Functional role of the PAHX-AP1 interaction unresolved","Ischemia association is correlative"]},{"year":2007,"claim":"Defined BAI1's core signaling mechanism: the TSP repeats directly recognize phosphatidylserine and the receptor assembles a trimeric ELMO/Dock180 complex to activate Rac and engulf apoptotic cells.","evidence":"Co-IP, PS-binding and pulldown assays, knockdown, and in vivo engulfment assays","pmids":["17960134"],"confidence":"High","gaps":["Did not address G-protein involvement","Generality beyond apoptotic-cell clearance unknown at the time"]},{"year":2011,"claim":"Extended BAI1 ligand recognition to innate immunity by showing TSP-repeat binding of Gram-negative LPS drives non-opsonic phagocytosis through the same ELMO/Dock/Rac1 axis.","evidence":"Recombinant ectodomain competition, knockdown/overexpression in macrophages, Rac assays, peritoneal infection model","pmids":["21245295"],"confidence":"High","gaps":["Did not explain why Gram-positive bacteria are not recognized","Downstream microbicidal consequences not yet defined"]},{"year":2012,"claim":"Resolved how the anti-angiogenic Vasculostatin-40 fragment is generated, defining a furin-then-MMP-14 proteolytic cascade that releases the BAI1 N terminus.","evidence":"Biochemical proteolysis, protease inhibition, cell-based cleavage, and in vitro angiogenesis assays","pmids":["22330140"],"confidence":"High","gaps":["Regulation of the cleavage in vivo not established","Receptor/target through which Vstat40 acts not identified"]},{"year":2013,"claim":"Showed BAI1 organizes excitatory synapses by recruiting the Par3/Tiam1 polarity complex for local Rac1 activation, and that this is genetically separable from the ELMO/Dock engulfment pathway.","evidence":"Co-IP, neuronal knockdown, and domain-specific mutant rescue with Rac1/F-actin imaging","pmids":["23595754"],"confidence":"High","gaps":["Upstream synaptic ligand for this function not defined","Did not test G-protein coupling"]},{"year":2013,"claim":"Demonstrated PS recognition by BAI1 functions beyond clearance, mediating contact-dependent myoblast fusion and muscle regeneration through ELMO/Dock180/Rac1.","evidence":"Overexpression, knockout mice, apoptotic-cell add-back, and in vivo muscle injury","pmids":["23615608"],"confidence":"High","gaps":["How transient PS exposure is spatially restricted during fusion unclear","Relationship to canonical fusion machinery not mapped"]},{"year":2014,"claim":"Defined a division of labor in neuronal engulfment, with BAI1 controlling phagosome formation and cargo transport while TIM-4 stabilizes phagosomes.","evidence":"Live imaging and genetic knockdown of BAI1 and TIM-4 in zebrafish microglia","pmids":["24898390"],"confidence":"High","gaps":["Molecular basis of the BAI1/TIM-4 cooperation not detailed","Whether the two receptors physically interact unknown"]},{"year":2015,"claim":"Uncovered a non-engulfment neuronal role: BAI1 stabilizes PSD-95 by binding MDM2 and blocking its ubiquitination, controlling synaptic plasticity and learning.","evidence":"Knockout mice, BAI1-MDM2 co-IP, ubiquitination assays, viral PSD-95 rescue, and LTP/LTD electrophysiology","pmids":["25751059"],"confidence":"High","gaps":["How BAI1 ligand signaling regulates MDM2 sequestration unknown","Whether this couples to G-protein signaling unaddressed"]},{"year":2015,"claim":"Probed BAI1 activation mechanism, showing constitutive signaling persists in a stalkless receptor, indicating stalk/Stachel-independent activation modes.","evidence":"Engineered stalkless mutants assayed by TGFα shedding, NFAT-luciferase, β-arrestin recruitment, and SRF-luciferase","pmids":["26710850"],"confidence":"Medium","gaps":["Physiological ligand driving constitutive activity not defined","Reconciliation with later Stachel-dependent synaptogenesis unresolved"]},{"year":2016,"claim":"Connected BAI1 Rac1 activation to antimicrobial effector output, showing it drives phagosomal NADPH-oxidase ROS production and bacterial killing in vivo.","evidence":"BAI1-deficient primary macrophages, Rac assays, ROS measurement, killing assays, and peritoneal infection","pmids":["26838550"],"confidence":"High","gaps":["Direct link from BAI1 to NADPH oxidase assembly not structurally defined"]},{"year":2018,"claim":"Dissected BAI1's prosynaptogenic logic into Stachel-dependent Rac1 activation, trans-synaptic vGluT1 clustering, and a Neuroligin-1 receptor complex, all requiring the N-terminal segment.","evidence":"In utero electroporation knockdown, Stachel peptide activation, mixed-culture trans-synaptic assay, BAI1-NRLN1 co-IP, in vivo spine analysis","pmids":["30120207"],"confidence":"High","gaps":["Stoichiometry and structural basis of the BAI1-NRLN1 complex undefined","How three mechanisms are temporally coordinated unclear"]},{"year":2018,"claim":"Established BAI1 as a tumor suppressor in medulloblastoma, stabilizing p53 by antagonizing MDM2 and being epigenetically silenced via MBD2 at its methylated promoter.","evidence":"Adgrb1 knockout crossed to Ptch1+/− tumor model, p53 ubiquitination assay, MBD2 ChIP, and pharmacological rescue","pmids":["29894688"],"confidence":"High","gaps":["How MDM2 substrate selection (PSD-95 vs p53) is contextually determined unknown"]},{"year":2019,"claim":"Provided the atomic-resolution basis of the BAI1–ELMO interaction and showed disease mutations cluster at this interface and disrupt complex formation.","evidence":"X-ray crystallography of the ELMO2 RAE supramodule with BAI1 tail fragment, plus co-IP and interface mutagenesis","pmids":["30604775"],"confidence":"High","gaps":["Structure of full-length receptor-bound complex not solved","Conformational coupling to G-protein activation unaddressed"]},{"year":2019,"claim":"Identified a distinct, RhoA-based BAI1 function: a late developmental association with Bcr stimulates its RhoA-GEF activity to terminate dendritic growth, separable from Rac1 synaptogenesis.","evidence":"Loss-of-function and overexpression in neurons, RhoA activation assays, BAI1-Bcr co-IP, domain mutant rescue","pmids":["31461398"],"confidence":"High","gaps":["Signal that triggers the developmental switch to Bcr binding unknown","How BAI1 toggles between Rac1 and RhoA outputs undefined"]},{"year":2022,"claim":"Showed extracellular PS exposure tunes BAI1 G-protein signaling through the TSP repeats and that BAI1 complexes with the PS flippase ATP11A, linking lipid asymmetry to receptor output.","evidence":"ATP11A co-expression, ANO6 knockout cells, co-IP, G-protein signaling assays, and TSP truncation mutants","pmids":["36370845"],"confidence":"High","gaps":["Which G-protein pathways are engaged in physiological cells not fully resolved","Link between PS-modulated G-protein signaling and ELMO/Rac1 engulfment unclear"]},{"year":2024,"claim":"Extended BAI1's postsynaptic organizing role to sensory transmission, showing it is required to cluster GluR2-4 AMPA receptors at cochlear ribbon synapses for hearing.","evidence":"Bai1 knockout mice, AMPA subunit immunostaining, auditory brainstem response, and confocal/EM synapse imaging","pmids":["38564333"],"confidence":"High","gaps":["Whether BAI1 traffics or anchors AMPA receptors not distinguished","Molecular intermediaries at the ribbon synapse PSD unidentified"]},{"year":2025,"claim":"Broadened BAI1 into a stem-cell quiescence receptor, showing C1q signals through BAI1 to suppress the cell cycle via MDM2/p53 and to drive metabolic reprogramming through endocytic regulation of p32.","evidence":"Loss-of-function, MDM2/p53 assays, endocytosis and metabolic profiling, and hNSC transplant in spinal cord injury","pmids":["41381494"],"confidence":"Medium","gaps":["Mechanism relies on loss-of-function without full reconstitution","Whether C1q binds BAI1 directly not established"]},{"year":2025,"claim":"Implicated BAI1 in glial synaptic pruning, showing it is required for astrocyte phagocytosis of excitatory presynaptic elements and constraint of synapse density.","evidence":"Adgrb1 knockout mice, astrocyte phagocytosis assays, synaptic-marker immunostaining, and KO astrocyte RNA-seq","pmids":["40930306"],"confidence":"Medium","gaps":["Ligand recognized by astrocytic BAI1 during pruning not identified","Whether the ELMO/Rac1 axis mediates this pruning untested"]},{"year":null,"claim":"How BAI1 integrates a single receptor architecture to selectively route signals between ELMO/Rac1 engulfment, Par3/Tiam1 spinogenesis, Bcr/RhoA growth arrest, MDM2 sequestration, and G-protein output remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model couples ligand identity to downstream effector choice","Endogenous G-protein subtype(s) and their physiological roles undefined","How extracellular cleavage and PS sensing feed back onto intracellular signaling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,6,18]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,14,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8,16]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,16,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,13]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,11,15,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,9,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,17,20]}],"complexes":["BAI1/ELMO/Dock180 module","BAI1-Neuroligin-1 receptor complex"],"partners":["ELMO1","DOCK180","PARD3","TIAM1","MDM2","BCR","NLGN1","ATP11A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14514","full_name":"Adhesion G protein-coupled receptor B1","aliases":["Brain-specific angiogenesis inhibitor 1"],"length_aa":1584,"mass_kda":173.5,"function":"Phosphatidylserine receptor which enhances the engulfment of apoptotic cells (PubMed:24509909). Also mediates the binding and engulfment of Gram-negative bacteria (PubMed:26838550). Stimulates production of reactive oxygen species by macrophages in response to Gram-negative bacteria, resulting in enhanced microbicidal macrophage activity (PubMed:26838550). In the gastric mucosa, required for recognition and engulfment of apoptotic gastric epithelial cells (PubMed:24509909). Promotes myoblast fusion (By similarity). Activates the Rho pathway in a G-protein-dependent manner (PubMed:23782696). Inhibits MDM2-mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4 stability and regulating synaptic plasticity (By similarity). Required for the formation of dendritic spines by ensuring the correct localization of PARD3 and TIAM1 (By similarity). Potent inhibitor of angiogenesis in brain and may play a significant role as a mediator of the p53/TP53 signal in suppression of glioblastoma (PubMed:11875720) Inhibits angiogenesis in a CD36-dependent manner Inhibits angiogenesis","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O14514/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADGRB1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADGRB1","total_profiled":1310},"omim":[{"mim_id":"602682","title":"ADHESION G PROTEIN-COUPLED RECEPTOR B1; ADGRB1","url":"https://www.omim.org/entry/602682"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":46.0}],"url":"https://www.proteinatlas.org/search/ADGRB1"},"hgnc":{"alias_symbol":[],"prev_symbol":["BAI1"]},"alphafold":{"accession":"O14514","domains":[{"cath_id":"2.60.120,2.60.120","chopping":"45-106_121-150_169-202","consensus_level":"medium","plddt":62.5005,"start":45,"end":202},{"cath_id":"2.60.220.50","chopping":"737-892_900-943","consensus_level":"high","plddt":77.1628,"start":737,"end":943},{"cath_id":"1.20.1070.10","chopping":"950-1195","consensus_level":"high","plddt":81.1772,"start":950,"end":1195}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14514","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14514-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14514-F1-predicted_aligned_error_v6.png","plddt_mean":62.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADGRB1","jax_strain_url":"https://www.jax.org/strain/search?query=ADGRB1"},"sequence":{"accession":"O14514","fasta_url":"https://rest.uniprot.org/uniprotkb/O14514.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14514/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14514"}},"corpus_meta":[{"pmid":"17960134","id":"PMC_17960134","title":"BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module.","date":"2007","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/17960134","citation_count":676,"is_preprint":false},{"pmid":"9393972","id":"PMC_9393972","title":"A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis.","date":"1997","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9393972","citation_count":258,"is_preprint":false},{"pmid":"23615608","id":"PMC_23615608","title":"Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23615608","citation_count":250,"is_preprint":false},{"pmid":"24898390","id":"PMC_24898390","title":"Distinct roles for BAI1 and TIM-4 in the engulfment of dying neurons by microglia.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24898390","citation_count":171,"is_preprint":false},{"pmid":"21245295","id":"PMC_21245295","title":"Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21245295","citation_count":131,"is_preprint":false},{"pmid":"23595754","id":"PMC_23595754","title":"The adhesion-GPCR BAI1 regulates synaptogenesis by controlling the recruitment of the Par3/Tiam1 polarity complex to synaptic sites.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23595754","citation_count":119,"is_preprint":false},{"pmid":"26710850","id":"PMC_26710850","title":"Stalk-dependent and Stalk-independent Signaling by the Adhesion G Protein-coupled Receptors GPR56 (ADGRG1) and BAI1 (ADGRB1).","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26710850","citation_count":112,"is_preprint":false},{"pmid":"32020421","id":"PMC_32020421","title":"Decylubiquinone suppresses breast cancer growth and metastasis by inhibiting angiogenesis via the ROS/p53/ BAI1 signaling pathway.","date":"2020","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/32020421","citation_count":109,"is_preprint":false},{"pmid":"9533023","id":"PMC_9533023","title":"Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1).","date":"1997","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9533023","citation_count":93,"is_preprint":false},{"pmid":"9647739","id":"PMC_9647739","title":"Cloning and characterization of BAI-associated protein 1: a PDZ domain-containing protein that interacts with BAI1.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9647739","citation_count":81,"is_preprint":false},{"pmid":"25751059","id":"PMC_25751059","title":"BAI1 regulates spatial learning and synaptic plasticity in the hippocampus.","date":"2015","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/25751059","citation_count":81,"is_preprint":false},{"pmid":"29894688","id":"PMC_29894688","title":"BAI1 Suppresses Medulloblastoma Formation by Protecting p53 from Mdm2-Mediated Degradation.","date":"2018","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/29894688","citation_count":74,"is_preprint":false},{"pmid":"22330140","id":"PMC_22330140","title":"A proprotein convertase/MMP-14 proteolytic cascade releases a novel 40 kDa vasculostatin from tumor suppressor BAI1.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22330140","citation_count":74,"is_preprint":false},{"pmid":"10343108","id":"PMC_10343108","title":"Identification of BAIAP2 (BAI-associated protein 2), a novel human homologue of hamster IRSp53, whose SH3 domain interacts with the cytoplasmic domain of BAI1.","date":"1999","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10343108","citation_count":72,"is_preprint":false},{"pmid":"21724586","id":"PMC_21724586","title":"Overexpression of MBD2 in glioblastoma maintains epigenetic silencing and inhibits the antiangiogenic function of the tumor suppressor gene BAI1.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21724586","citation_count":71,"is_preprint":false},{"pmid":"21509575","id":"PMC_21509575","title":"Emerging roles for the BAI1 protein family in the regulation of phagocytosis, synaptogenesis, neurovasculature, and tumor development.","date":"2011","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/21509575","citation_count":64,"is_preprint":false},{"pmid":"26838550","id":"PMC_26838550","title":"The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against Gram-negative bacteria.","date":"2016","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/26838550","citation_count":59,"is_preprint":false},{"pmid":"30120207","id":"PMC_30120207","title":"The Adhesion-GPCR BAI1 Promotes Excitatory Synaptogenesis by Coordinating Bidirectional Trans-synaptic Signaling.","date":"2018","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30120207","citation_count":55,"is_preprint":false},{"pmid":"11245925","id":"PMC_11245925","title":"Characterization of mouse brain-specific angiogenesis inhibitor 1 (BAI1) and phytanoyl-CoA alpha-hydroxylase-associated protein 1, a novel BAI1-binding protein.","date":"2001","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/11245925","citation_count":49,"is_preprint":false},{"pmid":"10639598","id":"PMC_10639598","title":"Vascularization is decreased in pulmonary adenocarcinoma expressing brain-specific angiogenesis inhibitor 1 (BAI1).","date":"2000","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10639598","citation_count":46,"is_preprint":false},{"pmid":"9790924","id":"PMC_9790924","title":"Cloning and characterization of BAP3 (BAI-associated protein 3), a C2 domain-containing protein that interacts with BAI1.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9790924","citation_count":44,"is_preprint":false},{"pmid":"12074842","id":"PMC_12074842","title":"Brain-specific angiogenesis inhibitor 1 (BAI1) is expressed in human cerebral neuronal cells.","date":"2002","source":"Neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/12074842","citation_count":42,"is_preprint":false},{"pmid":"31582835","id":"PMC_31582835","title":"EZH2 targeting reduces medulloblastoma growth through epigenetic reactivation of the BAI1/p53 tumor suppressor pathway.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31582835","citation_count":41,"is_preprint":false},{"pmid":"16244591","id":"PMC_16244591","title":"Antiangiogenic activity of BAI1 in vivo: implications for gene therapy of human glioblastomas.","date":"2006","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/16244591","citation_count":39,"is_preprint":false},{"pmid":"27852701","id":"PMC_27852701","title":"BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection-Implications for Oncolytic Viral Therapy.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/27852701","citation_count":33,"is_preprint":false},{"pmid":"33340495","id":"PMC_33340495","title":"LncRNA embryonic stem cells expressed 1 (Lncenc1) is identified as a novel regulator in neuropathic pain by interacting with EZH2 and downregulating the expression of Bai1 in mouse microglia.","date":"2020","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33340495","citation_count":33,"is_preprint":false},{"pmid":"35114205","id":"PMC_35114205","title":"Mice lacking full length Adgrb1 (Bai1) exhibit social deficits, increased seizure susceptibility, and altered brain development.","date":"2022","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35114205","citation_count":32,"is_preprint":false},{"pmid":"31461398","id":"PMC_31461398","title":"The adhesion-GPCR BAI1 shapes dendritic arbors via Bcr-mediated RhoA activation causing late growth arrest.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31461398","citation_count":31,"is_preprint":false},{"pmid":"30604775","id":"PMC_30604775","title":"Structure of BAI1/ELMO2 complex reveals an action mechanism of adhesion GPCRs via ELMO family scaffolds.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30604775","citation_count":31,"is_preprint":false},{"pmid":"26222696","id":"PMC_26222696","title":"BAI1-Associated Protein 2-Like 1 (BAIAP2L1) Is a Potential Biomarker in Ovarian Cancer.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26222696","citation_count":30,"is_preprint":false},{"pmid":"31692031","id":"PMC_31692031","title":"Molecular chaperone HspB2 inhibited pancreatic cancer cell proliferation via activating p53 downstream gene RPRM, BAI1, and TSAP6.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31692031","citation_count":23,"is_preprint":false},{"pmid":"28259299","id":"PMC_28259299","title":"Regulatory roles of brain-specific angiogenesis inhibitor 1(BAI1) protein in inflammation, tumorigenesis and phagocytosis: A brief review.","date":"2017","source":"Critical reviews in oncology/hematology","url":"https://pubmed.ncbi.nlm.nih.gov/28259299","citation_count":21,"is_preprint":false},{"pmid":"36370845","id":"PMC_36370845","title":"Phosphatidylserine exposure modulates adhesion GPCR BAI1 (ADGRB1) signaling activity.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36370845","citation_count":18,"is_preprint":false},{"pmid":"30483805","id":"PMC_30483805","title":"BAI1‑associated protein 2‑like 2 is a potential biomarker in lung cancer.","date":"2018","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/30483805","citation_count":18,"is_preprint":false},{"pmid":"39120980","id":"PMC_39120980","title":"CircUGP2 Suppresses Intrahepatic Cholangiocarcinoma Progression via p53 Signaling Through Interacting With PURB to Regulate ADGRB1 Transcription and Sponging miR-3191-5p.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39120980","citation_count":15,"is_preprint":false},{"pmid":"35738517","id":"PMC_35738517","title":"Maternal exposure to atmospheric PM2.5 and fetal brain development: Associations with BAI1 methylation and thyroid hormones.","date":"2022","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/35738517","citation_count":15,"is_preprint":false},{"pmid":"38564333","id":"PMC_38564333","title":"BAI1 localizes AMPA receptors at the cochlear afferent post-synaptic density and is essential for hearing.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38564333","citation_count":15,"is_preprint":false},{"pmid":"32255478","id":"PMC_32255478","title":"BAI1 acts as a tumor suppressor in lung cancer A549 cells by inducing metabolic reprogramming via the SCD1/HMGCR module.","date":"2020","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/32255478","citation_count":14,"is_preprint":false},{"pmid":"38941066","id":"PMC_38941066","title":"Novel Isoforms of Adhesion G Protein-Coupled Receptor B1 (ADGRB1/BAI1) Generated from an Alternative Promoter in Intron 17.","date":"2024","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/38941066","citation_count":7,"is_preprint":false},{"pmid":"38763505","id":"PMC_38763505","title":"The regulation of BAI1 in astrocytes through the STAT3/EZH2 axis relieves neuronal apoptosis in rats with Alzheimer's disease.","date":"2024","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/38763505","citation_count":5,"is_preprint":false},{"pmid":"38702885","id":"PMC_38702885","title":"A functional schizophrenia-associated genetic variant near the TSNARE1 and ADGRB1 genes.","date":"2024","source":"HGG advances","url":"https://pubmed.ncbi.nlm.nih.gov/38702885","citation_count":4,"is_preprint":false},{"pmid":"31676871","id":"PMC_31676871","title":"Correction: EZH2 targeting reduces medulloblastoma growth through epigenetic reactivation of the BAI1/p53 tumor suppressor pathway.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31676871","citation_count":4,"is_preprint":false},{"pmid":"40170352","id":"PMC_40170352","title":"The dual-targeted transcription factor BAI1 orchestrates nuclear and plastid gene transcription in land plants.","date":"2025","source":"Molecular plant","url":"https://pubmed.ncbi.nlm.nih.gov/40170352","citation_count":2,"is_preprint":false},{"pmid":"33934543","id":"PMC_33934543","title":"BAI1 nuclear expression reflects the survival of nonsmoking non-small cell lung cancer patients.","date":"2021","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33934543","citation_count":2,"is_preprint":false},{"pmid":"40930306","id":"PMC_40930306","title":"ADGRB1 contributes to astrocyte-mediated phagocytosis of excitatory synapses.","date":"2025","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40930306","citation_count":2,"is_preprint":false},{"pmid":"41381494","id":"PMC_41381494","title":"C1q drives neural stem cell quiescence by regulating cell cycle and metabolism through BAI1.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41381494","citation_count":1,"is_preprint":false},{"pmid":"38187620","id":"PMC_38187620","title":"A Functional Schizophrenia-associated genetic variant near the TSNARE1 and ADGRB1 genes.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38187620","citation_count":1,"is_preprint":false},{"pmid":"40628822","id":"PMC_40628822","title":"Nuclear localization and upregulation of BAI1 in alveolar macrophages during LPS-Induced acute lung injury.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40628822","citation_count":0,"is_preprint":false},{"pmid":"41630910","id":"PMC_41630910","title":"Functional diversity of BAI1 (ADGRB1): From angiostasis to synaptic remodeling and disease therapeutics.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41630910","citation_count":0,"is_preprint":false},{"pmid":"42256885","id":"PMC_42256885","title":"A BAI1-PSTB-Hydrogel promotes diabetic wound healing by targeting mtDNA leakage and the cGAS-STING axis to alleviate endothelial senescence.","date":"2026","source":"Bioactive materials","url":"https://pubmed.ncbi.nlm.nih.gov/42256885","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.02.636169","title":"Regulation of hippocampal excitatory synapse development by the adhesion G-protein coupled receptor Brain-specific angiogenesis inhibitor 2 (BAI2/ADGRB2)","date":"2025-02-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.02.636169","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26579,"output_tokens":5727,"usd":0.082821,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14286,"output_tokens":6449,"usd":0.116328,"stage2_stop_reason":"end_turn"},"total_usd":0.199149,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"BAI1 functions as a phosphatidylserine recognition receptor on apoptotic cells: its thrombospondin type 1 repeats in the extracellular region directly bind phosphatidylserine, and BAI1 forms a trimeric complex with ELMO and Dock180 to activate Rac GTPase and promote apoptotic cell engulfment.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, phosphatidylserine-binding assays, loss-of-function (knockdown/interference), in vivo engulfment assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, direct binding assays, in vivo functional studies), replicated across multiple experimental systems (ex vivo and in vivo)\",\n      \"pmids\": [\"17960134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"BAI1 is a p53-target gene; its extracellular thrombospondin type 1 repeats mediate inhibition of angiogenesis, as demonstrated by a recombinant TSP-repeat protein inhibiting bFGF-induced neovascularization in the rat cornea.\",\n      \"method\": \"Recombinant protein in vivo angiogenesis assay (rat cornea model), gene cloning and characterization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo reconstitution with recombinant domain, single lab, single method for functional assay\",\n      \"pmids\": [\"9393972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"BAI1 interacts with BAP1 (a MAGUK family PDZ domain-containing protein) via a QTEV motif in the C-terminal region of BAI1 and PDZ domains of BAP1; both proteins co-localize at the cytoplasmic membrane and cell-cell junctions, and BAI1 expression induces filopodia-like extensions.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunocytochemistry in COS-7 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus co-localization, single lab, two methods\",\n      \"pmids\": [\"9647739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"BAI1 interacts via its proline-rich cytoplasmic region with the SH3 domain of BAIAP2 (IRSp53 homologue); BAIAP2 localizes to the plasma membrane only when co-expressed with BAI1, and BAI1 protein is predominantly found in growth cone-enriched fractions.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, double-color immunofluorescence, subcellular fractionation\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid confirmed by in vitro binding, co-localization and fractionation, single lab\",\n      \"pmids\": [\"10343108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"BAI1 interacts with BAP3, a C2 domain-containing protein homologous to Munc13, through a region distinct from the C2 domains; interaction was mapped by deletion-mutant analysis in the yeast two-hybrid system.\",\n      \"method\": \"Yeast two-hybrid, deletion-mutant analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid only, single lab, single method\",\n      \"pmids\": [\"9790924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"BAI1 interacts with PAHX-AP1 (BAP4) via its cytoplasmic region, confirmed by GST-pulldown and co-immunoprecipitation from brain lysate; BAI1 is predominantly expressed in neurons of cortex and hippocampus and its expression is decreased in the ischemic hemisphere after focal cerebral ischemia.\",\n      \"method\": \"GST-pulldown, co-immunoprecipitation from brain lysate, in situ hybridization, Western blot\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal pulldown and Co-IP from native brain tissue, two orthogonal methods, single lab\",\n      \"pmids\": [\"11245925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BAI1 acts as a pattern recognition receptor on macrophages that recognizes Gram-negative bacterial lipopolysaccharide via its thrombospondin repeats, and promotes non-opsonic phagocytosis through ELMO/Dock-dependent Rac1 activation; inhibition of the BAI1/ELMO1 interaction prevents Rac activation and bacterial uptake. BAI1 does not recognize Gram-positive bacteria.\",\n      \"method\": \"Recombinant ectodomain competition, BAI1 knockdown and overexpression in macrophages and non-phagocytic cells, Rac activation assay, peritoneal infection model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (recombinant competition, KD, OE, Rac GTPase assays, in vivo infection), consistent results across systems\",\n      \"pmids\": [\"21245295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The N terminus of BAI1 is proteolytically cleaved extracellularly by a two-step cascade: proprotein convertases (primarily furin) activate latent MMP-14, which then directly cleaves BAI1 to release a bioactive 40 kDa fragment (Vasculostatin-40) that inhibits angiogenesis.\",\n      \"method\": \"Biochemical proteolysis assays, protease inhibition, cell-based cleavage assays, in vitro angiogenesis assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic cascade demonstrated with protease inhibitors and reconstitution, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22330140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BAI1 interacts with the Par3/Tiam1 polarity complex and recruits these proteins to dendritic spines to promote spinogenesis and synaptogenesis via local Rac1 activation; a BAI1 mutant that cannot interact with ELMO/DOCK180 still rescues spine defects (ELMO interaction is dispensable for this function), while a mutant lacking Par3/Tiam1 interaction fails to rescue spine or Par3 localization defects.\",\n      \"method\": \"Co-immunoprecipitation, BAI1 knockdown in hippocampal neurons, rescue experiments with BAI1 mutants, immunofluorescence of Rac1 and F-actin\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis via domain-specific mutants, Co-IP, and cellular rescue experiments; multiple orthogonal approaches in single lab\",\n      \"pmids\": [\"23595754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BAI1 acts as a phosphatidylserine receptor on myoblasts that promotes myoblast fusion through the ELMO/Dock180/Rac1 signaling axis; apoptotic myoblasts expose phosphatidylserine and signal in a contact-dependent manner through BAI1 on neighboring healthy myoblasts to promote fusion. In vivo, Bai1−/− mice have smaller myofibers and impaired muscle regeneration after injury.\",\n      \"method\": \"BAI1 overexpression and knockout, apoptosis blockade, addition of exogenous apoptotic myoblasts, in vivo muscle injury model (Bai1−/− mice)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (OE, KO mice, rescue with apoptotic cells, in vivo injury), replicated in primary human myoblasts\",\n      \"pmids\": [\"23615608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish microglia, BAI1 specifically controls phagosome formation around dying neurons and intracellular cargo transport during neuronal engulfment, whereas TIM-4 is required for phagosome stabilization; combined activity of both receptors is needed for complete clearance of dying neurons.\",\n      \"method\": \"Live imaging in zebrafish, genetic knockdown of BAI1 and TIM-4, quantitative phagocytosis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live single-cell resolution imaging with genetic KD, ortholog in zebrafish with consistent molecular context\",\n      \"pmids\": [\"24898390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BAI1 prevents MDM2-mediated polyubiquitination and proteasomal degradation of PSD-95 through a direct interaction with MDM2; loss of BAI1 in mice leads to reduced PSD-95 protein levels, thinning of the postsynaptic density, enhanced LTP, impaired LTD, and hippocampus-dependent spatial learning deficits that are rescued by viral restoration of PSD-95.\",\n      \"method\": \"BAI1 knockout mice, co-immunoprecipitation of BAI1-MDM2 complex, ubiquitination assay, viral gene delivery rescue, electrophysiology (LTP/LTD)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, in vivo KO, ubiquitination assay, and functional rescue by gene therapy; multiple orthogonal methods\",\n      \"pmids\": [\"25751059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BAI1 constitutive signaling activity does not require the membrane-proximal stalk peptide revealed by GAIN domain cleavage; a stalkless BAI1 mutant (B1-SL) retains robust signaling activity across multiple assays, supporting stalk-independent activation of BAI1.\",\n      \"method\": \"Engineered stalkless mutant receptors, battery of signaling assays (TGFα shedding, NFAT-luciferase, β-arrestin recruitment, SRF-luciferase)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling assays with engineered mutants, single lab\",\n      \"pmids\": [\"26710850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BAI1 mediates phagosomal ROS production in macrophages challenged with Gram-negative bacteria by activating Rac1 GTPase, which stimulates NADPH oxidase; BAI1-deficient macrophages show attenuated Rac activity, reduced ROS, and impaired bacterial killing, and BAI1-deficient mice show increased susceptibility to Gram-negative peritoneal infection.\",\n      \"method\": \"Primary BAI1-deficient macrophages, Rac GTPase activation assay, ROS measurement, bacterial killing assays, in vivo peritoneal infection model\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO primary cells plus in vivo model, multiple mechanistic readouts (Rac activity, ROS, microbicidal killing), consistent results\",\n      \"pmids\": [\"26838550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BAI1 prevents MDM2-mediated p53 polyubiquitination and degradation; loss of BAI1 (ADGRB1) in mice increases proliferation of cerebellar granule neuron precursors and accelerates tumor growth in the Ptch1+/− medulloblastoma model; ADGRB1 is epigenetically silenced in medulloblastomas by MBD2 binding to the hypermethylated promoter.\",\n      \"method\": \"Adgrb1 knockout mice crossed with Ptch1+/− tumor model, p53 ubiquitination assay, chromatin immunoprecipitation for MBD2, in vivo tumor growth assays, MBD2 pathway inhibitor treatment\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo tumor model, biochemical ubiquitination assay, ChIP, pharmacological rescue; multiple orthogonal methods in one study\",\n      \"pmids\": [\"29894688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BAI1 promotes excitatory synaptogenesis via three distinct mechanisms: (1) Stachel peptide-dependent activation drives synaptic Rac1 activation and spinogenesis; (2) BAI1 acts trans-synaptically to induce clustering of presynaptic vGluT1 in contacting axons; (3) BAI1 forms a receptor complex with Neuroligin-1 (NRLN1) to mediate NRLN1-dependent spine growth and synapse development. The N-terminal extracellular segment is required for both prospinogenic and prosynaptogenic functions.\",\n      \"method\": \"In utero electroporation knockdown, Stachel peptide activation, mixed-culture trans-synaptic assay, co-immunoprecipitation of BAI1-NRLN1, in vivo hippocampal spine analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vivo KD, peptide activation, Co-IP, trans-synaptic assay) in single study with consistent results\",\n      \"pmids\": [\"30120207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of the ELMO2 RAE supramodule (RBD-ARR-ELMO) in complex with a conserved fragment of the BAI1 C-terminal cytoplasmic tail reveals the molecular basis of BAI/ELMO interaction; disease-causing mutations in BAI and ELMO map to this interface and disrupt complex formation.\",\n      \"method\": \"X-ray crystallography, co-immunoprecipitation, mutagenesis of interface residues\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis and biochemical validation of the complex\",\n      \"pmids\": [\"30604775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BAI1 regulates dendritic arbor growth arrest by coupling to the RhoA pathway: BAI1 associates with Bcr late in development and stimulates its cryptic RhoA-GEF activity (together with Bcr's Rac1-GAP activity) to terminate arborization; BAI1 loss lowers RhoA activation and causes dendritic hypertrophy. This function is independent of BAI1's Rac1-dependent synaptogenic pathway.\",\n      \"method\": \"BAI1 loss-of-function and overexpression in hippocampal neurons, RhoA activation assay, co-immunoprecipitation of BAI1-Bcr, domain mutant rescue experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, GTPase activation assay, multiple mutants, and loss-of-function with specific phenotypic readout; multiple orthogonal methods\",\n      \"pmids\": [\"31461398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Extracellular phosphatidylserine (PS) exposure modulates BAI1 G protein-dependent signaling: reducing PS in the outer leaflet (via co-expression of the PS flippase ATP11A or deletion of the scramblase ANO6) markedly reduces BAI1 signaling activity; ATP11A also forms a protein complex with BAI1 detected by co-immunoprecipitation. A truncated BAI1 lacking the TSP repeats is insensitive to PS reduction, demonstrating the TSP repeats mediate PS-dependent signaling.\",\n      \"method\": \"Co-expression of PS flippase ATP11A, ANO6 knockout cells, co-immunoprecipitation, G protein signaling assays, truncation mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent PS-reduction methods (ATP11A co-expression and ANO6 KO) with consistent results, Co-IP, domain mapping; multiple orthogonal methods single lab\",\n      \"pmids\": [\"36370845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAI1 is required for clustering of AMPA receptor subunits GluR2-4 at the postsynaptic density of spiral ganglion neuron (SGN) afferent synapses in the cochlea; Bai1-deficient mice have normal inner hair cells but fail to transmit auditory information to SGNs, indicating BAI1 is essential for trafficking or anchoring AMPA receptors at cochlear ribbon synapses.\",\n      \"method\": \"Bai1 knockout mice, immunostaining for AMPA receptor subunits, auditory brainstem response and hearing threshold measurement, confocal and electron microscopy of synapses\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with specific molecular (AMPA receptor clustering) and functional (hearing threshold) phenotypic readouts, multiple imaging modalities\",\n      \"pmids\": [\"38564333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C1q acts through BAI1 to drive neural stem cell (NSC) quiescence via two parallel BAI1-dependent mechanisms: (1) BAI1-dependent negative regulation of MDM2 causing cell cycle suppression through p53; (2) endocytic internalization of the C1q-BAI1 complex driving regulation of p32 (C1qBP) and metabolic reprogramming toward aerobic glycolysis. These functions were validated in human NSCs and in a mouse spinal cord injury model.\",\n      \"method\": \"BAI1 loss-of-function, MDM2/p53 pathway assay, endocytosis assay, metabolic profiling, in vivo spinal cord injury model with hNSC transplant\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic readouts and in vivo validation, but mechanistic details rely heavily on loss-of-function without full reconstitution; single lab\",\n      \"pmids\": [\"41381494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ADGRB1/BAI1 is required for astrocyte-mediated phagocytosis of excitatory presynaptic elements; Adgrb1-knockout astrocytes show reduced phagocytic capacity, less engulfment of presynaptic material, and a higher density of excitatory synapses in vivo, indicating BAI1 mediates synaptic pruning by astrocytes.\",\n      \"method\": \"Adgrb1 knockout mice, cultured astrocyte phagocytosis assay, immunostaining of pre- and post-synaptic markers, RNA-seq of KO astrocytes\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with specific molecular and cellular phenotypic readouts, in vitro and in vivo consistency, single lab\",\n      \"pmids\": [\"40930306\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BAI1 (ADGRB1) is a multi-functional adhesion GPCR whose extracellular thrombospondin type 1 repeats directly bind phosphatidylserine on apoptotic cells and bacterial LPS, coupling these ligands to intracellular ELMO/Dock180/Rac1-dependent actin remodeling for phagocytosis and myoblast fusion; in neurons it recruits the Par3/Tiam1 complex to dendritic spines for Rac1-dependent synaptogenesis, signals through Bcr-mediated RhoA activation to terminate dendrite growth, interacts with Neuroligin-1 for bidirectional trans-synaptic organization, stabilizes PSD-95 by protecting it from MDM2-mediated ubiquitination, and localizes AMPA receptors at cochlear ribbon synapse PSDs; its N terminus is proteolytically released by a furin/MMP-14 cascade to generate an anti-angiogenic Vasculostatin-40 fragment, and extracellular PS exposure itself modulates BAI1 G-protein signaling through the TSP repeat domain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADGRB1 (BAI1) is an adhesion GPCR that functions as an engulfment and synaptic-organizing receptor, coupling extracellular ligand recognition to Rho-family GTPase signaling [#0, #8]. Its extracellular thrombospondin type 1 repeats directly bind phosphatidylserine displayed on apoptotic cells and lipopolysaccharide on Gram-negative bacteria, and these ligands are transduced through a cytoplasmic ELMO/Dock180 module that activates Rac1 to drive non-opsonic phagocytosis, apoptotic cell clearance, and phagosomal NADPH-oxidase-dependent ROS production for bacterial killing [#0, #6, #13]; the same PS-recognition/Rac1 axis promotes contact-dependent myoblast fusion and muscle regeneration in vivo [#9], and the structural basis of BAI1 engagement of the ELMO RAE supramodule has been resolved by crystallography [#16]. PS exposure on the outer membrane leaflet additionally modulates BAI1 G-protein signaling through the TSP repeats, and BAI1 forms a complex with the PS flippase ATP11A [#18]. In neurons BAI1 organizes excitatory synapses through multiple parallel routes: Stachel/Par3-Tiam1-dependent local Rac1 activation drives spinogenesis and synaptogenesis, BAI1 acts trans-synaptically and forms a receptor complex with Neuroligin-1 to coordinate pre- and post-synaptic assembly, and it is required for AMPA receptor clustering at cochlear ribbon synapses [#8, #15, #19]. BAI1 also stabilizes PSD-95 by sequestering MDM2 to block its ubiquitination, supporting postsynaptic density integrity, synaptic plasticity, and spatial learning [#11], while a developmentally late association with Bcr couples BAI1 to RhoA activation to terminate dendritic arbor growth, independently of its Rac1 synaptogenic function [#17]. Through MDM2 antagonism BAI1 stabilizes p53 to restrain cerebellar precursor proliferation, and ADGRB1 is epigenetically silenced in medulloblastoma [#14]. The N terminus is proteolytically released by a furin-activated MMP-14 cascade to generate the anti-angiogenic Vasculostatin-40 fragment, consistent with BAI1's identification as a p53-target anti-angiogenic gene [#1, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established BAI1's founding identity as a p53-inducible gene whose extracellular TSP repeats carry anti-angiogenic activity, framing it as a tumor-suppressor-associated receptor.\",\n      \"evidence\": \"Gene cloning plus recombinant TSP-repeat protein in a rat corneal neovascularization assay\",\n      \"pmids\": [\"9393972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the receptor's ligand or signaling output\", \"Single functional assay for the anti-angiogenic effect\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"First mapped cytoplasmic binding partners (BAP1/MAGUK, BAP3/Munc13-homolog), indicating BAI1 couples to scaffolding and membrane-associated machinery.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and co-localization in COS-7 cells; deletion-mutant mapping\",\n      \"pmids\": [\"9647739\", \"9790924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BAP3 interaction rests on yeast two-hybrid alone\", \"Functional consequence of the scaffolding interactions undefined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Linked BAI1 to actin-based membrane remodeling via its proline-rich tail binding the SH3 domain of BAIAP2/IRSp53 and enriched localization in growth cones.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, immunofluorescence, and subcellular fractionation\",\n      \"pmids\": [\"10343108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No demonstration of in vivo cytoskeletal phenotype\", \"Did not connect to a defined signaling pathway\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed BAI1 is a neuronal protein (cortex, hippocampus) with an additional cytoplasmic partner (PAHX-AP1/BAP4) and is downregulated after cerebral ischemia, placing it in a brain-injury context.\",\n      \"evidence\": \"GST-pulldown and co-IP from brain lysate, in situ hybridization, Western blot\",\n      \"pmids\": [\"11245925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the PAHX-AP1 interaction unresolved\", \"Ischemia association is correlative\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined BAI1's core signaling mechanism: the TSP repeats directly recognize phosphatidylserine and the receptor assembles a trimeric ELMO/Dock180 complex to activate Rac and engulf apoptotic cells.\",\n      \"evidence\": \"Co-IP, PS-binding and pulldown assays, knockdown, and in vivo engulfment assays\",\n      \"pmids\": [\"17960134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address G-protein involvement\", \"Generality beyond apoptotic-cell clearance unknown at the time\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended BAI1 ligand recognition to innate immunity by showing TSP-repeat binding of Gram-negative LPS drives non-opsonic phagocytosis through the same ELMO/Dock/Rac1 axis.\",\n      \"evidence\": \"Recombinant ectodomain competition, knockdown/overexpression in macrophages, Rac assays, peritoneal infection model\",\n      \"pmids\": [\"21245295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain why Gram-positive bacteria are not recognized\", \"Downstream microbicidal consequences not yet defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how the anti-angiogenic Vasculostatin-40 fragment is generated, defining a furin-then-MMP-14 proteolytic cascade that releases the BAI1 N terminus.\",\n      \"evidence\": \"Biochemical proteolysis, protease inhibition, cell-based cleavage, and in vitro angiogenesis assays\",\n      \"pmids\": [\"22330140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of the cleavage in vivo not established\", \"Receptor/target through which Vstat40 acts not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed BAI1 organizes excitatory synapses by recruiting the Par3/Tiam1 polarity complex for local Rac1 activation, and that this is genetically separable from the ELMO/Dock engulfment pathway.\",\n      \"evidence\": \"Co-IP, neuronal knockdown, and domain-specific mutant rescue with Rac1/F-actin imaging\",\n      \"pmids\": [\"23595754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream synaptic ligand for this function not defined\", \"Did not test G-protein coupling\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated PS recognition by BAI1 functions beyond clearance, mediating contact-dependent myoblast fusion and muscle regeneration through ELMO/Dock180/Rac1.\",\n      \"evidence\": \"Overexpression, knockout mice, apoptotic-cell add-back, and in vivo muscle injury\",\n      \"pmids\": [\"23615608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How transient PS exposure is spatially restricted during fusion unclear\", \"Relationship to canonical fusion machinery not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a division of labor in neuronal engulfment, with BAI1 controlling phagosome formation and cargo transport while TIM-4 stabilizes phagosomes.\",\n      \"evidence\": \"Live imaging and genetic knockdown of BAI1 and TIM-4 in zebrafish microglia\",\n      \"pmids\": [\"24898390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the BAI1/TIM-4 cooperation not detailed\", \"Whether the two receptors physically interact unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Uncovered a non-engulfment neuronal role: BAI1 stabilizes PSD-95 by binding MDM2 and blocking its ubiquitination, controlling synaptic plasticity and learning.\",\n      \"evidence\": \"Knockout mice, BAI1-MDM2 co-IP, ubiquitination assays, viral PSD-95 rescue, and LTP/LTD electrophysiology\",\n      \"pmids\": [\"25751059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BAI1 ligand signaling regulates MDM2 sequestration unknown\", \"Whether this couples to G-protein signaling unaddressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Probed BAI1 activation mechanism, showing constitutive signaling persists in a stalkless receptor, indicating stalk/Stachel-independent activation modes.\",\n      \"evidence\": \"Engineered stalkless mutants assayed by TGFα shedding, NFAT-luciferase, β-arrestin recruitment, and SRF-luciferase\",\n      \"pmids\": [\"26710850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological ligand driving constitutive activity not defined\", \"Reconciliation with later Stachel-dependent synaptogenesis unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected BAI1 Rac1 activation to antimicrobial effector output, showing it drives phagosomal NADPH-oxidase ROS production and bacterial killing in vivo.\",\n      \"evidence\": \"BAI1-deficient primary macrophages, Rac assays, ROS measurement, killing assays, and peritoneal infection\",\n      \"pmids\": [\"26838550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link from BAI1 to NADPH oxidase assembly not structurally defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Dissected BAI1's prosynaptogenic logic into Stachel-dependent Rac1 activation, trans-synaptic vGluT1 clustering, and a Neuroligin-1 receptor complex, all requiring the N-terminal segment.\",\n      \"evidence\": \"In utero electroporation knockdown, Stachel peptide activation, mixed-culture trans-synaptic assay, BAI1-NRLN1 co-IP, in vivo spine analysis\",\n      \"pmids\": [\"30120207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the BAI1-NRLN1 complex undefined\", \"How three mechanisms are temporally coordinated unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established BAI1 as a tumor suppressor in medulloblastoma, stabilizing p53 by antagonizing MDM2 and being epigenetically silenced via MBD2 at its methylated promoter.\",\n      \"evidence\": \"Adgrb1 knockout crossed to Ptch1+/− tumor model, p53 ubiquitination assay, MBD2 ChIP, and pharmacological rescue\",\n      \"pmids\": [\"29894688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MDM2 substrate selection (PSD-95 vs p53) is contextually determined unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the atomic-resolution basis of the BAI1–ELMO interaction and showed disease mutations cluster at this interface and disrupt complex formation.\",\n      \"evidence\": \"X-ray crystallography of the ELMO2 RAE supramodule with BAI1 tail fragment, plus co-IP and interface mutagenesis\",\n      \"pmids\": [\"30604775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length receptor-bound complex not solved\", \"Conformational coupling to G-protein activation unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a distinct, RhoA-based BAI1 function: a late developmental association with Bcr stimulates its RhoA-GEF activity to terminate dendritic growth, separable from Rac1 synaptogenesis.\",\n      \"evidence\": \"Loss-of-function and overexpression in neurons, RhoA activation assays, BAI1-Bcr co-IP, domain mutant rescue\",\n      \"pmids\": [\"31461398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal that triggers the developmental switch to Bcr binding unknown\", \"How BAI1 toggles between Rac1 and RhoA outputs undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed extracellular PS exposure tunes BAI1 G-protein signaling through the TSP repeats and that BAI1 complexes with the PS flippase ATP11A, linking lipid asymmetry to receptor output.\",\n      \"evidence\": \"ATP11A co-expression, ANO6 knockout cells, co-IP, G-protein signaling assays, and TSP truncation mutants\",\n      \"pmids\": [\"36370845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which G-protein pathways are engaged in physiological cells not fully resolved\", \"Link between PS-modulated G-protein signaling and ELMO/Rac1 engulfment unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended BAI1's postsynaptic organizing role to sensory transmission, showing it is required to cluster GluR2-4 AMPA receptors at cochlear ribbon synapses for hearing.\",\n      \"evidence\": \"Bai1 knockout mice, AMPA subunit immunostaining, auditory brainstem response, and confocal/EM synapse imaging\",\n      \"pmids\": [\"38564333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BAI1 traffics or anchors AMPA receptors not distinguished\", \"Molecular intermediaries at the ribbon synapse PSD unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened BAI1 into a stem-cell quiescence receptor, showing C1q signals through BAI1 to suppress the cell cycle via MDM2/p53 and to drive metabolic reprogramming through endocytic regulation of p32.\",\n      \"evidence\": \"Loss-of-function, MDM2/p53 assays, endocytosis and metabolic profiling, and hNSC transplant in spinal cord injury\",\n      \"pmids\": [\"41381494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism relies on loss-of-function without full reconstitution\", \"Whether C1q binds BAI1 directly not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated BAI1 in glial synaptic pruning, showing it is required for astrocyte phagocytosis of excitatory presynaptic elements and constraint of synapse density.\",\n      \"evidence\": \"Adgrb1 knockout mice, astrocyte phagocytosis assays, synaptic-marker immunostaining, and KO astrocyte RNA-seq\",\n      \"pmids\": [\"40930306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand recognized by astrocytic BAI1 during pruning not identified\", \"Whether the ELMO/Rac1 axis mediates this pruning untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BAI1 integrates a single receptor architecture to selectively route signals between ELMO/Rac1 engulfment, Par3/Tiam1 spinogenesis, Bcr/RhoA growth arrest, MDM2 sequestration, and G-protein output remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model couples ligand identity to downstream effector choice\", \"Endogenous G-protein subtype(s) and their physiological roles undefined\", \"How extracellular cleavage and PS sensing feed back onto intracellular signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 14, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8, 16]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 16, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 13]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 11, 15, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 9, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 17, 20]}\n    ],\n    \"complexes\": [\"BAI1/ELMO/Dock180 module\", \"BAI1-Neuroligin-1 receptor complex\"],\n    \"partners\": [\"ELMO1\", \"DOCK180\", \"PARD3\", \"TIAM1\", \"MDM2\", \"BCR\", \"NLGN1\", \"ATP11A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}