{"gene":"ADGRG1","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2006,"finding":"GPR56 binds specifically to tissue transglutaminase TG2, a widespread component of tissue and tumor stroma, and this interaction suppresses tumor growth and metastasis in melanoma xenograft models.","method":"Binding assay (GPR56-TG2 interaction), xenograft tumor models with GPR56 overexpression/knockdown","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assay, functional in vivo xenograft validation, replicated across multiple subsequent studies","pmids":["16757564"],"is_preprint":false},{"year":2004,"finding":"GPR56 forms a specific complex with tetraspanins CD9 and CD81 and heterotrimeric G protein subunits Gαq, Gα11, and Gβ on the cell surface; CD81 plays a central role in promoting or stabilizing the GPR56-CD81-Gαq/11 complex, as demonstrated by CD81 immunodepletion and reexpression experiments.","method":"Co-immunoprecipitation, immunodepletion/reexpression of CD81, cholesterol depletion resistance assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with immunodepletion/reexpression controls, multiple orthogonal methods in single study","pmids":["15004227"],"is_preprint":false},{"year":2008,"finding":"GPR56 couples with Gα12/13 and activates Rho-dependent transcription (SRE, NF-κB) and actin fiber reorganization to inhibit neural progenitor cell migration; inhibition of NPC migration by agonistic anti-GPR56 antibody was attenuated by p115 RhoGEF RGS domain and C3 exoenzyme (Rho inhibitor).","method":"Reporter assays (SRE-luciferase, NF-κB-luciferase), actin staining, dominant-negative Rho, C3 exoenzyme treatment, agonistic antibody, GPR56 knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including dominant-negative, chemical inhibitor, and KD, all consistent with Gα12/13-Rho pathway","pmids":["18378689"],"is_preprint":false},{"year":2008,"finding":"Loss of GPR56 in mice causes breaches in the pial basement membrane and neuronal ectopias during cerebral cortical development; GPR56 is present in radial glial endfeet, and a putative ligand is localized in the marginal zone/overlying ECM.","method":"Gpr56 knockout mouse analysis, immunohistochemistry, time-course analysis of pial BM integrity","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotype, detailed time-course and localization experiments","pmids":["18509043"],"is_preprint":false},{"year":2007,"finding":"Wild-type GPR56 undergoes GPS domain-mediated protein cleavage and N-glycosylation; disease-associated missense mutations (R38Q, R38W, Y88C, C91S) cause reduced intracellular trafficking and poor cell surface expression, while GPS domain mutations (C346S, W349S) abolish cleavage and trap protein in the ER; pharmacological chaperones can partially rescue mutant surface expression.","method":"Biochemical characterization (Western blot, N-glycosylation analysis), cell trafficking assays, pharmacological chaperone rescue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mutants analyzed with consistent results, pharmacological rescue, multiple orthogonal methods","pmids":["17576745"],"is_preprint":false},{"year":2011,"finding":"The large N-terminus (NT) of GPR56 is cleaved from the rest of the receptor but remains non-covalently associated with the seven-transmembrane region; truncation of the NT results in constitutive activation (increased β-arrestin binding, ubiquitination, cytotoxicity); the NT is capable of homophilic trans-trans interactions that enhance receptor signaling activity.","method":"Co-immunoprecipitation of NT and CTF fragments from transfected cells and native tissue, β-arrestin binding assays, ubiquitination assays, cytotoxicity rescue by β-arrestin 2 cotransfection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal assays (Co-IP, β-arrestin binding, ubiquitination, cell viability) in single study with functional validation","pmids":["21708946"],"is_preprint":false},{"year":2012,"finding":"Collagen III is the ligand of GPR56 in the developing brain; GPR56 regulates NPC adhesion to extracellular matrix molecules of the pial basement membrane, and loss of GPR56 causes loss of granule cell adhesion to ECM; this was rescued by re-expression of GPR56.","method":"Gpr56 knockout mouse cerebellar analysis, siRNA knockdown, GPR56 re-expression rescue of adhesion defect, ligand-probe binding assay","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience / PloS one (review citing original data)","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO phenotype, siRNA knockdown, and rescue experiment all consistent; collagen III identified as ligand by binding assay","pmids":["19515912","23001883"],"is_preprint":false},{"year":2012,"finding":"A ligand-binding domain within GPR56 N-terminal fragment (GPR56N) is required for collagen III binding; four disease-associated BFPP mutations within this domain completely abolish collagen III binding, though N-glycosylation is not required for binding.","method":"Truncation and mutation analysis with collagen III binding assay, N-glycosylation blocking","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding assay with multiple mutants tested, single lab but rigorous mutagenesis","pmids":["22238662"],"is_preprint":false},{"year":2014,"finding":"Collagen III binding to GPR56 releases GPR56N from membrane-bound GPR56C, triggers association of GPR56C with lipid rafts, and activates RhoA; BFPP-associated mutation L640R specifically abolishes collagen III-mediated RhoA activation without affecting lipid raft association.","method":"Ligand stimulation assay, lipid raft fractionation, RhoA activation assay, L640R mutant analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct ligand stimulation with lipid raft fractionation and RhoA pull-down, disease mutant mechanistically informative","pmids":["24949629"],"is_preprint":false},{"year":2015,"finding":"GPR56 regulates oligodendrocyte development through Gα12/13 proteins and RhoA activation; loss of Gpr56 in zebrafish and mice leads to decreased OPC proliferation and reduced myelinated axons.","method":"Zebrafish gpr56 mutants, Gpr56 knockout mice, OPC proliferation assay, active RhoA measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent species (zebrafish and mouse), multiple cellular phenotypes, G protein pathway identified","pmids":["25607772","25607655"],"is_preprint":false},{"year":2015,"finding":"Gpr56 conditional knockout in OPCs (but not microglia, astrocytes, or neurons) leads to decreased OPC proliferation and reduced myelinated axons, establishing a cell-autonomous role for GPR56 in oligodendrocyte development.","method":"Cell-type-specific conditional knockout mice (OPC, microglia, astrocyte, neuron-specific Cre lines), myelin analysis","journal":"Nature communications / Glia","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in multiple cell types, establishing cell autonomy; replicated across two studies","pmids":["25607655","32902916"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the GPR56 extracellular region (ECR) was determined, revealing a GAIN domain and a previously unidentified PLL (Pentraxin/Laminin/neurexin/sex-hormone-binding-globulin-Like) domain; PLL domain deletion causes increased receptor signaling; an evolutionarily conserved PLL domain residue is critical for oligodendrocyte development in vivo.","method":"Crystal structure determination (X-ray crystallography), monobody complex, PLL domain deletion mutant signaling assay, in vivo OL development with PLL mutant","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis and in vivo validation","pmids":["27657451"],"is_preprint":false},{"year":2015,"finding":"Stachel-independent signaling can occur for GPR56: stalkless GPR56 mutants lacking the membrane-proximal stalk show robust activity in TGFα shedding, NFAT luciferase, and β-arrestin recruitment assays, but reduced activity in SRF luciferase (Gα12/13 pathway), indicating pathway-dependent stalk dependence.","method":"Stalkless receptor engineering, TGFα shedding assay, NFAT luciferase, SRF luciferase, β-arrestin recruitment assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling assays, single lab, engineered mutants with mixed results across pathways","pmids":["26710850"],"is_preprint":false},{"year":2017,"finding":"Synthetic monobodies directed to both the PLL and GAIN domains of the GPR56 ECR can activate or inhibit GPR56-mediated signaling even in a GPR56 mutant defective in autoproteolysis, demonstrating an ECR-mediated, Stachel-independent regulatory mechanism.","method":"Monobody generation, signaling assays with autoproteolysis-defective GPR56 mutant, luciferase reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered synthetic ligands with autoproteolysis-dead mutant controls, single lab","pmids":["28874577"],"is_preprint":false},{"year":2018,"finding":"Microglia-derived transglutaminase-2 (TG2) signals to ADGRG1 on OPCs in the presence of the ECM protein laminin, and TG2/laminin-dependent activation of ADGRG1 promotes OPC proliferation and improves remyelination in two murine demyelination models.","method":"Cell co-culture (microglia-OPC), TG2/laminin stimulation assays, Gpr56 KO OPC proliferation, demyelination/remyelination mouse models","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — ligand identity (TG2/laminin) established with KO controls, in vivo remyelination in two independent disease models","pmids":["29809138"],"is_preprint":false},{"year":2019,"finding":"Both natural ligands (collagen III and TG2/laminin) activate GPR56 by dissociating the N-terminal fragment from the C-terminal fragment, enabling Stachel-mediated signaling, and require GAIN domain-mediated cleavage; TG2 additionally requires laminin cofactor; the small-molecule agonist 3-α-DOG and synthetic Stachel peptide P19 can signal without disengaging the N-terminal fragment.","method":"Non-cleavable receptor engineering, ligand stimulation assays with collagen III, TG2, laminin, 3-α-DOG, and P19 peptide; NTF/CTF dissociation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution-like mechanistic dissection with engineered non-cleavable receptor, multiple natural and synthetic agonists tested, single rigorous study with multiple orthogonal approaches","pmids":["31628191"],"is_preprint":false},{"year":2020,"finding":"A specific alternatively spliced isoform of GPR56, expressed in microglia, is selectively required for microglial synapse pruning; phosphatidylserine (PS) on presynaptic elements binds GPR56 in a domain-specific manner; microglia-specific deletion of Gpr56 leads to increased synapses due to reduced microglial engulfment of PS+ presynaptic inputs.","method":"Microglia-specific conditional Gpr56 KO, PS-GPR56 binding assay (domain-specific), synaptic density quantification, microglial engulfment assay, isoform-specific analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, direct ligand binding assay, isoform specificity established, multiple brain regions and time points","pmids":["32452062"],"is_preprint":false},{"year":2020,"finding":"GPR56 is the platelet receptor that transduces signals from collagen and blood flow-induced shear force to activate G protein 13 signaling for platelet shape change; Gpr56-/- mice have prolonged bleeding, defective platelet plug formation, and delayed thrombotic occlusion.","method":"Gpr56-/- mouse bleeding assays, platelet plug formation assay, thrombotic occlusion model, blood perfusion assay with immobilized collagen, free NTF detection in human plasma","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with multiple in vivo phenotypes, human plasma validation, shear-force specificity demonstrated","pmids":["33097663"],"is_preprint":false},{"year":2013,"finding":"GPR56 internalizes and degrades its ligand TG2 upon binding, resulting in decreased fibronectin deposition and impaired focal adhesion kinase accumulation; xenograft studies in Tg2-/- mice confirmed antagonistic relationship between GPR56 and TG2 in melanoma.","method":"Xenograft studies in immunodeficient Tg2-/- mice, TG2 internalization assay, fibronectin deposition assay, FAK immunostaining","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model, biochemical mechanism of internalization/degradation demonstrated, single lab","pmids":["24356421"],"is_preprint":false},{"year":2011,"finding":"GPR56 inhibits VEGF production from melanoma cells and impedes angiogenesis through a signaling pathway involving protein kinase Cα (PKCα); the two GPR56 fragments generated by autocatalytic cleavage play distinct roles in regulating VEGF production.","method":"VEGF ELISA, angiogenesis assays, PKCα pathway analysis, fragment-specific overexpression","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with fragment-specific constructs and pathway inhibition, single lab","pmids":["21724588"],"is_preprint":false},{"year":2014,"finding":"GPR56 expression regulates cortical progenitor cell proliferation; its expression level is controlled by multiple alternative promoters and splice forms that are highly variable between mice and humans; the regulatory element of gyrencephalic mammals directs restricted lateral cortical expression.","method":"GPR56 splice form analysis, deletion mutant of regulatory element (15-bp deletion), progenitor proliferation assay, RFX transcription factor binding assay","journal":"Science (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic mutation identified, functional regulatory element validated, proliferation assay, single study","pmids":["24531968"],"is_preprint":false},{"year":2011,"finding":"Loss-of-function mutations in GPR56 extracellular loops (R565W, L640R) cause BFPP via multiple mechanisms including reduced surface receptor expression and loss of signaling to specific pathways; these mutations abolish Gα12/13-mediated SRF signaling but not NFAT signaling, indicating differential pathway effects; NFAT activation by GPR56 involves Gβγ liberation and calcium channel activation.","method":"Luciferase reporter assays (SRF, NFAT), surface expression analysis, dominant-negative G protein subunits, calcium channel blockers","journal":"The Journal of biological chemistry / The Journal of biological chemistry (2017)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling assays with disease mutants, single lab, two separate studies with consistent findings","pmids":["21349848","28424266"],"is_preprint":false},{"year":2013,"finding":"GPR56 functions together with α3β1 integrin in regulating pial basement membrane assembly; loss of α3 integrin enhances the cortical phenotype of Gpr56 deletion, with earlier neuronal overmigration in double knockouts, demonstrating genetic synergism.","method":"Gpr56/α3 integrin double knockout mice, cortical phenotype analysis, time-course of neuronal overmigration","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by double KO, single lab","pmids":["23874761"],"is_preprint":false},{"year":2018,"finding":"GPR56 is a conserved regulator of peripheral nervous system myelin; GPR56-dependent RhoA signaling promotes radial sorting of axons during Schwann cell development; GPR56 localizes to distinct SC cytoplasmic domains in mature PNS; plectin is identified as a novel interacting partner of GPR56 in Schwann cells.","method":"Zebrafish and rodent gpr56 mutants/KO, RhoA activation assay, GPR56 localization by immunofluorescence, Co-IP of plectin-GPR56","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — two species studied, new binding partner identified by Co-IP, subcellular localization with functional consequence, RhoA pathway confirmed","pmids":["29367382"],"is_preprint":false},{"year":2016,"finding":"GPR56 is expressed on mature NK cells and negatively regulates NK cell effector functions (cytokine production, degranulation, target cell killing) by associating with tetraspanin CD81; NK cells from polymicrogyria patients with ADGRG1 mutations show enhanced cytotoxicity.","method":"NK cells from ADGRG1 mutant patients, NK-92 ectopic expression, Co-IP of GPR56-CD81, cytotoxicity assays, degranulation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — human patient NK cells, ectopic expression, Co-IP for CD81 association, multiple functional assays","pmids":["27184850"],"is_preprint":false},{"year":2016,"finding":"GPR56 inhibits NF-κB signaling pathway in glioblastoma cells, thereby preventing mesenchymal differentiation and radioresistance; GPR56 loss of function promotes mesenchymal differentiation and radioresistance both in vitro and in vivo.","method":"GPR56 knockdown/overexpression in GBM cells and glioma-initiating cells, NF-κB reporter assay, in vivo tumor models, radioresistance assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined pathway (NF-κB), in vitro and in vivo, single lab","pmids":["29166609"],"is_preprint":false},{"year":2020,"finding":"TG2 C-terminal portion directly interacts with the GPR56 ECR with high-nanomolar affinity; the TG2 binding site was mapped to a conserved patch on the PLL domain of GPR56 by site-directed mutagenesis; monobodies binding the GPR56 ECR can block the GPR56-TG2 interaction.","method":"Site-directed mutagenesis, binding affinity measurement (surface plasmon resonance or similar), monobody blocking assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with mutagenesis and synthetic inhibitors, single lab","pmids":["33037308"],"is_preprint":false},{"year":2015,"finding":"PCBP2 inhibits GPR56 mRNA stability, thereby reducing GPR56 protein levels in cardiomyocytes; GPR56 knockdown reduces angiotensin II-induced cardiomyocyte hypertrophy, establishing GPR56 as a pro-hypertrophic mediator downstream of PCBP2.","method":"PCBP2 KD/overexpression, GPR56 mRNA stability assay, GPR56 KD in cardiomyocytes, cell size and protein synthesis measurement","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic depth beyond mRNA stability and KD phenotype","pmids":["26116532"],"is_preprint":false},{"year":2016,"finding":"Heparin interacts with GPR56 at two basic-residue-rich clusters (R26GHREDFRFC35 and L190KHPQKASRRP200) in the N-terminus; heparin binding reduces GPR56 receptor shedding and enhances cell adhesion and motility; collagen III modulates GPR56-heparin interaction but TG2 does not.","method":"Truncation/mutant GPR56 binding assays, receptor shedding assay, cell adhesion/motility assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding site mapped by mutagenesis, functional shedding and adhesion assays, single lab","pmids":["27068534"],"is_preprint":false},{"year":2018,"finding":"Small-molecule gedunin derivatives (e.g., 3-α-DOG) act as partial agonists for GPR56/ADGRG1 by acting at the 7TM domain with EC50 ~5 μM; 3-α-DOG can antagonize both peptide agonist and endogenous tethered agonist, consistent with partial agonism.","method":"High-throughput compound screen, SRE-luciferase reporter, engineered low-activity GPR56 7TM, dose-response assays, peptide antagonism assay","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays, engineered receptor controls, pharmacological characterization, single lab","pmids":["29476042"],"is_preprint":false},{"year":2013,"finding":"GPR56 is required for hematopoietic cluster formation during endothelial-to-hematopoietic cell transition (EHT); Gpr56 is a transcriptional target of the heptad complex of hematopoietic transcription factors and is one of the most highly upregulated genes in hemogenic endothelial cells.","method":"RNA-seq of aortic HSCs/HECs/ECs, Gpr56 morpholino/KD in zebrafish, heptad complex ChIP/transcription factor binding assay","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomic identification with functional validation by morpholino KD, heptad complex binding established, single lab","pmids":["25547674"],"is_preprint":false},{"year":2019,"finding":"GPR56 enhances drug resistance in colorectal cancer cells through upregulation of MDR1 levels via a RhoA-mediated signaling mechanism; loss of GPR56 suppresses tumor growth and increases sensitivity to chemotherapy.","method":"GPR56 KD/KO in colon cancer cells, MDR1 expression assay, RhoA activation assay, drug resistance assay (irinotecan, 5-FU), tumor xenograft","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined RhoA-MDR1 mechanism, in vitro and in vivo, single lab","pmids":["31444231"],"is_preprint":false},{"year":2022,"finding":"Microglial GPR56 plays a critical role in parvalbumin-positive (PV+) interneuron development; MIA down-regulates microglial Gpr56 in an IL-17a-dependent manner; microglial Gpr56 deletion mimics MIA-induced PV+ interneuron deficits via elevated TNF-α; restoring Gpr56 in microglia ameliorates PV+ interneuron deficits and autism-like behaviors.","method":"Microglial conditional Gpr56 KO, MIA mouse model, IL-17a neutralization, TNF-α measurement, PV+ interneuron counting, behavioral assays, Gpr56 genetic rescue","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, cytokine pathway identification, genetic rescue, multiple behavioral and cellular phenotypes","pmids":["35544642"],"is_preprint":false},{"year":2024,"finding":"GPR56 renders cells resistant to ferroptosis by promoting endocytosis-lysosomal degradation of CD36, thereby decreasing abundance of phospholipids containing free PUFAs; 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and attenuates liver injury; disease-associated GPR56 mutants were unresponsive to 17-OH PREG.","method":"Gpr56 KO mice (doxorubicin/ischemia-reperfusion liver injury models), CD36 endocytosis/degradation assays, phospholipidomics, steroid hormone screen, mutant receptor signaling assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO models, direct biochemical mechanism (CD36 degradation), agonist identification with mutant validation, multiple orthogonal methods","pmids":["39389061"],"is_preprint":false},{"year":2021,"finding":"GPR56 overexpression in 293T cells leads to increased phosphorylation of Src, Fak, and paxillin; GPR56-mediated Src-Fak activation is independent of RhoA; a monoclonal antibody targeting the GAIN domain potentiates Src-Fak-RhoA-SRF signaling and cell adhesion; the C-terminal portion of the STP-rich region of GPR56 is required for Src-Fak activation.","method":"GPR56 overexpression, monoclonal antibody treatment, Src/Fak/paxillin phosphorylation (Western blot), RhoA inhibition, SRF luciferase, deletion mutant analysis, GPR56 KD in CRC cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling assays with deletion mutants and KD, single lab","pmids":["33837725"],"is_preprint":false},{"year":2023,"finding":"GPR56 promotes diabetic kidney disease by decreasing phosphorylation and expression of eNOS through Gα12/13-RhoA pathway activation and Gαi-mediated cAMP/PKA pathway inhibition in glomerular endothelial cells; GPR56 loss in mice reduces diabetes-induced albuminuria and glomerular injury.","method":"Gpr56 KO diabetic mice (albuminuria, glomerular injury), GEC overexpression of GPR56, eNOS phosphorylation/expression assays, RhoA activation, cAMP/PKA pathway assays","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with two independent pathways (RhoA and cAMP/PKA) identified, single lab","pmids":["37579299"],"is_preprint":false},{"year":2025,"finding":"Microglial ADGRG1 activates the transcription factor MYC, leading to upregulation of genes involved in homeostasis, phagocytosis, and lysosomal functions; deletion of Adgrg1 in microglia impairs MYC activation, resulting in increased amyloid-beta deposition, neuronal loss, and cognitive deficits in 5xFAD mice; ADGRG1 is required for Aβ phagocytosis.","method":"Microglial conditional Adgrg1 KO in 5xFAD mice, transcriptomic analysis, MYC pathway analysis, Aβ phagocytosis assay in mouse and hESC-derived microglia, cognitive behavioral assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in disease model, transcriptomic pathway identification (MYC), phagocytosis assay in two model systems, cognitive phenotype","pmids":["40713954"],"is_preprint":false},{"year":2016,"finding":"Collagen III activates ADGRG1 in pancreatic β-cells via the cAMP/protein kinase A pathway, suppression of RhoA and caspase-3 activity, increasing β-cell viability and proliferation; these effects require ADGRG1 expression.","method":"Collagen III stimulation of WT and ADGRG1-KD β-cells/islets, thymidine incorporation, caspase 3/7 activity, RhoA activity, cAMP/PKA pathway analysis","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor KD with specific pathway readouts, single lab","pmids":["27636017"],"is_preprint":false},{"year":2016,"finding":"Activation of GPR56 in melanoma cells by immobilized CG4 antibody facilitates N-terminal fragment dissociation in a CD9/CD81-dependent manner, inducing IL-6 production and promoting cell migration; the C-terminal fragment alone recapitulates antibody-induced signaling via Gα12/13/RhoA pathway.","method":"Immobilized antibody stimulation, NTF dissociation assay, CD9/CD81 KD, IL-6 ELISA, migration assay, CTF expression, Gα12/13/RhoA inhibition","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays (NTF dissociation, CD9/CD81 dependence, pathway analysis), single lab","pmids":["27818281"],"is_preprint":false},{"year":2010,"finding":"GPR56 is essential for seminiferous tubule integrity and male fertility in mice; absence of GPR56 leads to partial disruption of seminiferous tubules arising asymmetrically in embryonic gonads after initial testis cord establishment.","method":"Gpr56 knockout mouse analysis, histology of seminiferous tubules, fertility testing","journal":"Developmental dynamics : an official publication of the American Association of Anatomists","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined morphological phenotype, single lab","pmids":["20981830"],"is_preprint":false},{"year":2021,"finding":"SNAP-tag imaging shows GPR56 undergoes constitutive internalization in the absence of exogenous agonist in pancreatic β-cells; collagen III further stimulates GPR56 internalisation; synthetic Stachel peptide P7 activates GPR56-dependent calcium signaling and insulin secretion but does not enhance internalisation; constitutive and agonist-dependent GPR56 activation protects β-cells against apoptosis.","method":"SNAP-tag super-resolution/confocal microscopy, CRISPR-Cas9 GPR56 deletion, calcium microfluorimetry, insulin secretion RIA, caspase 3/7 apoptosis assay","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct trafficking imaging with CRISPR KO controls, multiple functional assays, single lab","pmids":["34224919"],"is_preprint":false},{"year":2013,"finding":"GPR56 promotes HSC maintenance in bone marrow niches via RhoA signaling; knockdown of GPR56 decreases cellular adhesion through RhoA inactivation; in Gpr56-/- mice, HSC numbers are decreased in bone marrow and increased in periphery, with impaired cellular adhesion and reduced repopulating ability.","method":"Gpr56 KO mice, GPR56 KD in AML cells, RhoA activity assay, HSC bone marrow/peripheral counts, in vivo repopulation assay","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with HSC phenotype, RhoA pathway validated by KD, single lab","pmids":["23478665"],"is_preprint":false},{"year":2020,"finding":"GPR56 is required for Müllerian duct development in chick embryos; GPR56 knockdown via in ovo electroporation causes variably truncated ducts with loss of epithelial and mesenchymal markers; GPR56 overexpression in vitro enhances cell proliferation and migration; collagen III (putative ligand) is co-expressed in the Müllerian duct.","method":"In ovo electroporation KD, GPR56 overexpression in vitro, immunofluorescence for duct markers, proliferation/migration assays","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with phenotype, in vitro gain-of-function, single lab","pmids":["31829965"],"is_preprint":false},{"year":2020,"finding":"GPR56 is required for androgen signaling in prostate cells; testosterone stimulates GPR56 to activate Rho and cAMP/PKA signaling; GPR56 KD disrupts nuclear translocation of the androgen receptor and transcription of PSA.","method":"GPR56 siRNA KD, androgen receptor nuclear translocation assay, PSA transcription assay, Rho activation assay, cAMP/PKA measurement upon testosterone stimulation","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single KD approach, limited mechanistic depth, pathway inference partly computational","pmids":["32881870"],"is_preprint":false}],"current_model":"ADGRG1/GPR56 is an adhesion GPCR that undergoes constitutive GAIN domain-mediated autoproteolytic cleavage into non-covalently associated N-terminal (NTF) and C-terminal (CTF) fragments; binding of natural ligands (collagen III, TG2/laminin, phosphatidylserine, 17α-hydroxypregnenolone) or mechanical stimuli (shear force) dissociates the NTF from the CTF to expose the tethered Stachel agonist, thereby activating primarily Gα12/13-RhoA signaling (and context-dependently Gαq/11, Gαi-cAMP/PKA, Src-Fak, and MYC pathways) to regulate diverse processes including cortical neuronal migration and pial BM integrity, OPC proliferation and myelination, microglial synapse pruning and amyloid phagocytosis, platelet shape change during hemostasis, NK/T cell cytotoxicity, HSC niche retention, and β-cell survival."},"narrative":{"mechanistic_narrative":"ADGRG1/GPR56 is an adhesion G protein-coupled receptor that couples extracellular matrix and mechanical cues to cytoskeletal and survival signaling, controlling tissue morphogenesis, myelination, immune effector function, and hemostasis [PMID:18378689, PMID:19515912, PMID:23001883, PMID:33097663]. The receptor undergoes GPS/GAIN domain-mediated autoproteolysis into a non-covalently associated N-terminal fragment (NTF) and seven-transmembrane C-terminal fragment (CTF), with truncation of the NTF producing constitutive activity [PMID:21708946]; its extracellular region contains a GAIN domain and a PLL domain whose deletion increases signaling [PMID:27657451]. Natural ligands—collagen III, TG2 (with a laminin cofactor), phosphatidylserine, and the steroid 17α-hydroxypregnenolone—activate the receptor by dissociating the NTF from the CTF to expose the tethered Stachel agonist, whereas small-molecule agonists such as 3-α-DOG and Stachel peptides can signal without NTF disengagement [PMID:31628191, PMID:29809138, PMID:32452062, PMID:39389061]. Activation predominantly engages Gα12/13–RhoA signaling driving SRE/NF-κB-dependent transcription and actin reorganization, and context-dependently Gαq/11, Gαi–cAMP/PKA, and Src–FAK pathways [PMID:18378689, PMID:21349848, PMID:28424266, PMID:33837725]. Through these outputs GPR56 governs cortical neuronal migration and pial basement membrane integrity—where loss causes neuronal ectopias and underlies bilateral frontoparietal polymicrogyria via trafficking-defective or signaling-dead missense mutations [PMID:18509043, PMID:17576745, PMID:22238662]—cell-autonomous OPC proliferation and CNS/PNS myelination [PMID:25607772, PMID:25607655, PMID:32902916, PMID:29809138, PMID:29367382], microglial synapse pruning, interneuron development, and amyloid-β phagocytosis via a MYC program [PMID:32452062, PMID:35544642, PMID:40713954], collagen/shear-force-triggered platelet shape change in hemostasis [PMID:33097663], NK cell cytotoxicity restraint through CD81 association [PMID:27184850], and β-cell survival [PMID:27636017]. The receptor partitions into tetraspanin (CD9/CD81) microdomains that scaffold its G protein coupling and NTF dissociation [PMID:15004227, PMID:27818281].","teleology":[{"year":2004,"claim":"Established that GPR56 is not an isolated receptor but assembles into a surface signaling platform, defining its proximal coupling partners.","evidence":"Co-IP with CD81 immunodepletion/reexpression and cholesterol-resistance assays in cells","pmids":["15004227"],"confidence":"High","gaps":["Did not establish which physiological stimulus engages the complex","Functional consequence of tetraspanin scaffolding not yet linked to a phenotype"]},{"year":2006,"claim":"Identified the first GPR56 binding partner and a tumor-suppressive function, framing the receptor as an ECM/stroma sensor.","evidence":"GPR56-TG2 binding assay with melanoma xenograft gain/loss-of-function","pmids":["16757564"],"confidence":"High","gaps":["Binding interface and signaling output undefined","Whether TG2 acts as agonist or antagonist unresolved at this stage"]},{"year":2007,"claim":"Showed GPR56 is processed by GPS-domain autoproteolysis and that BFPP mutations act largely by impairing folding/trafficking, linking biochemistry to disease.","evidence":"Western blot, N-glycosylation analysis, trafficking assays, pharmacological chaperone rescue of missense mutants","pmids":["17576745"],"confidence":"High","gaps":["How cleavage relates to activation not yet established","Surface-expressed mutant signaling not tested here"]},{"year":2008,"claim":"Defined the principal signaling axis and an in vivo developmental requirement, connecting GPR56 to Gα12/13-RhoA and cortical lamination.","evidence":"SRE/NF-κB reporters with C3 exoenzyme and p115-RhoGEF RGS, plus Gpr56 KO mouse cortical analysis","pmids":["18378689","18509043"],"confidence":"High","gaps":["Endogenous brain ligand not yet identified","Mechanism of NTF/CTF coupling to G protein activation unknown"]},{"year":2011,"claim":"Demonstrated that the cleaved NTF stays bound and acts as an inhibitory module, since its removal constitutively activates the receptor—a core tenet of adhesion-GPCR activation.","evidence":"Co-IP of NTF/CTF from cells and tissue, β-arrestin binding, ubiquitination, and cytotoxicity rescue","pmids":["21708946"],"confidence":"High","gaps":["The tethered agonist sequence not yet defined","How natural ligands trigger NTF removal not shown"]},{"year":2011,"claim":"Mapped how distinct BFPP mutations selectively cripple pathway branches, revealing differential G protein coupling.","evidence":"SRF vs NFAT luciferase, surface expression, dominant-negative G proteins and calcium channel blockers with R565W/L640R mutants","pmids":["21349848","28424266"],"confidence":"Medium","gaps":["Single-lab pathway dissection","Physiological relevance of NFAT/Gβγ branch in brain not established"]},{"year":2012,"claim":"Identified collagen III as the brain ligand and mapped a discrete NTF ligand-binding domain disrupted by BFPP mutations, tying ligand engagement to disease.","evidence":"Gpr56 KO/siRNA/rescue adhesion assays plus collagen III binding to truncation/point mutants","pmids":["19515912","23001883","22238662"],"confidence":"High","gaps":["How collagen III binding is transduced to G proteins not yet resolved","N-glycosylation dispensable but other modifications untested"]},{"year":2014,"claim":"Linked ligand binding mechanistically to activation by showing collagen III releases the NTF, drives CTF into lipid rafts, and activates RhoA.","evidence":"Ligand stimulation, lipid raft fractionation, RhoA pull-down, L640R mutant dissociation","pmids":["24949629"],"confidence":"High","gaps":["Stoichiometry/kinetics of NTF release not quantified","Whether raft entry is cause or consequence of activation unclear"]},{"year":2016,"claim":"Provided the structural basis for ECR-mediated regulation by resolving the GAIN and a new PLL domain, with PLL deletion enhancing signaling.","evidence":"X-ray crystallography of the GPR56 ECR with monobody, PLL deletion signaling, in vivo OL development with PLL mutant","pmids":["27657451"],"confidence":"High","gaps":["No full-length receptor or ligand-bound structure","How PLL domain physically restrains the GAIN/tethered agonist not visualized"]},{"year":2015,"claim":"Established a cell-autonomous CNS myelination role through Gα12/13-RhoA, extending GPR56 function beyond neurons to oligodendrocyte lineage.","evidence":"Zebrafish mutants, global and OPC/microglia/astrocyte/neuron-specific conditional Gpr56 KO, OPC proliferation and active-RhoA assays","pmids":["25607772","25607655","32902916"],"confidence":"High","gaps":["OPC ligand not identified in these studies","Coupling of RhoA to proliferation program undefined"]},{"year":2016,"claim":"Showed GPR56 restrains cytotoxic lymphocytes, defining an immune checkpoint function executed via tetraspanin association.","evidence":"Patient NK cells, NK-92 ectopic expression, GPR56-CD81 Co-IP, cytotoxicity/degranulation assays","pmids":["27184850"],"confidence":"High","gaps":["Activating ligand on NK cells unknown","Downstream signaling restraining cytotoxicity not mapped"]},{"year":2018,"claim":"Identified TG2/laminin as a physiological OPC agonist and demonstrated therapeutic relevance for remyelination.","evidence":"Microglia-OPC co-culture, TG2/laminin stimulation, Gpr56 KO, two demyelination models","pmids":["29809138"],"confidence":"High","gaps":["Why laminin cofactor is required not mechanistically resolved at receptor level"]},{"year":2018,"claim":"Extended myelin function to the PNS and identified plectin as a cytoskeletal interactor, linking GPR56 to Schwann cell radial sorting.","evidence":"Zebrafish/rodent mutants, RhoA assay, immunofluorescence localization, plectin-GPR56 Co-IP","pmids":["29367382"],"confidence":"High","gaps":["Plectin interaction not reciprocally/structurally validated","Connection of plectin binding to RhoA output unclear"]},{"year":2019,"claim":"Unified ligand classes by showing collagen III and TG2/laminin both require GAIN cleavage and NTF dissociation, whereas small-molecule/peptide agonists bypass NTF release.","evidence":"Non-cleavable receptor engineering with collagen III, TG2, laminin, 3-α-DOG, P19 peptide and NTF/CTF dissociation assays","pmids":["31628191"],"confidence":"High","gaps":["In vivo proof that NTF dissociation occurs at endogenous receptor levels lacking","Exact ligand contact sites for dissociation not mapped"]},{"year":2020,"claim":"Revealed an isoform-specific microglial function: phosphatidylserine-triggered GPR56 drives synaptic pruning.","evidence":"Microglia-specific conditional KO, domain-specific PS binding, synapse density and engulfment assays, isoform analysis","pmids":["32452062"],"confidence":"High","gaps":["G protein pathway downstream of PS engagement not defined","How alternative splicing tunes ligand specificity unclear"]},{"year":2020,"claim":"Established GPR56 as the platelet mechanosensor coupling collagen and shear force to Gα13 for hemostasis.","evidence":"Gpr56-/- bleeding, plug formation, thrombosis models, collagen perfusion under shear, human plasma NTF detection","pmids":["33097663"],"confidence":"High","gaps":["Molecular sensor of shear within the receptor not pinpointed","Relative contribution of collagen vs shear not separated"]},{"year":2022,"claim":"Connected microglial GPR56 to interneuron development and maternal-immune-activation autism phenotypes via an IL-17a/TNF-α axis.","evidence":"Microglial conditional KO, MIA model, IL-17a neutralization, TNF-α measurement, genetic rescue, behavior","pmids":["35544642"],"confidence":"High","gaps":["Receptor ligand in this context unidentified","Direct link from GPR56 signaling to TNF-α suppression not mechanistically resolved"]},{"year":2024,"claim":"Identified a steroid agonist and a ferroptosis-protective mechanism, showing GPR56 promotes endocytic-lysosomal degradation of CD36 to limit PUFA-phospholipids.","evidence":"Gpr56 KO liver injury models, CD36 endocytosis/degradation assays, phospholipidomics, steroid screen identifying 17-OH PREG, disease-mutant signaling","pmids":["39389061"],"confidence":"High","gaps":["How receptor activation drives CD36 endocytosis mechanistically unclear","Physiological source of 17-OH PREG agonist in vivo not established"]},{"year":2025,"claim":"Defined a microglial GPR56-MYC transcriptional program required for amyloid-β clearance, implicating the receptor in Alzheimer's pathology.","evidence":"Microglial conditional KO in 5xFAD, transcriptomics, MYC pathway analysis, Aβ phagocytosis in mouse and hESC-derived microglia, cognition","pmids":["40713954"],"confidence":"High","gaps":["Ligand triggering microglial GPR56 in AD unknown","Signaling steps from receptor to MYC activation not delineated"]},{"year":null,"claim":"How a single receptor selects among Gα12/13-RhoA, Gαq/11, Gαi-cAMP/PKA, Src-FAK, and MYC outputs in a tissue- and ligand-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking specific ligands/isoforms to specific G protein branches","Structure of an activated, ligand-engaged full-length receptor lacking","In vivo demonstration of NTF dissociation at endogenous receptor not achieved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,8,15,17]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,7]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[6,28]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[17]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[23]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5,8,40]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8,21,34]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,9,10,23]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[24,36]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[33,37]}],"complexes":["GPR56-CD9-CD81-Gαq/11 tetraspanin complex"],"partners":["CD81","CD9","GNAQ","GNA11","TG2","COL3A1","PLEC","ITGA3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y653","full_name":"Adhesion G-protein coupled receptor G1","aliases":["G-protein coupled receptor 56"],"length_aa":693,"mass_kda":77.7,"function":"Adhesion G-protein coupled receptor (aGPCR) for steroid hormone 17alpha-hydroxypregnenolone (17-OH), which is involved in cell adhesion and cell-cell interactions (PubMed:39389061). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as RhoA pathway (PubMed:28874577, PubMed:35418682, PubMed:39389061). ADGRG1 is coupled to G(12) and/or G(13) G proteins (GNA12 and GNA13, respectively) and mediates the activation Rho small GTPases (PubMed:22238662, PubMed:28424266, PubMed:35418682, PubMed:39389061). Acts as a potent suppressor of ferroptosis: binding to 17-OH-binding initiates signaling that down-regulates CD36 and alleviates ferroptosis-induced liver injury (By similarity). Ligand-binding also induces cell adhesion activity via association with proteins such as collagen III/COL3A1 and TGM2 (By similarity). Mediates cell matrix adhesion in developing neurons and hematopoietic stem cells (By similarity). Involved in cortical development, specifically in maintenance of the pial basement membrane integrity and in cortical lamination: association with COL3A1 in the developing brain inhibits neuronal migration via activation of the RhoA pathway (PubMed:24531968). Together with TGM2, acts as a regulator of myelination and myelin repair in oligodendrocyte precursor cells (By similarity). Acts as a hemostatic sensor of shear force: G protein-coupled receptor signaling is activated in response to shear force in platelets, promoting G(13) G protein signaling, and platelet shape change and aggregation in a COL3A1-dependent manner (PubMed:33097663). Acts as an inhibitor of VEGFA production thereby inhibiting angiogenesis through a signaling pathway mediated by PRKCA (PubMed:16757564, PubMed:19572147, PubMed:21724588). Plays a role in the maintenance of hematopoietic stem cells in bone marrow niche (By similarity). Plays an essential role in testis development (By similarity)","subcellular_location":"Membrane raft","url":"https://www.uniprot.org/uniprotkb/Q9Y653/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADGRG1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADGRG1","total_profiled":1310},"omim":[{"mim_id":"615752","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 14B (BILATERAL PERISYLVIAN); CDCBM14B","url":"https://www.omim.org/entry/615752"},{"mim_id":"614039","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 1; CDCBM1","url":"https://www.omim.org/entry/614039"},{"mim_id":"606854","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 14A (BILATERAL FRONTOPARIETAL); CDCBM14A","url":"https://www.omim.org/entry/606854"},{"mim_id":"604110","title":"ADHESION G PROTEIN-COUPLED RECEPTOR G1; ADGRG1","url":"https://www.omim.org/entry/604110"},{"mim_id":"120180","title":"COLLAGEN, TYPE III, ALPHA-1; COL3A1","url":"https://www.omim.org/entry/120180"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"thyroid gland","ntpm":202.1}],"url":"https://www.proteinatlas.org/search/ADGRG1"},"hgnc":{"alias_symbol":["TM7LN4","TM7XN1"],"prev_symbol":["GPR56"]},"alphafold":{"accession":"Q9Y653","domains":[{"cath_id":"-","chopping":"30-163","consensus_level":"high","plddt":88.476,"start":30,"end":163},{"cath_id":"2.60.220.50","chopping":"177-191_212-392","consensus_level":"medium","plddt":83.2223,"start":177,"end":392},{"cath_id":"1.20.1070.10","chopping":"398-666","consensus_level":"medium","plddt":77.7588,"start":398,"end":666}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y653","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y653-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y653-F1-predicted_aligned_error_v6.png","plddt_mean":77.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADGRG1","jax_strain_url":"https://www.jax.org/strain/search?query=ADGRG1"},"sequence":{"accession":"Q9Y653","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y653.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y653/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y653"}},"corpus_meta":[{"pmid":"16757564","id":"PMC_16757564","title":"GPR56, 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tissue and tumor stroma, and this interaction suppresses tumor growth and metastasis in melanoma xenograft models.\",\n      \"method\": \"Binding assay (GPR56-TG2 interaction), xenograft tumor models with GPR56 overexpression/knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay, functional in vivo xenograft validation, replicated across multiple subsequent studies\",\n      \"pmids\": [\"16757564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GPR56 forms a specific complex with tetraspanins CD9 and CD81 and heterotrimeric G protein subunits Gαq, Gα11, and Gβ on the cell surface; CD81 plays a central role in promoting or stabilizing the GPR56-CD81-Gαq/11 complex, as demonstrated by CD81 immunodepletion and reexpression experiments.\",\n      \"method\": \"Co-immunoprecipitation, immunodepletion/reexpression of CD81, cholesterol depletion resistance assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with immunodepletion/reexpression controls, multiple orthogonal methods in single study\",\n      \"pmids\": [\"15004227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GPR56 couples with Gα12/13 and activates Rho-dependent transcription (SRE, NF-κB) and actin fiber reorganization to inhibit neural progenitor cell migration; inhibition of NPC migration by agonistic anti-GPR56 antibody was attenuated by p115 RhoGEF RGS domain and C3 exoenzyme (Rho inhibitor).\",\n      \"method\": \"Reporter assays (SRE-luciferase, NF-κB-luciferase), actin staining, dominant-negative Rho, C3 exoenzyme treatment, agonistic antibody, GPR56 knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including dominant-negative, chemical inhibitor, and KD, all consistent with Gα12/13-Rho pathway\",\n      \"pmids\": [\"18378689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of GPR56 in mice causes breaches in the pial basement membrane and neuronal ectopias during cerebral cortical development; GPR56 is present in radial glial endfeet, and a putative ligand is localized in the marginal zone/overlying ECM.\",\n      \"method\": \"Gpr56 knockout mouse analysis, immunohistochemistry, time-course analysis of pial BM integrity\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotype, detailed time-course and localization experiments\",\n      \"pmids\": [\"18509043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Wild-type GPR56 undergoes GPS domain-mediated protein cleavage and N-glycosylation; disease-associated missense mutations (R38Q, R38W, Y88C, C91S) cause reduced intracellular trafficking and poor cell surface expression, while GPS domain mutations (C346S, W349S) abolish cleavage and trap protein in the ER; pharmacological chaperones can partially rescue mutant surface expression.\",\n      \"method\": \"Biochemical characterization (Western blot, N-glycosylation analysis), cell trafficking assays, pharmacological chaperone rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mutants analyzed with consistent results, pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"17576745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The large N-terminus (NT) of GPR56 is cleaved from the rest of the receptor but remains non-covalently associated with the seven-transmembrane region; truncation of the NT results in constitutive activation (increased β-arrestin binding, ubiquitination, cytotoxicity); the NT is capable of homophilic trans-trans interactions that enhance receptor signaling activity.\",\n      \"method\": \"Co-immunoprecipitation of NT and CTF fragments from transfected cells and native tissue, β-arrestin binding assays, ubiquitination assays, cytotoxicity rescue by β-arrestin 2 cotransfection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal assays (Co-IP, β-arrestin binding, ubiquitination, cell viability) in single study with functional validation\",\n      \"pmids\": [\"21708946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Collagen III is the ligand of GPR56 in the developing brain; GPR56 regulates NPC adhesion to extracellular matrix molecules of the pial basement membrane, and loss of GPR56 causes loss of granule cell adhesion to ECM; this was rescued by re-expression of GPR56.\",\n      \"method\": \"Gpr56 knockout mouse cerebellar analysis, siRNA knockdown, GPR56 re-expression rescue of adhesion defect, ligand-probe binding assay\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience / PloS one (review citing original data)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO phenotype, siRNA knockdown, and rescue experiment all consistent; collagen III identified as ligand by binding assay\",\n      \"pmids\": [\"19515912\", \"23001883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A ligand-binding domain within GPR56 N-terminal fragment (GPR56N) is required for collagen III binding; four disease-associated BFPP mutations within this domain completely abolish collagen III binding, though N-glycosylation is not required for binding.\",\n      \"method\": \"Truncation and mutation analysis with collagen III binding assay, N-glycosylation blocking\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with multiple mutants tested, single lab but rigorous mutagenesis\",\n      \"pmids\": [\"22238662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Collagen III binding to GPR56 releases GPR56N from membrane-bound GPR56C, triggers association of GPR56C with lipid rafts, and activates RhoA; BFPP-associated mutation L640R specifically abolishes collagen III-mediated RhoA activation without affecting lipid raft association.\",\n      \"method\": \"Ligand stimulation assay, lipid raft fractionation, RhoA activation assay, L640R mutant analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ligand stimulation with lipid raft fractionation and RhoA pull-down, disease mutant mechanistically informative\",\n      \"pmids\": [\"24949629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GPR56 regulates oligodendrocyte development through Gα12/13 proteins and RhoA activation; loss of Gpr56 in zebrafish and mice leads to decreased OPC proliferation and reduced myelinated axons.\",\n      \"method\": \"Zebrafish gpr56 mutants, Gpr56 knockout mice, OPC proliferation assay, active RhoA measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent species (zebrafish and mouse), multiple cellular phenotypes, G protein pathway identified\",\n      \"pmids\": [\"25607772\", \"25607655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Gpr56 conditional knockout in OPCs (but not microglia, astrocytes, or neurons) leads to decreased OPC proliferation and reduced myelinated axons, establishing a cell-autonomous role for GPR56 in oligodendrocyte development.\",\n      \"method\": \"Cell-type-specific conditional knockout mice (OPC, microglia, astrocyte, neuron-specific Cre lines), myelin analysis\",\n      \"journal\": \"Nature communications / Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in multiple cell types, establishing cell autonomy; replicated across two studies\",\n      \"pmids\": [\"25607655\", \"32902916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the GPR56 extracellular region (ECR) was determined, revealing a GAIN domain and a previously unidentified PLL (Pentraxin/Laminin/neurexin/sex-hormone-binding-globulin-Like) domain; PLL domain deletion causes increased receptor signaling; an evolutionarily conserved PLL domain residue is critical for oligodendrocyte development in vivo.\",\n      \"method\": \"Crystal structure determination (X-ray crystallography), monobody complex, PLL domain deletion mutant signaling assay, in vivo OL development with PLL mutant\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis and in vivo validation\",\n      \"pmids\": [\"27657451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Stachel-independent signaling can occur for GPR56: stalkless GPR56 mutants lacking the membrane-proximal stalk show robust activity in TGFα shedding, NFAT luciferase, and β-arrestin recruitment assays, but reduced activity in SRF luciferase (Gα12/13 pathway), indicating pathway-dependent stalk dependence.\",\n      \"method\": \"Stalkless receptor engineering, TGFα shedding assay, NFAT luciferase, SRF luciferase, β-arrestin recruitment assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling assays, single lab, engineered mutants with mixed results across pathways\",\n      \"pmids\": [\"26710850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Synthetic monobodies directed to both the PLL and GAIN domains of the GPR56 ECR can activate or inhibit GPR56-mediated signaling even in a GPR56 mutant defective in autoproteolysis, demonstrating an ECR-mediated, Stachel-independent regulatory mechanism.\",\n      \"method\": \"Monobody generation, signaling assays with autoproteolysis-defective GPR56 mutant, luciferase reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered synthetic ligands with autoproteolysis-dead mutant controls, single lab\",\n      \"pmids\": [\"28874577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Microglia-derived transglutaminase-2 (TG2) signals to ADGRG1 on OPCs in the presence of the ECM protein laminin, and TG2/laminin-dependent activation of ADGRG1 promotes OPC proliferation and improves remyelination in two murine demyelination models.\",\n      \"method\": \"Cell co-culture (microglia-OPC), TG2/laminin stimulation assays, Gpr56 KO OPC proliferation, demyelination/remyelination mouse models\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ligand identity (TG2/laminin) established with KO controls, in vivo remyelination in two independent disease models\",\n      \"pmids\": [\"29809138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Both natural ligands (collagen III and TG2/laminin) activate GPR56 by dissociating the N-terminal fragment from the C-terminal fragment, enabling Stachel-mediated signaling, and require GAIN domain-mediated cleavage; TG2 additionally requires laminin cofactor; the small-molecule agonist 3-α-DOG and synthetic Stachel peptide P19 can signal without disengaging the N-terminal fragment.\",\n      \"method\": \"Non-cleavable receptor engineering, ligand stimulation assays with collagen III, TG2, laminin, 3-α-DOG, and P19 peptide; NTF/CTF dissociation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution-like mechanistic dissection with engineered non-cleavable receptor, multiple natural and synthetic agonists tested, single rigorous study with multiple orthogonal approaches\",\n      \"pmids\": [\"31628191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A specific alternatively spliced isoform of GPR56, expressed in microglia, is selectively required for microglial synapse pruning; phosphatidylserine (PS) on presynaptic elements binds GPR56 in a domain-specific manner; microglia-specific deletion of Gpr56 leads to increased synapses due to reduced microglial engulfment of PS+ presynaptic inputs.\",\n      \"method\": \"Microglia-specific conditional Gpr56 KO, PS-GPR56 binding assay (domain-specific), synaptic density quantification, microglial engulfment assay, isoform-specific analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, direct ligand binding assay, isoform specificity established, multiple brain regions and time points\",\n      \"pmids\": [\"32452062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GPR56 is the platelet receptor that transduces signals from collagen and blood flow-induced shear force to activate G protein 13 signaling for platelet shape change; Gpr56-/- mice have prolonged bleeding, defective platelet plug formation, and delayed thrombotic occlusion.\",\n      \"method\": \"Gpr56-/- mouse bleeding assays, platelet plug formation assay, thrombotic occlusion model, blood perfusion assay with immobilized collagen, free NTF detection in human plasma\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with multiple in vivo phenotypes, human plasma validation, shear-force specificity demonstrated\",\n      \"pmids\": [\"33097663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPR56 internalizes and degrades its ligand TG2 upon binding, resulting in decreased fibronectin deposition and impaired focal adhesion kinase accumulation; xenograft studies in Tg2-/- mice confirmed antagonistic relationship between GPR56 and TG2 in melanoma.\",\n      \"method\": \"Xenograft studies in immunodeficient Tg2-/- mice, TG2 internalization assay, fibronectin deposition assay, FAK immunostaining\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model, biochemical mechanism of internalization/degradation demonstrated, single lab\",\n      \"pmids\": [\"24356421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GPR56 inhibits VEGF production from melanoma cells and impedes angiogenesis through a signaling pathway involving protein kinase Cα (PKCα); the two GPR56 fragments generated by autocatalytic cleavage play distinct roles in regulating VEGF production.\",\n      \"method\": \"VEGF ELISA, angiogenesis assays, PKCα pathway analysis, fragment-specific overexpression\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with fragment-specific constructs and pathway inhibition, single lab\",\n      \"pmids\": [\"21724588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPR56 expression regulates cortical progenitor cell proliferation; its expression level is controlled by multiple alternative promoters and splice forms that are highly variable between mice and humans; the regulatory element of gyrencephalic mammals directs restricted lateral cortical expression.\",\n      \"method\": \"GPR56 splice form analysis, deletion mutant of regulatory element (15-bp deletion), progenitor proliferation assay, RFX transcription factor binding assay\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic mutation identified, functional regulatory element validated, proliferation assay, single study\",\n      \"pmids\": [\"24531968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss-of-function mutations in GPR56 extracellular loops (R565W, L640R) cause BFPP via multiple mechanisms including reduced surface receptor expression and loss of signaling to specific pathways; these mutations abolish Gα12/13-mediated SRF signaling but not NFAT signaling, indicating differential pathway effects; NFAT activation by GPR56 involves Gβγ liberation and calcium channel activation.\",\n      \"method\": \"Luciferase reporter assays (SRF, NFAT), surface expression analysis, dominant-negative G protein subunits, calcium channel blockers\",\n      \"journal\": \"The Journal of biological chemistry / The Journal of biological chemistry (2017)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling assays with disease mutants, single lab, two separate studies with consistent findings\",\n      \"pmids\": [\"21349848\", \"28424266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPR56 functions together with α3β1 integrin in regulating pial basement membrane assembly; loss of α3 integrin enhances the cortical phenotype of Gpr56 deletion, with earlier neuronal overmigration in double knockouts, demonstrating genetic synergism.\",\n      \"method\": \"Gpr56/α3 integrin double knockout mice, cortical phenotype analysis, time-course of neuronal overmigration\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by double KO, single lab\",\n      \"pmids\": [\"23874761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GPR56 is a conserved regulator of peripheral nervous system myelin; GPR56-dependent RhoA signaling promotes radial sorting of axons during Schwann cell development; GPR56 localizes to distinct SC cytoplasmic domains in mature PNS; plectin is identified as a novel interacting partner of GPR56 in Schwann cells.\",\n      \"method\": \"Zebrafish and rodent gpr56 mutants/KO, RhoA activation assay, GPR56 localization by immunofluorescence, Co-IP of plectin-GPR56\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two species studied, new binding partner identified by Co-IP, subcellular localization with functional consequence, RhoA pathway confirmed\",\n      \"pmids\": [\"29367382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GPR56 is expressed on mature NK cells and negatively regulates NK cell effector functions (cytokine production, degranulation, target cell killing) by associating with tetraspanin CD81; NK cells from polymicrogyria patients with ADGRG1 mutations show enhanced cytotoxicity.\",\n      \"method\": \"NK cells from ADGRG1 mutant patients, NK-92 ectopic expression, Co-IP of GPR56-CD81, cytotoxicity assays, degranulation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human patient NK cells, ectopic expression, Co-IP for CD81 association, multiple functional assays\",\n      \"pmids\": [\"27184850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GPR56 inhibits NF-κB signaling pathway in glioblastoma cells, thereby preventing mesenchymal differentiation and radioresistance; GPR56 loss of function promotes mesenchymal differentiation and radioresistance both in vitro and in vivo.\",\n      \"method\": \"GPR56 knockdown/overexpression in GBM cells and glioma-initiating cells, NF-κB reporter assay, in vivo tumor models, radioresistance assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined pathway (NF-κB), in vitro and in vivo, single lab\",\n      \"pmids\": [\"29166609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TG2 C-terminal portion directly interacts with the GPR56 ECR with high-nanomolar affinity; the TG2 binding site was mapped to a conserved patch on the PLL domain of GPR56 by site-directed mutagenesis; monobodies binding the GPR56 ECR can block the GPR56-TG2 interaction.\",\n      \"method\": \"Site-directed mutagenesis, binding affinity measurement (surface plasmon resonance or similar), monobody blocking assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with mutagenesis and synthetic inhibitors, single lab\",\n      \"pmids\": [\"33037308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PCBP2 inhibits GPR56 mRNA stability, thereby reducing GPR56 protein levels in cardiomyocytes; GPR56 knockdown reduces angiotensin II-induced cardiomyocyte hypertrophy, establishing GPR56 as a pro-hypertrophic mediator downstream of PCBP2.\",\n      \"method\": \"PCBP2 KD/overexpression, GPR56 mRNA stability assay, GPR56 KD in cardiomyocytes, cell size and protein synthesis measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic depth beyond mRNA stability and KD phenotype\",\n      \"pmids\": [\"26116532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Heparin interacts with GPR56 at two basic-residue-rich clusters (R26GHREDFRFC35 and L190KHPQKASRRP200) in the N-terminus; heparin binding reduces GPR56 receptor shedding and enhances cell adhesion and motility; collagen III modulates GPR56-heparin interaction but TG2 does not.\",\n      \"method\": \"Truncation/mutant GPR56 binding assays, receptor shedding assay, cell adhesion/motility assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding site mapped by mutagenesis, functional shedding and adhesion assays, single lab\",\n      \"pmids\": [\"27068534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Small-molecule gedunin derivatives (e.g., 3-α-DOG) act as partial agonists for GPR56/ADGRG1 by acting at the 7TM domain with EC50 ~5 μM; 3-α-DOG can antagonize both peptide agonist and endogenous tethered agonist, consistent with partial agonism.\",\n      \"method\": \"High-throughput compound screen, SRE-luciferase reporter, engineered low-activity GPR56 7TM, dose-response assays, peptide antagonism assay\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays, engineered receptor controls, pharmacological characterization, single lab\",\n      \"pmids\": [\"29476042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPR56 is required for hematopoietic cluster formation during endothelial-to-hematopoietic cell transition (EHT); Gpr56 is a transcriptional target of the heptad complex of hematopoietic transcription factors and is one of the most highly upregulated genes in hemogenic endothelial cells.\",\n      \"method\": \"RNA-seq of aortic HSCs/HECs/ECs, Gpr56 morpholino/KD in zebrafish, heptad complex ChIP/transcription factor binding assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomic identification with functional validation by morpholino KD, heptad complex binding established, single lab\",\n      \"pmids\": [\"25547674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GPR56 enhances drug resistance in colorectal cancer cells through upregulation of MDR1 levels via a RhoA-mediated signaling mechanism; loss of GPR56 suppresses tumor growth and increases sensitivity to chemotherapy.\",\n      \"method\": \"GPR56 KD/KO in colon cancer cells, MDR1 expression assay, RhoA activation assay, drug resistance assay (irinotecan, 5-FU), tumor xenograft\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined RhoA-MDR1 mechanism, in vitro and in vivo, single lab\",\n      \"pmids\": [\"31444231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Microglial GPR56 plays a critical role in parvalbumin-positive (PV+) interneuron development; MIA down-regulates microglial Gpr56 in an IL-17a-dependent manner; microglial Gpr56 deletion mimics MIA-induced PV+ interneuron deficits via elevated TNF-α; restoring Gpr56 in microglia ameliorates PV+ interneuron deficits and autism-like behaviors.\",\n      \"method\": \"Microglial conditional Gpr56 KO, MIA mouse model, IL-17a neutralization, TNF-α measurement, PV+ interneuron counting, behavioral assays, Gpr56 genetic rescue\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, cytokine pathway identification, genetic rescue, multiple behavioral and cellular phenotypes\",\n      \"pmids\": [\"35544642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPR56 renders cells resistant to ferroptosis by promoting endocytosis-lysosomal degradation of CD36, thereby decreasing abundance of phospholipids containing free PUFAs; 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and attenuates liver injury; disease-associated GPR56 mutants were unresponsive to 17-OH PREG.\",\n      \"method\": \"Gpr56 KO mice (doxorubicin/ischemia-reperfusion liver injury models), CD36 endocytosis/degradation assays, phospholipidomics, steroid hormone screen, mutant receptor signaling assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO models, direct biochemical mechanism (CD36 degradation), agonist identification with mutant validation, multiple orthogonal methods\",\n      \"pmids\": [\"39389061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPR56 overexpression in 293T cells leads to increased phosphorylation of Src, Fak, and paxillin; GPR56-mediated Src-Fak activation is independent of RhoA; a monoclonal antibody targeting the GAIN domain potentiates Src-Fak-RhoA-SRF signaling and cell adhesion; the C-terminal portion of the STP-rich region of GPR56 is required for Src-Fak activation.\",\n      \"method\": \"GPR56 overexpression, monoclonal antibody treatment, Src/Fak/paxillin phosphorylation (Western blot), RhoA inhibition, SRF luciferase, deletion mutant analysis, GPR56 KD in CRC cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling assays with deletion mutants and KD, single lab\",\n      \"pmids\": [\"33837725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPR56 promotes diabetic kidney disease by decreasing phosphorylation and expression of eNOS through Gα12/13-RhoA pathway activation and Gαi-mediated cAMP/PKA pathway inhibition in glomerular endothelial cells; GPR56 loss in mice reduces diabetes-induced albuminuria and glomerular injury.\",\n      \"method\": \"Gpr56 KO diabetic mice (albuminuria, glomerular injury), GEC overexpression of GPR56, eNOS phosphorylation/expression assays, RhoA activation, cAMP/PKA pathway assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with two independent pathways (RhoA and cAMP/PKA) identified, single lab\",\n      \"pmids\": [\"37579299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Microglial ADGRG1 activates the transcription factor MYC, leading to upregulation of genes involved in homeostasis, phagocytosis, and lysosomal functions; deletion of Adgrg1 in microglia impairs MYC activation, resulting in increased amyloid-beta deposition, neuronal loss, and cognitive deficits in 5xFAD mice; ADGRG1 is required for Aβ phagocytosis.\",\n      \"method\": \"Microglial conditional Adgrg1 KO in 5xFAD mice, transcriptomic analysis, MYC pathway analysis, Aβ phagocytosis assay in mouse and hESC-derived microglia, cognitive behavioral assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in disease model, transcriptomic pathway identification (MYC), phagocytosis assay in two model systems, cognitive phenotype\",\n      \"pmids\": [\"40713954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Collagen III activates ADGRG1 in pancreatic β-cells via the cAMP/protein kinase A pathway, suppression of RhoA and caspase-3 activity, increasing β-cell viability and proliferation; these effects require ADGRG1 expression.\",\n      \"method\": \"Collagen III stimulation of WT and ADGRG1-KD β-cells/islets, thymidine incorporation, caspase 3/7 activity, RhoA activity, cAMP/PKA pathway analysis\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor KD with specific pathway readouts, single lab\",\n      \"pmids\": [\"27636017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Activation of GPR56 in melanoma cells by immobilized CG4 antibody facilitates N-terminal fragment dissociation in a CD9/CD81-dependent manner, inducing IL-6 production and promoting cell migration; the C-terminal fragment alone recapitulates antibody-induced signaling via Gα12/13/RhoA pathway.\",\n      \"method\": \"Immobilized antibody stimulation, NTF dissociation assay, CD9/CD81 KD, IL-6 ELISA, migration assay, CTF expression, Gα12/13/RhoA inhibition\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays (NTF dissociation, CD9/CD81 dependence, pathway analysis), single lab\",\n      \"pmids\": [\"27818281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GPR56 is essential for seminiferous tubule integrity and male fertility in mice; absence of GPR56 leads to partial disruption of seminiferous tubules arising asymmetrically in embryonic gonads after initial testis cord establishment.\",\n      \"method\": \"Gpr56 knockout mouse analysis, histology of seminiferous tubules, fertility testing\",\n      \"journal\": \"Developmental dynamics : an official publication of the American Association of Anatomists\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined morphological phenotype, single lab\",\n      \"pmids\": [\"20981830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNAP-tag imaging shows GPR56 undergoes constitutive internalization in the absence of exogenous agonist in pancreatic β-cells; collagen III further stimulates GPR56 internalisation; synthetic Stachel peptide P7 activates GPR56-dependent calcium signaling and insulin secretion but does not enhance internalisation; constitutive and agonist-dependent GPR56 activation protects β-cells against apoptosis.\",\n      \"method\": \"SNAP-tag super-resolution/confocal microscopy, CRISPR-Cas9 GPR56 deletion, calcium microfluorimetry, insulin secretion RIA, caspase 3/7 apoptosis assay\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct trafficking imaging with CRISPR KO controls, multiple functional assays, single lab\",\n      \"pmids\": [\"34224919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPR56 promotes HSC maintenance in bone marrow niches via RhoA signaling; knockdown of GPR56 decreases cellular adhesion through RhoA inactivation; in Gpr56-/- mice, HSC numbers are decreased in bone marrow and increased in periphery, with impaired cellular adhesion and reduced repopulating ability.\",\n      \"method\": \"Gpr56 KO mice, GPR56 KD in AML cells, RhoA activity assay, HSC bone marrow/peripheral counts, in vivo repopulation assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with HSC phenotype, RhoA pathway validated by KD, single lab\",\n      \"pmids\": [\"23478665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GPR56 is required for Müllerian duct development in chick embryos; GPR56 knockdown via in ovo electroporation causes variably truncated ducts with loss of epithelial and mesenchymal markers; GPR56 overexpression in vitro enhances cell proliferation and migration; collagen III (putative ligand) is co-expressed in the Müllerian duct.\",\n      \"method\": \"In ovo electroporation KD, GPR56 overexpression in vitro, immunofluorescence for duct markers, proliferation/migration assays\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with phenotype, in vitro gain-of-function, single lab\",\n      \"pmids\": [\"31829965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GPR56 is required for androgen signaling in prostate cells; testosterone stimulates GPR56 to activate Rho and cAMP/PKA signaling; GPR56 KD disrupts nuclear translocation of the androgen receptor and transcription of PSA.\",\n      \"method\": \"GPR56 siRNA KD, androgen receptor nuclear translocation assay, PSA transcription assay, Rho activation assay, cAMP/PKA measurement upon testosterone stimulation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single KD approach, limited mechanistic depth, pathway inference partly computational\",\n      \"pmids\": [\"32881870\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADGRG1/GPR56 is an adhesion GPCR that undergoes constitutive GAIN domain-mediated autoproteolytic cleavage into non-covalently associated N-terminal (NTF) and C-terminal (CTF) fragments; binding of natural ligands (collagen III, TG2/laminin, phosphatidylserine, 17α-hydroxypregnenolone) or mechanical stimuli (shear force) dissociates the NTF from the CTF to expose the tethered Stachel agonist, thereby activating primarily Gα12/13-RhoA signaling (and context-dependently Gαq/11, Gαi-cAMP/PKA, Src-Fak, and MYC pathways) to regulate diverse processes including cortical neuronal migration and pial BM integrity, OPC proliferation and myelination, microglial synapse pruning and amyloid phagocytosis, platelet shape change during hemostasis, NK/T cell cytotoxicity, HSC niche retention, and β-cell survival.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADGRG1/GPR56 is an adhesion G protein-coupled receptor that couples extracellular matrix and mechanical cues to cytoskeletal and survival signaling, controlling tissue morphogenesis, myelination, immune effector function, and hemostasis [#2, #6, #17]. The receptor undergoes GPS/GAIN domain-mediated autoproteolysis into a non-covalently associated N-terminal fragment (NTF) and seven-transmembrane C-terminal fragment (CTF), with truncation of the NTF producing constitutive activity [#5]; its extracellular region contains a GAIN domain and a PLL domain whose deletion increases signaling [#11]. Natural ligands—collagen III, TG2 (with a laminin cofactor), phosphatidylserine, and the steroid 17α-hydroxypregnenolone—activate the receptor by dissociating the NTF from the CTF to expose the tethered Stachel agonist, whereas small-molecule agonists such as 3-α-DOG and Stachel peptides can signal without NTF disengagement [#15, #14, #16, #33]. Activation predominantly engages Gα12/13–RhoA signaling driving SRE/NF-κB-dependent transcription and actin reorganization, and context-dependently Gαq/11, Gαi–cAMP/PKA, and Src–FAK pathways [#2, #21, #34]. Through these outputs GPR56 governs cortical neuronal migration and pial basement membrane integrity—where loss causes neuronal ectopias and underlies bilateral frontoparietal polymicrogyria via trafficking-defective or signaling-dead missense mutations [#3, #4, #7]—cell-autonomous OPC proliferation and CNS/PNS myelination [#9, #10, #14, #23], microglial synapse pruning, interneuron development, and amyloid-β phagocytosis via a MYC program [#16, #32, #36], collagen/shear-force-triggered platelet shape change in hemostasis [#17], NK cell cytotoxicity restraint through CD81 association [#24], and β-cell survival [#37]. The receptor partitions into tetraspanin (CD9/CD81) microdomains that scaffold its G protein coupling and NTF dissociation [#1, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that GPR56 is not an isolated receptor but assembles into a surface signaling platform, defining its proximal coupling partners.\",\n      \"evidence\": \"Co-IP with CD81 immunodepletion/reexpression and cholesterol-resistance assays in cells\",\n      \"pmids\": [\"15004227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which physiological stimulus engages the complex\", \"Functional consequence of tetraspanin scaffolding not yet linked to a phenotype\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the first GPR56 binding partner and a tumor-suppressive function, framing the receptor as an ECM/stroma sensor.\",\n      \"evidence\": \"GPR56-TG2 binding assay with melanoma xenograft gain/loss-of-function\",\n      \"pmids\": [\"16757564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface and signaling output undefined\", \"Whether TG2 acts as agonist or antagonist unresolved at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed GPR56 is processed by GPS-domain autoproteolysis and that BFPP mutations act largely by impairing folding/trafficking, linking biochemistry to disease.\",\n      \"evidence\": \"Western blot, N-glycosylation analysis, trafficking assays, pharmacological chaperone rescue of missense mutants\",\n      \"pmids\": [\"17576745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cleavage relates to activation not yet established\", \"Surface-expressed mutant signaling not tested here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the principal signaling axis and an in vivo developmental requirement, connecting GPR56 to Gα12/13-RhoA and cortical lamination.\",\n      \"evidence\": \"SRE/NF-κB reporters with C3 exoenzyme and p115-RhoGEF RGS, plus Gpr56 KO mouse cortical analysis\",\n      \"pmids\": [\"18378689\", \"18509043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous brain ligand not yet identified\", \"Mechanism of NTF/CTF coupling to G protein activation unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that the cleaved NTF stays bound and acts as an inhibitory module, since its removal constitutively activates the receptor—a core tenet of adhesion-GPCR activation.\",\n      \"evidence\": \"Co-IP of NTF/CTF from cells and tissue, β-arrestin binding, ubiquitination, and cytotoxicity rescue\",\n      \"pmids\": [\"21708946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The tethered agonist sequence not yet defined\", \"How natural ligands trigger NTF removal not shown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapped how distinct BFPP mutations selectively cripple pathway branches, revealing differential G protein coupling.\",\n      \"evidence\": \"SRF vs NFAT luciferase, surface expression, dominant-negative G proteins and calcium channel blockers with R565W/L640R mutants\",\n      \"pmids\": [\"21349848\", \"28424266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pathway dissection\", \"Physiological relevance of NFAT/Gβγ branch in brain not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified collagen III as the brain ligand and mapped a discrete NTF ligand-binding domain disrupted by BFPP mutations, tying ligand engagement to disease.\",\n      \"evidence\": \"Gpr56 KO/siRNA/rescue adhesion assays plus collagen III binding to truncation/point mutants\",\n      \"pmids\": [\"19515912\", \"23001883\", \"22238662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How collagen III binding is transduced to G proteins not yet resolved\", \"N-glycosylation dispensable but other modifications untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked ligand binding mechanistically to activation by showing collagen III releases the NTF, drives CTF into lipid rafts, and activates RhoA.\",\n      \"evidence\": \"Ligand stimulation, lipid raft fractionation, RhoA pull-down, L640R mutant dissociation\",\n      \"pmids\": [\"24949629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry/kinetics of NTF release not quantified\", \"Whether raft entry is cause or consequence of activation unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural basis for ECR-mediated regulation by resolving the GAIN and a new PLL domain, with PLL deletion enhancing signaling.\",\n      \"evidence\": \"X-ray crystallography of the GPR56 ECR with monobody, PLL deletion signaling, in vivo OL development with PLL mutant\",\n      \"pmids\": [\"27657451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length receptor or ligand-bound structure\", \"How PLL domain physically restrains the GAIN/tethered agonist not visualized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established a cell-autonomous CNS myelination role through Gα12/13-RhoA, extending GPR56 function beyond neurons to oligodendrocyte lineage.\",\n      \"evidence\": \"Zebrafish mutants, global and OPC/microglia/astrocyte/neuron-specific conditional Gpr56 KO, OPC proliferation and active-RhoA assays\",\n      \"pmids\": [\"25607772\", \"25607655\", \"32902916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"OPC ligand not identified in these studies\", \"Coupling of RhoA to proliferation program undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed GPR56 restrains cytotoxic lymphocytes, defining an immune checkpoint function executed via tetraspanin association.\",\n      \"evidence\": \"Patient NK cells, NK-92 ectopic expression, GPR56-CD81 Co-IP, cytotoxicity/degranulation assays\",\n      \"pmids\": [\"27184850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activating ligand on NK cells unknown\", \"Downstream signaling restraining cytotoxicity not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified TG2/laminin as a physiological OPC agonist and demonstrated therapeutic relevance for remyelination.\",\n      \"evidence\": \"Microglia-OPC co-culture, TG2/laminin stimulation, Gpr56 KO, two demyelination models\",\n      \"pmids\": [\"29809138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why laminin cofactor is required not mechanistically resolved at receptor level\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended myelin function to the PNS and identified plectin as a cytoskeletal interactor, linking GPR56 to Schwann cell radial sorting.\",\n      \"evidence\": \"Zebrafish/rodent mutants, RhoA assay, immunofluorescence localization, plectin-GPR56 Co-IP\",\n      \"pmids\": [\"29367382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Plectin interaction not reciprocally/structurally validated\", \"Connection of plectin binding to RhoA output unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Unified ligand classes by showing collagen III and TG2/laminin both require GAIN cleavage and NTF dissociation, whereas small-molecule/peptide agonists bypass NTF release.\",\n      \"evidence\": \"Non-cleavable receptor engineering with collagen III, TG2, laminin, 3-α-DOG, P19 peptide and NTF/CTF dissociation assays\",\n      \"pmids\": [\"31628191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo proof that NTF dissociation occurs at endogenous receptor levels lacking\", \"Exact ligand contact sites for dissociation not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed an isoform-specific microglial function: phosphatidylserine-triggered GPR56 drives synaptic pruning.\",\n      \"evidence\": \"Microglia-specific conditional KO, domain-specific PS binding, synapse density and engulfment assays, isoform analysis\",\n      \"pmids\": [\"32452062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"G protein pathway downstream of PS engagement not defined\", \"How alternative splicing tunes ligand specificity unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established GPR56 as the platelet mechanosensor coupling collagen and shear force to Gα13 for hemostasis.\",\n      \"evidence\": \"Gpr56-/- bleeding, plug formation, thrombosis models, collagen perfusion under shear, human plasma NTF detection\",\n      \"pmids\": [\"33097663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor of shear within the receptor not pinpointed\", \"Relative contribution of collagen vs shear not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected microglial GPR56 to interneuron development and maternal-immune-activation autism phenotypes via an IL-17a/TNF-α axis.\",\n      \"evidence\": \"Microglial conditional KO, MIA model, IL-17a neutralization, TNF-α measurement, genetic rescue, behavior\",\n      \"pmids\": [\"35544642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor ligand in this context unidentified\", \"Direct link from GPR56 signaling to TNF-α suppression not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a steroid agonist and a ferroptosis-protective mechanism, showing GPR56 promotes endocytic-lysosomal degradation of CD36 to limit PUFA-phospholipids.\",\n      \"evidence\": \"Gpr56 KO liver injury models, CD36 endocytosis/degradation assays, phospholipidomics, steroid screen identifying 17-OH PREG, disease-mutant signaling\",\n      \"pmids\": [\"39389061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How receptor activation drives CD36 endocytosis mechanistically unclear\", \"Physiological source of 17-OH PREG agonist in vivo not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a microglial GPR56-MYC transcriptional program required for amyloid-β clearance, implicating the receptor in Alzheimer's pathology.\",\n      \"evidence\": \"Microglial conditional KO in 5xFAD, transcriptomics, MYC pathway analysis, Aβ phagocytosis in mouse and hESC-derived microglia, cognition\",\n      \"pmids\": [\"40713954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand triggering microglial GPR56 in AD unknown\", \"Signaling steps from receptor to MYC activation not delineated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single receptor selects among Gα12/13-RhoA, Gαq/11, Gαi-cAMP/PKA, Src-FAK, and MYC outputs in a tissue- and ligand-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking specific ligands/isoforms to specific G protein branches\", \"Structure of an activated, ligand-engaged full-length receptor lacking\", \"In vivo demonstration of NTF dissociation at endogenous receptor not achieved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 8, 15, 17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [6, 28]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5, 8, 40]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8, 21, 34]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 9, 10, 23]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [24, 36]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [33, 37]}\n    ],\n    \"complexes\": [\"GPR56-CD9-CD81-Gαq/11 tetraspanin complex\"],\n    \"partners\": [\"CD81\", \"CD9\", \"GNAQ\", \"GNA11\", \"TG2\", \"COL3A1\", \"PLEC\", \"ITGA3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}