Affinage

ADGRG1

Adhesion G-protein coupled receptor G1 · UniProt Q9Y653

Length
693 aa
Mass
77.7 kDa
Annotated
2026-06-09
100 papers in source corpus 47 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2004 High

    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

    PMID:15004227

    Open questions at the time
    • Did not establish which physiological stimulus engages the complex
    • Functional consequence of tetraspanin scaffolding not yet linked to a phenotype
  2. 2006 High

    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

    PMID:16757564

    Open questions at the time
    • Binding interface and signaling output undefined
    • Whether TG2 acts as agonist or antagonist unresolved at this stage
  3. 2007 High

    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

    PMID:17576745

    Open questions at the time
    • How cleavage relates to activation not yet established
    • Surface-expressed mutant signaling not tested here
  4. 2008 High

    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

    PMID:18378689 PMID:18509043

    Open questions at the time
    • Endogenous brain ligand not yet identified
    • Mechanism of NTF/CTF coupling to G protein activation unknown
  5. 2011 High

    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

    PMID:21708946

    Open questions at the time
    • The tethered agonist sequence not yet defined
    • How natural ligands trigger NTF removal not shown
  6. 2011 Medium

    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

    PMID:21349848 PMID:28424266

    Open questions at the time
    • Single-lab pathway dissection
    • Physiological relevance of NFAT/Gβγ branch in brain not established
  7. 2012 High

    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

    PMID:19515912 PMID:22238662 PMID:23001883

    Open questions at the time
    • How collagen III binding is transduced to G proteins not yet resolved
    • N-glycosylation dispensable but other modifications untested
  8. 2014 High

    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

    PMID:24949629

    Open questions at the time
    • Stoichiometry/kinetics of NTF release not quantified
    • Whether raft entry is cause or consequence of activation unclear
  9. 2016 High

    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

    PMID:27657451

    Open questions at the time
    • No full-length receptor or ligand-bound structure
    • How PLL domain physically restrains the GAIN/tethered agonist not visualized
  10. 2015 High

    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

    PMID:25607655 PMID:25607772 PMID:32902916

    Open questions at the time
    • OPC ligand not identified in these studies
    • Coupling of RhoA to proliferation program undefined
  11. 2016 High

    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

    PMID:27184850

    Open questions at the time
    • Activating ligand on NK cells unknown
    • Downstream signaling restraining cytotoxicity not mapped
  12. 2018 High

    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

    PMID:29809138

    Open questions at the time
    • Why laminin cofactor is required not mechanistically resolved at receptor level
  13. 2018 High

    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

    PMID:29367382

    Open questions at the time
    • Plectin interaction not reciprocally/structurally validated
    • Connection of plectin binding to RhoA output unclear
  14. 2019 High

    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

    PMID:31628191

    Open questions at the time
    • In vivo proof that NTF dissociation occurs at endogenous receptor levels lacking
    • Exact ligand contact sites for dissociation not mapped
  15. 2020 High

    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

    PMID:32452062

    Open questions at the time
    • G protein pathway downstream of PS engagement not defined
    • How alternative splicing tunes ligand specificity unclear
  16. 2020 High

    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

    PMID:33097663

    Open questions at the time
    • Molecular sensor of shear within the receptor not pinpointed
    • Relative contribution of collagen vs shear not separated
  17. 2022 High

    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

    PMID:35544642

    Open questions at the time
    • Receptor ligand in this context unidentified
    • Direct link from GPR56 signaling to TNF-α suppression not mechanistically resolved
  18. 2024 High

    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

    PMID:39389061

    Open questions at the time
    • How receptor activation drives CD36 endocytosis mechanistically unclear
    • Physiological source of 17-OH PREG agonist in vivo not established
  19. 2025 High

    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

    PMID:40713954

    Open questions at the time
    • Ligand triggering microglial GPR56 in AD unknown
    • Signaling steps from receptor to MYC activation not delineated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098631 cell adhesion mediator activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0008092 cytoskeletal protein binding 1 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-109582 Hemostasis 1
Partners
CD81CD9COL3A1GNA11GNAQITGA3PLECTG2
Complex memberships
GPR56-CD9-CD81-Gαq/11 tetraspanin complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. Binding assay (GPR56-TG2 interaction), xenograft tumor models with GPR56 overexpression/knockdown Proceedings of the National Academy of Sciences of the United States of America High 16757564
2004 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. Co-immunoprecipitation, immunodepletion/reexpression of CD81, cholesterol depletion resistance assay Molecular biology of the cell High 15004227
2008 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). Reporter assays (SRE-luciferase, NF-κB-luciferase), actin staining, dominant-negative Rho, C3 exoenzyme treatment, agonistic antibody, GPR56 knockdown The Journal of biological chemistry High 18378689
2008 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. Gpr56 knockout mouse analysis, immunohistochemistry, time-course analysis of pial BM integrity The Journal of neuroscience : the official journal of the Society for Neuroscience High 18509043
2007 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. Biochemical characterization (Western blot, N-glycosylation analysis), cell trafficking assays, pharmacological chaperone rescue Human molecular genetics High 17576745
2011 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. 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 The Journal of biological chemistry High 21708946
2012 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. Gpr56 knockout mouse cerebellar analysis, siRNA knockdown, GPR56 re-expression rescue of adhesion defect, ligand-probe binding assay The Journal of neuroscience : the official journal of the Society for Neuroscience / PloS one (review citing original data) High 19515912 23001883
2012 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. Truncation and mutation analysis with collagen III binding assay, N-glycosylation blocking PloS one High 22238662
2014 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. Ligand stimulation assay, lipid raft fractionation, RhoA activation assay, L640R mutant analysis PloS one High 24949629
2015 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. Zebrafish gpr56 mutants, Gpr56 knockout mice, OPC proliferation assay, active RhoA measurement Nature communications High 25607655 25607772
2015 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. Cell-type-specific conditional knockout mice (OPC, microglia, astrocyte, neuron-specific Cre lines), myelin analysis Nature communications / Glia High 25607655 32902916
2016 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. Crystal structure determination (X-ray crystallography), monobody complex, PLL domain deletion mutant signaling assay, in vivo OL development with PLL mutant Neuron High 27657451
2015 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. Stalkless receptor engineering, TGFα shedding assay, NFAT luciferase, SRF luciferase, β-arrestin recruitment assay The Journal of biological chemistry Medium 26710850
2017 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. Monobody generation, signaling assays with autoproteolysis-defective GPR56 mutant, luciferase reporter assays Proceedings of the National Academy of Sciences of the United States of America Medium 28874577
2018 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. Cell co-culture (microglia-OPC), TG2/laminin stimulation assays, Gpr56 KO OPC proliferation, demyelination/remyelination mouse models eLife High 29809138
2019 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. Non-cleavable receptor engineering, ligand stimulation assays with collagen III, TG2, laminin, 3-α-DOG, and P19 peptide; NTF/CTF dissociation assays The Journal of biological chemistry High 31628191
2020 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. Microglia-specific conditional Gpr56 KO, PS-GPR56 binding assay (domain-specific), synaptic density quantification, microglial engulfment assay, isoform-specific analysis The EMBO journal High 32452062
2020 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. Gpr56-/- mouse bleeding assays, platelet plug formation assay, thrombotic occlusion model, blood perfusion assay with immobilized collagen, free NTF detection in human plasma Proceedings of the National Academy of Sciences of the United States of America High 33097663
2013 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. Xenograft studies in immunodeficient Tg2-/- mice, TG2 internalization assay, fibronectin deposition assay, FAK immunostaining Cancer research Medium 24356421
2011 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. VEGF ELISA, angiogenesis assays, PKCα pathway analysis, fragment-specific overexpression Cancer research Medium 21724588
2014 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. GPR56 splice form analysis, deletion mutant of regulatory element (15-bp deletion), progenitor proliferation assay, RFX transcription factor binding assay Science (New York, N.Y.) Medium 24531968
2011 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. Luciferase reporter assays (SRF, NFAT), surface expression analysis, dominant-negative G protein subunits, calcium channel blockers The Journal of biological chemistry / The Journal of biological chemistry (2017) Medium 21349848 28424266
2013 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. Gpr56/α3 integrin double knockout mice, cortical phenotype analysis, time-course of neuronal overmigration PloS one Medium 23874761
2018 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. Zebrafish and rodent gpr56 mutants/KO, RhoA activation assay, GPR56 localization by immunofluorescence, Co-IP of plectin-GPR56 The Journal of experimental medicine High 29367382
2016 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. NK cells from ADGRG1 mutant patients, NK-92 ectopic expression, Co-IP of GPR56-CD81, cytotoxicity assays, degranulation assays Cell reports High 27184850
2016 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. GPR56 knockdown/overexpression in GBM cells and glioma-initiating cells, NF-κB reporter assay, in vivo tumor models, radioresistance assay Cell reports Medium 29166609
2020 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. Site-directed mutagenesis, binding affinity measurement (surface plasmon resonance or similar), monobody blocking assay Scientific reports Medium 33037308
2015 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. PCBP2 KD/overexpression, GPR56 mRNA stability assay, GPR56 KD in cardiomyocytes, cell size and protein synthesis measurement Biochemical and biophysical research communications Low 26116532
2016 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. Truncation/mutant GPR56 binding assays, receptor shedding assay, cell adhesion/motility assays Journal of cell science Medium 27068534
2018 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. High-throughput compound screen, SRE-luciferase reporter, engineered low-activity GPR56 7TM, dose-response assays, peptide antagonism assay Molecular pharmacology Medium 29476042
2013 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. RNA-seq of aortic HSCs/HECs/ECs, Gpr56 morpholino/KD in zebrafish, heptad complex ChIP/transcription factor binding assay The Journal of experimental medicine Medium 25547674
2019 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. GPR56 KD/KO in colon cancer cells, MDR1 expression assay, RhoA activation assay, drug resistance assay (irinotecan, 5-FU), tumor xenograft Molecular cancer research : MCR Medium 31444231
2022 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. Microglial conditional Gpr56 KO, MIA mouse model, IL-17a neutralization, TNF-α measurement, PV+ interneuron counting, behavioral assays, Gpr56 genetic rescue Science advances High 35544642
2024 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. Gpr56 KO mice (doxorubicin/ischemia-reperfusion liver injury models), CD36 endocytosis/degradation assays, phospholipidomics, steroid hormone screen, mutant receptor signaling assays Cell metabolism High 39389061
2021 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. GPR56 overexpression, monoclonal antibody treatment, Src/Fak/paxillin phosphorylation (Western blot), RhoA inhibition, SRF luciferase, deletion mutant analysis, GPR56 KD in CRC cells The Journal of biological chemistry Medium 33837725
2023 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. Gpr56 KO diabetic mice (albuminuria, glomerular injury), GEC overexpression of GPR56, eNOS phosphorylation/expression assays, RhoA activation, cAMP/PKA pathway assays Diabetes Medium 37579299
2025 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. Microglial conditional Adgrg1 KO in 5xFAD mice, transcriptomic analysis, MYC pathway analysis, Aβ phagocytosis assay in mouse and hESC-derived microglia, cognitive behavioral assays Neuron High 40713954
2016 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. Collagen III stimulation of WT and ADGRG1-KD β-cells/islets, thymidine incorporation, caspase 3/7 activity, RhoA activity, cAMP/PKA pathway analysis The Journal of clinical endocrinology and metabolism Medium 27636017
2016 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. Immobilized antibody stimulation, NTF dissociation assay, CD9/CD81 KD, IL-6 ELISA, migration assay, CTF expression, Gα12/13/RhoA inhibition The Journal of investigative dermatology Medium 27818281
2010 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. Gpr56 knockout mouse analysis, histology of seminiferous tubules, fertility testing Developmental dynamics : an official publication of the American Association of Anatomists Medium 20981830
2021 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. SNAP-tag super-resolution/confocal microscopy, CRISPR-Cas9 GPR56 deletion, calcium microfluorimetry, insulin secretion RIA, caspase 3/7 apoptosis assay Molecular metabolism Medium 34224919
2013 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. Gpr56 KO mice, GPR56 KD in AML cells, RhoA activity assay, HSC bone marrow/peripheral counts, in vivo repopulation assay Leukemia Medium 23478665
2020 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. In ovo electroporation KD, GPR56 overexpression in vitro, immunofluorescence for duct markers, proliferation/migration assays The Journal of endocrinology Medium 31829965
2020 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. GPR56 siRNA KD, androgen receptor nuclear translocation assay, PSA transcription assay, Rho activation assay, cAMP/PKA measurement upon testosterone stimulation PloS one Low 32881870

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America 227 16757564
2008 GPR56 regulates pial basement membrane integrity and cortical lamination. The Journal of neuroscience : the official journal of the Society for Neuroscience 188 18509043
2008 Orphan G protein-coupled receptor GPR56 regulates neural progenitor cell migration via a G alpha 12/13 and Rho pathway. The Journal of biological chemistry 169 18378689
2004 Dynamic regulation of a GPCR-tetraspanin-G protein complex on intact cells: central role of CD81 in facilitating GPR56-Galpha q/11 association. Molecular biology of the cell 165 15004227
2016 GPR56 identifies primary human acute myeloid leukemia cells with high repopulating potential in vivo. Blood 162 26834243
2014 Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning. Science (New York, N.Y.) 162 24531968
2020 A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding. The EMBO journal 155 32452062
2011 The N terminus of the adhesion G protein-coupled receptor GPR56 controls receptor signaling activity. The Journal of biological chemistry 155 21708946
2005 GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion. Oncogene 143 15674329
2018 Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells. eLife 124 29809138
2015 The adhesion GPCR Gpr56 regulates oligodendrocyte development via interactions with Gα12/13 and RhoA. Nature communications 122 25607772
2015 The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development. Nature communications 117 25607655
2015 Stalk-dependent and Stalk-independent Signaling by the Adhesion G Protein-coupled Receptors GPR56 (ADGRG1) and BAI1 (ADGRB1). The Journal of biological chemistry 112 26710850
2011 Specific expression of GPR56 by human cytotoxic lymphocytes. Journal of leukocyte biology 110 21724806
2014 Whole-transcriptome analysis of endothelial to hematopoietic stem cell transition reveals a requirement for Gpr56 in HSC generation. The Journal of experimental medicine 105 25547674
2022 Single cell sequencing identifies clonally expanded synovial CD4+ TPH cells expressing GPR56 in rheumatoid arthritis. Nature communications 102 35831277
2016 Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains. Neuron 102 27657451
2007 Disease-associated mutations affect GPR56 protein trafficking and cell surface expression. Human molecular genetics 99 17576745
2011 GPR56 Regulates VEGF production and angiogenesis during melanoma progression. Cancer research 94 21724588
2016 The Adhesion G Protein-Coupled Receptor GPR56/ADGRG1 Is an Inhibitory Receptor on Human NK Cells. Cell reports 93 27184850
2020 GPR56/ADGRG1 is a platelet collagen-responsive GPCR and hemostatic sensor of shear force. Proceedings of the National Academy of Sciences of the United States of America 86 33097663
1999 TM7XN1, a novel human EGF-TM7-like cDNA, detected with mRNA differential display using human melanoma cell lines with different metastatic potential. FEBS letters 76 10100861
2009 GPR56-regulated granule cell adhesion is essential for rostral cerebellar development. The Journal of neuroscience : the official journal of the Society for Neuroscience 75 19515912
2019 Killer-like receptors and GPR56 progressive expression defines cytokine production of human CD4+ memory T cells. Nature communications 74 31118448
2013 Maintenance of the hematopoietic stem cell pool in bone marrow niches by EVI1-regulated GPR56. Leukemia 73 23478665
2017 Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region. Proceedings of the National Academy of Sciences of the United States of America 72 28874577
2011 Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms. The Journal of biological chemistry 72 21349848
1999 GPR56, a novel secretin-like human G-protein-coupled receptor gene. Genomics 72 10049584
2017 GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma. Cell reports 67 29166609
2013 GPR56 inhibits melanoma growth by internalizing and degrading its ligand TG2. Cancer research 60 24356421
2018 Gedunin- and Khivorin-Derivatives Are Small-Molecule Partial Agonists for Adhesion G Protein-Coupled Receptors GPR56/ADGRG1 and GPR114/ADGRG5. Molecular pharmacology 58 29476042
2016 Adhesion G Protein-Coupled Receptor G1 (ADGRG1/GPR56) and Pancreatic β-Cell Function. The Journal of clinical endocrinology and metabolism 58 27636017
2012 Disease-associated mutations prevent GPR56-collagen III interaction. PloS one 58 22238662
2007 Orphan G protein-coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway. Molecular cancer therapeutics 58 17575113
2018 GPR56/ADGRG1 regulates development and maintenance of peripheral myelin. The Journal of experimental medicine 56 29367382
2014 Mechanism for adhesion G protein-coupled receptor GPR56-mediated RhoA activation induced by collagen III stimulation. PloS one 56 24949629
2019 GAIN domain-mediated cleavage is required for activation of G protein-coupled receptor 56 (GPR56) by its natural ligands and a small-molecule agonist. The Journal of biological chemistry 55 31628191
2018 GPR56 promotes proliferation of colorectal cancer cells and enhances metastasis via epithelial‑mesenchymal transition through PI3K/AKT signaling activation. Oncology reports 48 30066935
2012 GPR56 and the developing cerebral cortex: cells, matrix, and neuronal migration. Molecular neurobiology 48 23001883
2018 The adhesion receptor GPR56 is activated by extracellular matrix collagen III to improve β-cell function. Cellular and molecular life sciences : CMLS 47 29855662
2016 Heparin interacts with the adhesion GPCR GPR56, reduces receptor shedding, and promotes cell adhesion and motility. Journal of cell science 47 27068534
2019 GPR56 Drives Colorectal Tumor Growth and Promotes Drug Resistance through Upregulation of MDR1 Expression via a RhoA-Mediated Mechanism. Molecular cancer research : MCR 45 31444231
2010 GPR56 is essential for testis development and male fertility in mice. Developmental dynamics : an official publication of the American Association of Anatomists 44 20981830
2007 GPR56 and TG2: possible roles in suppression of tumor growth by the microenvironment. Cell cycle (Georgetown, Tex.) 44 17314516
2019 Adipose Tissue in Persons With HIV Is Enriched for CD4+ T Effector Memory and T Effector Memory RA+ Cells, Which Show Higher CD69 Expression and CD57, CX3CR1, GPR56 Co-expression With Increasing Glucose Intolerance. Frontiers in immunology 43 30941121
2013 GPR56 functions together with α3β1 integrin in regulating cerebral cortical development. PloS one 42 23874761
2021 The role of GPR56/ADGRG1 in health and disease. Biomedical journal 40 34654683
2016 GPR56/ADGRG1 Activation Promotes Melanoma Cell Migration via NTF Dissociation and CTF-Mediated Gα12/13/RhoA Signaling. The Journal of investigative dermatology 40 27818281
2015 The RNA-binding protein PCBP2 inhibits Ang II-induced hypertrophy of cardiomyocytes though promoting GPR56 mRNA degeneration. Biochemical and biophysical research communications 40 26116532
2008 Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations. Epilepsia 40 19016831
2022 Microglial GPR56 is the molecular target of maternal immune activation-induced parvalbumin-positive interneuron deficits. Science advances 39 35544642
2009 GPR56 as a novel marker identifying the CD56dull CD16+ NK cell subset both in blood stream and in inflamed peripheral tissues. International immunology 39 20008459
2016 GPR56 contributes to the development of acute myeloid leukemia in mice. Leukemia 36 27063597
2024 Sensing steroid hormone 17α-hydroxypregnenolone by GPR56 enables protection from ferroptosis-induced liver injury. Cell metabolism 34 39389061
2010 Splicing variants of the orphan G-protein-coupled receptor GPR56 regulate the activity of transcription factors associated with tumorigenesis. Journal of cancer research and clinical oncology 33 19572147
2015 Agonistic antibodies reveal the function of GPR56 in human glioma U87-MG cells. Biological & pharmaceutical bulletin 32 25832639
2017 Bi-allelic variants in COL3A1 encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts. Journal of medical genetics 31 28258187
2010 Clinical significance of GPR56, transglutaminase 2, and NF-κB in esophageal squamous cell carcinoma. Cancer investigation 31 20874003
2019 High GPR56 surface expression correlates with a leukemic stem cell gene signature in CD34-positive AML. Cancer medicine 30 30848055
2018 The Adhesion G-Protein-Coupled Receptor, GPR56/ADGRG1, Inhibits Cell-Extracellular Matrix Signaling to Prevent Metastatic Melanoma Growth. Frontiers in oncology 29 29450192
2017 Disease-associated extracellular loop mutations in the adhesion G protein-coupled receptor G1 (ADGRG1; GPR56) differentially regulate downstream signaling. The Journal of biological chemistry 29 28424266
2010 GPR56 plays varying roles in endogenous cancer progression. Clinical & experimental metastasis 29 20333450
2012 GPR56 in cancer progression: current status and future perspective. Future oncology (London, England) 28 22515446
2023 An antibody-drug conjugate targeting GPR56 demonstrates efficacy in preclinical models of colorectal cancer. British journal of cancer 27 36759728
2011 A novel GPR56 mutation causes bilateral frontoparietal polymicrogyria. Pediatric neurology 27 21723461
2007 Biochemical characterization of genetic mutations of GPR56 in patients with bilateral frontoparietal polymicrogyria (BFPP). Biochemical and biophysical research communications 27 18042463
2021 Role of ADGRG1/GPR56 in Tumor Progression. Cells 26 34943858
2018 The Activation and Signaling Mechanisms of GPR56/ADGRG1 in Melanoma Cell. Frontiers in oncology 26 30135857
2007 Characterization of GPR56 protein and its suppressed expression in human pancreatic cancer cells. Molecular and cellular biochemistry 26 17932623
2021 ADGRG1 enriches for functional human hematopoietic stem cells following ex vivo expansion-induced mitochondrial oxidative stress. The Journal of clinical investigation 25 34464351
2021 Anti-GPR56 monoclonal antibody potentiates GPR56-mediated Src-Fak signaling to modulate cell adhesion. The Journal of biological chemistry 23 33837725
2020 GPR56: An adhesion GPCR involved in brain development, neurological disorders and cancer. Brain research 23 32798453
2017 Expression of orphan GPR56 correlates with tumor progression in human epithelial ovarian cancer. Neoplasma 23 27881002
2015 High-level Gpr56 expression is dispensable for the maintenance and function of hematopoietic stem and progenitor cells in mice. Stem cell research 23 25840412
2020 Cell type-specific evaluation of ADGRG1/GPR56 function in developmental central nervous system myelination. Glia 21 32902916
2023 GPR56 Promotes Diabetic Kidney Disease Through eNOS Regulation in Glomerular Endothelial Cells. Diabetes 20 37579299
2022 The Novel Immune Checkpoint GPR56 Is Expressed on Tumor-Infiltrating Lymphocytes and Selectively Upregulated upon TCR Signaling. Cancers 20 35804934
2017 High levels of soluble GPR56/ADGRG1 are associated with positive rheumatoid factor and elevated tumor necrosis factor in patients with rheumatoid arthritis. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi 20 28690029
2009 GPR56 is highly expressed in neural stem cells but downregulated during differentiation. Neuroreport 20 19525879
2009 GPR56 and its related diseases. Progress in molecular biology and translational science 20 20374731
2021 Unexpected redundancy of Gpr56 and Gpr97 during hematopoietic cell development and differentiation. Blood advances 18 33560396
2021 Crucial contribution of GPR56/ADGRG1, expressed by breast cancer cells, to bone metastasis formation. Cancer science 18 34632664
2020 Specific and direct modulation of the interaction between adhesion GPCR GPR56/ADGRG1 and tissue transglutaminase 2 using synthetic ligands. Scientific reports 17 33037308
2013 Compound heterozygosity in GPR56 with bilateral frontoparietal polymicrogyria. Brain & development 17 23981349
2020 Activation of GPR56, a novel adhesion GPCR, is necessary for nuclear androgen receptor signaling in prostate cells. PloS one 16 32881870
2018 Suppression of GPR56 expression by pyrrole-imidazole polyamide represents a novel therapeutic drug for AML with high EVI1 expression. Scientific reports 14 30214063
2015 Bilateral frontoparietal polymicrogyria: a novel GPR56 mutation and an unusual phenotype. Neuropediatrics 14 25642806
2023 CD4+ T cells expressing CX3CR1, GPR56, with variable CD57 are associated with cardiometabolic diseases in persons with HIV. Frontiers in immunology 13 36865544
2020 Adhesion G-protein-coupled receptor, GPR56, is required for Müllerian duct development in the chick. The Journal of endocrinology 13 31829965
2024 GPR56 facilitates hepatocellular carcinoma metastasis by promoting the TGF-β signaling pathway. Cell death & disease 12 39353900
2017 Three Mutations in the Bilateral Frontoparietal Polymicrogyria Gene GPR56 in Pakistani Intellectual Disability Families. Journal of pediatric genetics 12 29707406
2015 GPR56-Related Polymicrogyria: Clinicoradiologic Profile of 4 Patients. Journal of child neurology 12 25922261
2023 The adhesion G protein-coupled receptor GPR56/ADGRG1 in cytotoxic lymphocytes. Basic & clinical pharmacology & toxicology 11 36750420
2022 Multi-Omics Analysis of Glioblastoma and Glioblastoma Cell Line: Molecular Insights Into the Functional Role of GPR56 and TG2 in Mesenchymal Transition. Frontiers in oncology 11 35600402
2021 SNAP-tag-enabled super-resolution imaging reveals constitutive and agonist-dependent trafficking of GPR56 in pancreatic β-cells. Molecular metabolism 11 34224919
2007 Stress and electroconvulsive seizure differentially alter GPR56 expression in the adult rat brain. Brain research 11 17945200
2021 Adhesion GPCR GPR56 Expression Profiling in Human Tissues. Cells 10 34944065
2014 Expression and immunoaffinity purification of recombinant soluble human GPR56 protein for the analysis of GPR56 receptor shedding by ELISA. Protein expression and purification 10 25437104
2023 Identification and clinical characteristics of a novel missense ADGRG1 variant in bilateral Frontoparietal Polymicrogyria: The electroclinical change from infancy to adulthood after Callosotomy in three siblings. Epilepsia open 9 36524291
2025 G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation. Neuron 8 40713954

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