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ADGRG1

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Target id: 186

Nomenclature: ADGRG1

Family: Adhesion Class GPCRs

Contents:

Gene and Protein Information Click here for help
Adhesion G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 693 16q21 ADGRG1 adhesion G protein-coupled receptor G1 20
Mouse 7 687 8 47.12 cM Adgrg1 adhesion G protein-coupled receptor G1
Rat 7 687 19p13 Adgrg1 adhesion G protein-coupled receptor G1
Previous and Unofficial Names Click here for help
BFPP | Cyt28 | GPR56 (G-protein coupled receptor 56) | TM7LN4 | TM7XN1
Database Links Click here for help
Specialist databases
GPCRdb gpr56_human (Hs), agrg1_mouse (Mm), gpr56_rat (Rn)
Other databases
Alphafold Q9Y653 (Hs), Q8K209 (Mm), Q8K3V3 (Rn)
ChEMBL Target CHEMBL4523929 (Hs)
Ensembl Gene ENSG00000205336 (Hs), ENSMUSG00000031785 (Mm), ENSRNOG00000014963 (Rn)
Entrez Gene 9289 (Hs), 14766 (Mm), 260326 (Rn)
Human Protein Atlas ENSG00000205336 (Hs)
KEGG Gene hsa:9289 (Hs), mmu:14766 (Mm), rno:260326 (Rn)
OMIM 604110 (Hs)
Orphanet ORPHA122266 (Hs)
Pharos Q9Y653 (Hs)
RefSeq Nucleotide NM_005682 (Hs), NM_018882 (Mm), NM_152242 (Rn)
RefSeq Protein NP_005673 (Hs), NP_061370 (Mm), NP_689448 (Rn)
UniProtKB Q9Y653 (Hs), Q8K209 (Mm), Q8K3V3 (Rn)
Wikipedia ADGRG1 (Hs)
Associated Protein Comments
Extracellular interactors: heparin [8].
Endogenous agonists
Peptides derived from the Stachel sequence: TYFAVLM  [33]
Agonist Comments
ADGRG1 has been shown to be activated by collagen III (COL3A1) [21] and transglutaminase 2 [37]. Human collagen III activates mouse and human ADGRG1 equally at a concentration of 84 nM [21]. The TYFAVLM peptide derived from the Stachel sequence has agonist activity [33]. 3-α-acetoxydihydrodeoxygedunin (PubChem CID 6708514) is a partial agonist at ADGRG1 [34].
Antagonist Comments
Dihydromunduletone (PubChem CID 3492326), a rotenoid derivative, is an antagonist at ADGRG1 [32].
Immunopharmacology Comments
An association between ADGRG1 and the tetraspanin CD81, negatively regulates the immediate effector functions (inflammatory cytokine and cytolytic protein production, degranulation, target cell killing) of mature NK cells [6].
Cell Type Associations
Immuno Cell Type:  T cells
Cell Ontology Term:   CD4-positive, alpha-beta T cell (CL:0000624)
Comment:  ADGRG1 is expressed by CD8+, CD4+ and γδ T cells.
References:  25
Immuno Cell Type:  Natural killer cells
Cell Ontology Term:   mature NK T cell (CL:0000814)
Comment:  ADGRG1 is expressed by mature NK cells and negatively regulates their natural cytotoxicity.
References:  6,25
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gq/G11 family
G12/G13 family 		Other - See Comments
Comments:  Activation of G12/13 leads to the corresponding phosphorylation of RhoGDP to RhoGTP. The downstream effectors of Gq/11 are unknown [31].
References:  21,31
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Other - See Comments
Comments:  In melanoma cells, GPR56C activates protein kinase C alpha (PKCα), which increases the expression of VEGF [31].
References:  31
Tissue Distribution Click here for help
Cytotoxic NK and T cells
Species:  Human
Technique:  Flow cytometry
References:  6,9,23,25,36
Tumor tissues, cancer cell lines, expression levels correlate inversely with the malignancy of melanomas
Species:  Human
Technique:  Western blot, Northern blot and immunohistochemistry
References:  12,15,30,39-40
Wide distribution with highest expression levels in brain, thyroid gland and heart, particularly high expression in hippocampus and hypothalamic nuclei
Species:  Human
Technique:  Northern blot, in situ hybridisation and EST
References:  4-5,20
Widely expressed. Highest in thyroid, testis, heart, brain, placenta, lung.
Species:  Human
Technique:  Northern blotting.
References:  20
Neural, hematopoietic and mesenchymal stem cells
Species:  Human
Technique:  Immunocytochemistry
References:  3,39
Testis Sertoli cells
Species:  Mouse
Technique:  Immunohistochemistry and in situ hybridisation
References:  7
Developing cortex (radial glia, neural progenitor cells) and cerebellum
Species:  Mouse
Technique:  Immunohistochemistry and in situ hybridisation
References:  3,13-14,17,19,27,41
Neural progenitor cells in adult brain after stress and electroconvulsive seizure
Species:  Rat
Technique:  Immunohistochemistry
References:  35
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Inhibits neuronal migration in the presence of collagen III, demonstrated by migration assay
Species:  Mouse
Tissue:  Brain
Response measured:  Neuronal migration
References:  21
Inhibits sponataneous and chemokine-induced migration, demonstrated by migration assay
Species:  Human
Tissue:  NK cells
Response measured:  Sponataneous and chemokine-induced migration
References:  25
ADGRG1 couples to G13 proteins.
Species:  Human
Tissue:  Exogenous expression system.
Response measured:  GTPγS binding.
References:  33
Physiological Functions Click here for help
Brain development, cortical patterning
Species:  Human
Tissue:  Brain
References:  2,22,24,26-28
Brain development, cortical patterning
Species:  Mouse
Tissue:  Brain
References:  17,19,21
Angiogenesis
Species:  Human
Tissue:  Melanoma
References:  39
Neural stem cells
Species:  Human
Tissue:  Brain
References:  3
Cerebellar development
Species:  Mouse
Tissue:  Cerebellum
References:  17
Tumor growth suppression
Species:  Human
Tissue:  Melanoma cell line
References:  38
ADGRG1 negatively regulates immediate effector functions in human NK cells.
Species:  Human
Tissue:  NK cells.
References:  6
Physiological Consequences of Altering Gene Expression Click here for help
Expression of Adgrg1 is inversely proportional to the metastatic potential of human melanoma cell lines.
Species:  Mouse
Tissue: 
Technique: 
References:  37,40
Male-specific sterility, malformation of male gonad
Species:  Mouse
Tissue:  Full KO, embryo examined
Technique:  Gene knockouts
References:  7
Cobblestone lissencephaly, cerebellar malformation
Species:  Mouse
Tissue:  Full KO, embryo examined
Technique:  Gene knockouts
References:  17,19
Cell type-specific ADGRG1 deficiency leads to dysregulation of central and peripheral myelination, in zebrafish and rodent models.
Species:  Mouse
Tissue: 
Technique: 
References:  1,11
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr56tm1Lex Gpr56tm1Lex/Gpr56tm1Lex
involves: 129 * BALB/c * C57BL/6 * FVB/N		 MGI:1340051  MP:0008030 abnormal Cajal-Retzius cell morphology PMID: 18509043 
Gpr56tm1Lex Gpr56tm1Lex/Gpr56tm1Lex
involves: 129 * BALB/c * C57BL/6 * FVB/N		 MGI:1340051  MP:0000788 abnormal cerebral cortex morphology PMID: 18509043 
Gpr56tm1Lex Gpr56tm1Lex/Gpr56tm1Lex
involves: 129 * BALB/c * C57BL/6 * FVB/N		 MGI:1340051  MP:0006009 abnormal neuronal migration PMID: 18509043 
Gpr56tm1Lex Gpr56tm1Lex/Gpr56tm1Lex
involves: 129 * BALB/c * C57BL/6 * FVB/N		 MGI:1340051  MP:0003648 abnormal radial glial cell morphology PMID: 18509043 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Bilateral frontoparietal polymicrogyria
OMIM: 606854
Orphanet: ORPHA101070
Comments:  A human brain cortical malformation called bilateral frontoparietal polymicrogyria cortex is associated with one of eleven different mutations of ADGRG1.
References:  2,22,24,26-28
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Frameshift: Deletion Human D224WfsX96 c.671delA Exon 5. Between STP/GPS 2
Frameshift: Deletion Human c.739_746delCAGGACC Exon 5; between STP/GPS 27
Frameshift: Insertion Human E56RfsX24 c.174_175insC Ligand binding domain 2
Missense Human R33P c.97C>G Ligand binding domain 24
Missense Human R38W c.112C>T Ligand binding domain 26-27
Missense Human R38Q c.113G>A Nucleotide transition in exon 3. Mutation affects the ligand binding domain of the protein. 26
Missense Human Y88C c.263A>G Ligand binding domain 27
Missense Human C91S c.272G>C Ligand binding domain 27
Missense Human C91Y c.272G>A Ligand binding domain 2
Missense Human C346S c.1036T>A GPS 27
Missense Human W349S c.1046G>C GPS 26
Nonsense Human R79X c.235C>T Ligand binding domain 24
Nonsense Human Q123X c.367C>T Mucin rich domain 2
Splice site Human 1G>C Exon 5. Between STP/GPS 27
Clinically-Relevant Mutations and Pathophysiology Comments
There are a total of 22 mutations in ADGRG1. A comprehensive list of these mutations can be found in [31].
General Comments
ADGRG1 (adhesion G protein-coupled receptor G1, formerly known as GPR56) is a receptor belonging to Family VIII Adhesion-GPCRs together with ADGRG2-7 [10]. The genes of ADGRG1, ADGRG3 and ADGRG5 are syntenically clustered on human chromosome 16 and mouse chromosome 8 suggesting the evolution from an ancestral gene through gene duplication and exon shuffling [25].

The C-terminal domain of transglutaminase TG2 consisting of two beta barrel domains has been found to bind to ADGRG1 [37] but has not yet been shown to activate the receptor.

Full coding sequence human cDNA is publicly available: IMAGE:3139174 [18] has Gln306 -> His a known polymorphism with 7% frequency, IMAGE:415209 [18] contains the more common allele. There are numerous transcript variants and the domain architecture can vary between transcript variants [16,29,29].

References

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1. Ackerman SD, Luo R, Poitelon Y, Mogha A, Harty BL, D'Rozario M, Sanchez NE, Lakkaraju AKK, Gamble P, Li J et al.. (2018) GPR56/ADGRG1 regulates development and maintenance of peripheral myelin. J Exp Med, 215 (3): 941-961. [PMID:29367382]

2. Bahi-Buisson N, Poirier K, Boddaert N, Fallet-Bianco C, Specchio N, Bertini E, Caglayan O, Lascelles K, Elie C, Rambaud J et al.. (2010) GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex. Brain, 133 (11): 3194-209. [PMID:20929962]

3. Bai Y, Du L, Shen L, Zhang Y, Zhang L. (2009) GPR56 is highly expressed in neural stem cells but downregulated during differentiation. Neuroreport, 20 (10): 918-22. [PMID:19525879]

4. Bjarnadóttir TK, Fredriksson R, Höglund PJ, Gloriam DE, Lagerström MC, Schiöth HB. (2004) The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics, 84 (1): 23-33. [PMID:15203201]

5. Bjarnadóttir TK, Geirardsdóttir K, Ingemansson M, Mirza MA, Fredriksson R, Schiöth HB. (2007) Identification of novel splice variants of Adhesion G protein-coupled receptors. Gene, 387 (1-2): 38-48. [PMID:17056209]

6. Chang GW, Hsiao CC, Peng YM, Vieira Braga FA, Kragten NA, Remmerswaal EB, van de Garde MD, Straussberg R, König GM, Kostenis E et al.. (2016) The Adhesion G Protein-Coupled Receptor GPR56/ADGRG1 Is an Inhibitory Receptor on Human NK Cells. Cell Rep, 15 (8): 1757-70. [PMID:27184850]

7. Chen G, Yang L, Begum S, Xu L. (2010) GPR56 is essential for testis development and male fertility in mice. Dev Dyn, 239 (12): 3358-67. [PMID:20981830]

8. Chiang NY, Chang GW, Huang YS, Peng YM, Hsiao CC, Kuo ML, Lin HH. (2016) Heparin interacts with the adhesion GPCR GPR56, reduces receptor shedding, and promotes cell adhesion and motility. J Cell Sci, 129 (11): 2156-69. [PMID:27068534]

9. Fransen NL, Hsiao CC, van der Poel M, Engelenburg HJ, Verdaasdonk K, Vincenten MCJ, Remmerswaal EBM, Kuhlmann T, Mason MRJ, Hamann J et al.. (2020) Tissue-resident memory T cells invade the brain parenchyma in multiple sclerosis white matter lesions. Brain, 143 (6): 1714-1730. [PMID:32400866]

10. Fredriksson R, Gloriam DE, Höglund PJ, Lagerström MC, Schiöth HB. (2003) There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini. Biochem Biophys Res Commun, 301 (3): 725-34. [PMID:12565841]

11. Giera S, Deng Y, Luo R, Ackerman SD, Mogha A, Monk KR, Ying Y, Jeong SJ, Makinodan M, Bialas AR et al.. (2015) The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development. Nat Commun, 6: 6121. [PMID:25607655]

12. Huang Y, Fan J, Yang J, Zhu GZ. (2008) Characterization of GPR56 protein and its suppressed expression in human pancreatic cancer cells. Mol Cell Biochem, 308 (1-2): 133-9. [PMID:17932623]

13. Iguchi T, Sakata K, Yoshizaki K, Tago K, Mizuno N, Itoh H. (2008) Orphan G protein-coupled receptor GPR56 regulates neural progenitor cell migration via a G alpha 12/13 and Rho pathway. J Biol Chem, 283 (21): 14469-78. [PMID:18378689]

14. Jeong SJ, Luo R, Li S, Strokes N, Piao X. (2012) Characterization of G protein-coupled receptor 56 protein expression in the mouse developing neocortex. J Comp Neurol, 520 (13): 2930-40. [PMID:22351047]

15. Ke N, Sundaram R, Liu G, Chionis J, Fan W, Rogers C, Awad T, Grifman M, Yu D, Wong-Staal F et al.. (2007) Orphan G protein-coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway. Mol Cancer Ther, 6 (6): 1840-50. [PMID:17575113]

16. Knierim AB, Röthe J, Çakir MV, Lede V, Wilde C, Liebscher I, Thor D, Schöneberg T. (2019) Genetic basis of functional variability in adhesion G protein-coupled receptors. Sci Rep, 9 (1): 11036. [PMID:31363148]

17. Koirala S, Jin Z, Piao X, Corfas G. (2009) GPR56-regulated granule cell adhesion is essential for rostral cerebellar development. J Neurosci, 29 (23): 7439-49. [PMID:19515912]

18. Lennon G, Auffray C, Polymeropoulos M, Soares MB. (1996) The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. Genomics, 33 (1): 151-2. [PMID:8617505]

19. Li S, Jin Z, Koirala S, Bu L, Xu L, Hynes RO, Walsh CA, Corfas G, Piao X. (2008) GPR56 regulates pial basement membrane integrity and cortical lamination. J Neurosci, 28 (22): 5817-26. [PMID:18509043]

20. Liu M, Parker RM, Darby K, Eyre HJ, Copeland NG, Crawford J, Gilbert DJ, Sutherland GR, Jenkins NA, Herzog H. (1999) GPR56, a novel secretin-like human G-protein-coupled receptor gene. Genomics, 55 (3): 296-305. [PMID:10049584]

21. Luo R, Jeong SJ, Jin Z, Strokes N, Li S, Piao X. (2011) G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination. Proc Natl Acad Sci USA, 108 (31): 12925-30. [PMID:21768377]

22. Luo R, Yang HM, Jin Z, Halley DJ, Chang BS, MacPherson L, Brueton L, Piao X. (2011) A novel GPR56 mutation causes bilateral frontoparietal polymicrogyria. Pediatr Neurol, 45 (1): 49-53. [PMID:21723461]

23. O'Connell RM, Rao DS, Chaudhuri AA, Baltimore D. (2010) Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol, 10 (2): 111-22. [PMID:20098459]

24. Parrini E, Ferrari AR, Dorn T, Walsh CA, Guerrini R. (2009) Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations. Epilepsia, 50 (6): 1344-53. [PMID:19016831]

25. Peng YM, van de Garde MD, Cheng KF, Baars PA, Remmerswaal EB, van Lier RA, Mackay CR, Lin HH, Hamann J. (2011) Specific expression of GPR56 by human cytotoxic lymphocytes. J Leukoc Biol, 90 (4): 735-40. [PMID:21724806]

26. Piao X, Chang BS, Bodell A, Woods K, Benzeev B, Topcu M, Guerrini R, Goldberg-Stern H, Sztriha L, Dobyns WB et al.. (2005) Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann Neurol, 58 (5): 680-7. [PMID:16240336]

27. Piao X, Hill RS, Bodell A, Chang BS, Basel-Vanagaite L, Straussberg R, Dobyns WB, Qasrawi B, Winter RM, Innes AM et al.. (2004) G protein-coupled receptor-dependent development of human frontal cortex. Science, 303 (5666): 2033-6. [PMID:15044805]

28. Quattrocchi CC, Zanni G, Napolitano A, Longo D, Cordelli DM, Barresi S, Randisi F, Valente EM, Verdolotti T, Genovese E et al.. (2013) Conventional magnetic resonance imaging and diffusion tensor imaging studies in children with novel GPR56 mutations: further delineation of a cobblestone-like phenotype. Neurogenetics, 14 (1): 77-83. [PMID:23274687]

29. Salzman GS, Ackerman SD, Ding C, Koide A, Leon K, Luo R, Stoveken HM, Fernandez CG, Tall GG, Piao X et al.. (2016) Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains. Neuron, 91 (6): 1292-1304. [PMID:27657451]

30. Shashidhar S, Lorente G, Nagavarapu U, Nelson A, Kuo J, Cummins J, Nikolich K, Urfer R, Foehr ED. (2005) GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion. Oncogene, 24 (10): 1673-82. [PMID:15674329]

31. Singer K, Luo R, Jeong SJ, Piao X. (2013) GPR56 and the developing cerebral cortex: cells, matrix, and neuronal migration. Mol Neurobiol, 47 (1): 186-96. [PMID:23001883]

32. Stoveken HM, Bahr LL, Anders MW, Wojtovich AP, Smrcka AV, Tall GG. (2016) Dihydromunduletone Is a Small-Molecule Selective Adhesion G Protein-Coupled Receptor Antagonist. Mol Pharmacol, 90 (3): 214-24. [PMID:27338081]

33. Stoveken HM, Hajduczok AG, Xu L, Tall GG. (2015) Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist. Proc Natl Acad Sci USA, 112 (19): 6194-9. [PMID:25918380]

34. Stoveken HM, Larsen SD, Smrcka AV, Tall GG. (2018) Gedunin- and Khivorin-Derivatives Are Small-Molecule Partial Agonists for Adhesion G Protein-Coupled Receptors GPR56/ADGRG1 and GPR114/ADGRG5. Mol Pharmacol, 93 (5): 477-488. [PMID:29476042]

35. Suzuki G, Kanda Y, Nibuya M, Hiramoto T, Tanaka T, Shimizu K, Watanabe Y, Nomura S. (2007) Stress and electroconvulsive seizure differentially alter GPR56 expression in the adult rat brain. Brain Res, 1183: 21-31. [PMID:17945200]

36. Truong KL, Schlickeiser S, Vogt K, Boës D, Stanko K, Appelt C, Streitz M, Grütz G, Stobutzki N, Meisel C et al.. (2019) Killer-like receptors and GPR56 progressive expression defines cytokine production of human CD4+ memory T cells. Nat Commun, 10 (1): 2263. [PMID:31118448]

37. Xu L, Begum S, Hearn JD, Hynes RO. (2006) GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. Proc Natl Acad Sci USA, 103 (24): 9023-8. [PMID:16757564]

38. Xu L, Hynes RO. (2007) GPR56 and TG2: possible roles in suppression of tumor growth by the microenvironment. Cell Cycle, 6 (2): 160-5. [PMID:17314516]

39. Yang L, Chen G, Mohanty S, Scott G, Fazal F, Rahman A, Begum S, Hynes RO, Xu L. (2011) GPR56 Regulates VEGF production and angiogenesis during melanoma progression. Cancer Res, 71 (16): 5558-68. [PMID:21724588]

40. Zendman AJ, Cornelissen IM, Weidle UH, Ruiter DJ, van Muijen GN. (1999) TM7XN1, a novel human EGF-TM7-like cDNA, detected with mRNA differential display using human melanoma cell lines with different metastatic potential. FEBS Lett, 446 (2-3): 292-8. [PMID:10100861]

41. Zhang GJ, Chen TB, Connolly B, Lin SA, Hargreaves R, Vanko A, Bednar B, Macneil DJ, Sur C, Williams DL. (2009) In vivo optical imaging of LacZ expression using lacZ transgenic mice. Assay Drug Dev Technol, 7 (4): 391-9. [PMID:19689207]

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