Nomenclature: GPR56

Family: Adhesion Class GPCRs

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
Adhesion G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 693 16q12.2-q21 GPR56 G protein-coupled receptor 56 14
Mouse 7 687 8 D1 Gpr56 G protein-coupled receptor 56
Rat 7 687 19p13 Gpr56 G protein-coupled receptor 56
Previous and Unofficial Names
BFPP
DKFZp781L1398
TM7LN4
TM7XN1
G-protein coupled receptor 56
Cyt28
Database Links
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Agonist Comments
GPR56 has been shown to be activated by collagen III (COL3A1) [15] and transglutaminase 2 [26]. Human collagen III activates mouse and human GPR56 equally at a concentration of 84 nM [15].
Primary Transduction Mechanisms
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 [24].
References:  15,24
Secondary Transduction Mechanisms
Transducer Effector/Response
Other - See Comments
Comments:  In melanoma cells, GPR56C activates protein kinase C alpha (PKCα), which increases the expression of VEGF [24].
References:  24
Tissue Distribution
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:  3-4,14
Neural, hematopoietic and mesenchymal stem cells
Species:  Human
Technique:  Immunocytochemistry
References:  2,28
Tumor tissues, cancer cell lines, expression levels correlate inversely with the malignancy of melanomas
Species:  Human
Technique:  Western blot, Northern blot and immunohistochemistry
References:  7,10,23,28-29
Widely expressed. Highest in thyroid, testis, heart, brain, placenta, lung.
Species:  Human
Technique:  Northern blotting.
References:  14
Cytotoxic NK and T cells
Species:  Human
Technique:  Flow cytometry
References:  17,19
Testis Sertoli cells
Species:  Mouse
Technique:  Immunohistochemistry and in situ hybridisation
References:  5
Developing cortex (radial glia, neural progenitor cells) and cerebellum
Species:  Mouse
Technique:  Immunohistochemistry and in situ hybridisation
References:  2,8-9,11,13,21,30
Neural progenitor cells in adult brain after stress and electroconvulsive seizure
Species:  Rat
Technique:  Immunohistochemistry
References:  25
Expression Datasets

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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]

There should be a chart of expression data here, you may need to enable JavaScript!
Functional Assays
Inhibits sponataneous and chemokine-induced migration, demonstrated by migration assay
Species:  Human
Tissue:  NK cells
Response measured:  Sponataneous and chemokine-induced migration
References:  19
Inhibits neuronal migration in the presence of collagen III, demonstrated by migration assay
Species:  Mouse
Tissue:  Brain
Response measured:  Neuronal migration
References:  15
Physiological Functions
Cerebellar development
Species:  Mouse
Tissue:  Cerebellum
References:  11
Neural stem cells
Species:  Human
Tissue:  Brain
References:  2
Tumor growth suppression
Species:  Human
Tissue:  Melanoma cell line
References:  27
Brain development, cortical patterning
Species:  Human
Tissue:  Brain
References:  1,16,18,20-22
Brain development, cortical patterning
Species:  Mouse
Tissue:  Brain
References:  11,13,15
Angiogenesis
Species:  Human
Tissue:  Melanoma
References:  28
Physiological Consequences of Altering Gene Expression
Expression of GPR56 is inversely proportional to the metastatic potential of human melanoma cell lines.
Species:  Mouse
Tissue: 
Technique: 
References:  26,29
Cobblestone lissencephaly, cerebellar malformation
Species:  Mouse
Tissue:  Full KO, embryo examined
Technique:  Gene knockouts
References:  11,13
Male-specific sterility, malformation of male gonad
Species:  Mouse
Tissue:  Full KO, embryo examined
Technique:  Gene knockouts
References:  5
Phenotypes, Alleles and Disease Models 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
Disease:  Bilateral frontoparietal polymicrogyria
OMIM:  606854
Orphanet:  101070
Comments: 
References:  1,16,18,20-22
Click column headers to sort
Type Species Molecular location Description Reference
Frameshift Human c.174_175insC Ligand binding domain 1
Frameshift Human c.739_746delCAGGACC Between STP/GPS 21
Frameshift Human c.671delA Between STP/GPS 1
Missense Human c.235C>T Ligand binding domain 18
Missense Human c.263A>G Ligand binding domain 21
Missense Human c.272G>A Ligand binding domain 1
Missense Human c.272G>C Ligand binding domain 21
Missense Human c.1046G>C GPS 20
Missense Human c.112C>T Ligand binding domain 20-21
Missense Human c.113G>A Ligand binding domain 20
Missense Human c.1036T>A GPS 21
Missense Human c.97C>G Ligand binding domain 18
Other Human c.367C>T Ligand binding domain/STP/nonsense mutation 1
Other Human c.768-1G>C Between STP/GPS; splicing mutation 21
Clinically-Relevant Mutations and Pathophysiology Comments
There are a total of 22 mutations in GPR56. A comprehensive list of these mutations can be found in [24].
General Comments
GPR56 is a receptor belonging to Family VIII Adhesion-GPCRs together with GPR64, GPR97, GPR112, GPR114, GPR126 and GPR128 [6]. The genes of GPR56, GPR97 and GPR114 are syntenically clustered on human chromosome 16 and mouse chromosome 8 suggesting the evolution from an ancestral gene through gene duplication and exon shuffling [19].

The C-terminal domain of transglutaminase TG2 consisting of two beta barrel domains has been found to bind to GPR56 [26] but has not yet been shown to activate the receptor.

Full coding sequence human cDNA is publicly available: IMAGE:3139174 [12] has Gln306 -> His a known polymorphism with 7% frequency, IMAGE:415209 [12] contains the more common allele.

REFERENCES

1. 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. Brain133 (11): 3194-209. [PMID:20929962]

2. Bai Y, Du L, Shen L, Zhang Y, Zhang L. (2009) GPR56 is highly expressed in neural stem cells but downregulated during differentiation. Neuroreport20 (10): 918-22. [PMID:19525879]

3. 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. Genomics84: 23-33. [PMID:15203201]

4. Bjarnadóttir TK, Geirardsdóttir K, Ingemansson M, Mirza MA, Fredriksson R, Schiöth HB. (2007) Identification of novel splice variants of Adhesion G protein-coupled receptors. Gene387 (1-2): 38-48. [PMID:17056209]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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. Genomics33: 151-152. [PMID:8617505]

13. 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]

14. 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. Genomics55: 296-305. [PMID:10049584]

15. 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. U.S.A.108 (31): 12925-30. [PMID:21768377]

16. 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]

17. 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]

18. Parrini E, Ferrari AR, Dorn T, Walsh CA, Guerrini R. (2009) Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations. Epilepsia50 (6): 1344-53. [PMID:19016831]

19. 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]

20. Piao X, Chang BS, Bodell A, Woods K, Benzeev B, Topcu M, Guerrini R, Goldberg-Stern H, Sztriha L, Dobyns WB, Barkovich AJ, Walsh CA. (2005) Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann Neurol58: 680-687. [PMID:16240336]

21. Piao X, Hill RS, Bodell A, Chang BS, Basel-Vanagaite L, Straussberg R, Dobyns WB, Qasrawi B, Winter RM, Innes AM, Voit T, Ross ME, Michaud JL, Déscarie JC, Barkovich AJ, Walsh CA. (2004) G protein-coupled receptor-dependent development of human frontal cortex. Science303: 2033-2036. [PMID:15044805]

22. 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. Neurogenetics14 (1): 77-83. [PMID:23274687]

23. 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. Oncogene24 (10): 1673-82. [PMID:15674329]

24. 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]

25. 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]

26. 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 U S A103: 9023-9028. [PMID:16757564]

27. Xu L, Hynes RO. (2007) GPR56 and TG2: possible roles in suppression of tumor growth by the microenvironment. Cell Cycle6 (2): 160-5. [PMID:17314516]

28. 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]

29. 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 Lett446: 292-298. [PMID:10100861]

30. 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 Technol7 (4): 391-9. [PMID:19689207]

To cite this database page, please use the following:

Xianhua Piao, Kathleen Singer, Lei Xu, Jörg Hamann, Tom I. Bonner.
Adhesion Class GPCRs: GPR56. Last modified on 23/07/2013. Accessed on 24/10/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=186.

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