Login Register Cart 0
Generic placeholder image

Current Drug Targets

Editor-in-Chief

ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

GPR56, an Adhesion GPCR with Multiple Roles in Human Diseases, Current Status and Future Perspective

Author(s): Yan Fan, Xiao-Yan Yan* and Wei Guan*

Volume 25, Issue 8, 2024

Published on: 14 May, 2024

Page: [558 - 573] Pages: 16

DOI: 10.2174/0113894501298344240507080149

Price: $65

Abstract

Human G protein-coupled receptor 56 (GPR56) belongs to a member of the adhesion G-protein coupled receptor (aGPCR) family and widely exists in the central nervous system and various types of tumor tissues. Recent studies have shown that abnormal expression or dysfunction of GPR56 is closely associated with many physiological and pathological processes, including brain development, neuropsychiatric disorders, cardiovascular diseases and cancer progression. In addition, GPR56 has been proven to enhance the susceptibility of some antipsychotics and anticarcinogens in response to the treatment of neuropsychological diseases and cancer. Although there have been some reports about the functions of GPR56, the underlying mechanisms implicated in these diseases have not been clarified thoroughly, especially in depression and epilepsy. Therefore, in this review, we described the molecular structure and signal transduction pathway of GPR56 and carried out a comprehensive summary of GPR56's function in the development of psychiatric disorders and cancer. Our review showed that GPR56 deficiency led to depressive-like behaviors and an increase in resistance to antipsychotic treatment. In contrast, the upregulation of GPR56 contributed to tumor cell proliferation and metastasis in malignant diseases such as glioblastoma, colorectal cancer, and ovarian cancer. Moreover, we elucidated specific signaling pathways downstream of GPR56 related to the pathogenesis of these diseases. In summary, our review provides compelling arguments for an attractive therapeutic target of GPR56 in improving the therapeutic efficiency for patients suffering from psychiatric disorders and cancer.

« Previous
Graphical Abstract

[1]
Liu Y, An S, Ward R, et al. G protein-coupled receptors as promising cancer targets. Cancer Lett 2016; 376(2): 226-39.
[http://dx.doi.org/10.1016/j.canlet.2016.03.031] [PMID: 27000991]
[2]
Weis WI, Kobilka BK. The Molecular Basis of G Protein–Coupled Receptor Activation. Annu Rev Biochem 2018; 87(1): 897-919.
[http://dx.doi.org/10.1146/annurev-biochem-060614-033910] [PMID: 29925258]
[3]
Kobilka BK. G protein coupled receptor structure and activation. Biochim Biophys Acta Biomembr 2007; 1768(4): 794-807.
[http://dx.doi.org/10.1016/j.bbamem.2006.10.021] [PMID: 17188232]
[4]
Komolov KE, Du Y, Duc NM, et al. Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5. Cell 2017; 169(3): 407-421.e16.
[http://dx.doi.org/10.1016/j.cell.2017.03.047] [PMID: 28431242]
[5]
Hauser AS, Chavali S, Masuho I, et al. Pharmacogenomics of GPCR Drug Targets. Cell 2018; 172(1-2): 41-54.e19.
[http://dx.doi.org/10.1016/j.cell.2017.11.033] [PMID: 29249361]
[6]
An W, Lin H, Ma L, et al. Progesterone activates GPR126 to promote breast cancer development via the Gi pathway. Proc Natl Acad Sci 2022; 119(15): e2117004119.
[http://dx.doi.org/10.1073/pnas.2117004119] [PMID: 35394864]
[7]
Jin Z, Luo R, Piao X. GPR56 and its related diseases. Prog Mol Biol Transl Sci 2009; 89: 1-13.
[http://dx.doi.org/10.1016/S1877-1173(09)89001-7] [PMID: 20374731]
[8]
Ganesh RA, Venkataraman K, Sirdeshmukh R. GPR56: An adhesion GPCR involved in brain development, neurological disorders and cancer. Brain Res 2020; 1747: 147055.
[http://dx.doi.org/10.1016/j.brainres.2020.147055] [PMID: 32798453]
[9]
Ng KF, Chen TC, Stacey M, Lin HH. Role of ADGRG1/GPR56 in Tumor Progression. Cells 2021; 10(12): 3352.
[http://dx.doi.org/10.3390/cells10123352] [PMID: 34943858]
[10]
Xu L, Begum S, Hearn JD, Hynes RO. GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. Proc Natl Acad Sci 2006; 103(24): 9023-8.
[http://dx.doi.org/10.1073/pnas.0602681103] [PMID: 16757564]
[11]
Liu M, Parker RMC, Darby K, et al. GPR56, a novel secretin-like human G-protein-coupled receptor gene. Genomics 1999; 55(3): 296-305.
[http://dx.doi.org/10.1006/geno.1998.5644] [PMID: 10049584]
[12]
Salzman GS, Ackerman SD, Ding C, et al. Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains. Neuron 2016; 91(6): 1292-304.
[http://dx.doi.org/10.1016/j.neuron.2016.08.022] [PMID: 27657451]
[13]
Salzman GS, Zhang S, Fernandez CG, Araç D, Koide S. Specific and direct modulation of the interaction between adhesion GPCR GPR56/ADGRG1 and tissue transglutaminase 2 using synthetic ligands. Sci Rep 2020; 10(1): 16912.
[http://dx.doi.org/10.1038/s41598-020-74044-6] [PMID: 33037308]
[14]
Liebscher I, Schön J, Petersen SC, et al. A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133. Cell Rep 2014; 9(6): 2018-26.
[http://dx.doi.org/10.1016/j.celrep.2014.11.036] [PMID: 25533341]
[15]
Lin HH, Hsiao CC, Pabst C, Hébert J, Schöneberg T, Hamann J. Adhesion GPCRs in Regulating Immune Responses and Inflammation. Adv Immunol 2017; 136: 163-201.
[http://dx.doi.org/10.1016/bs.ai.2017.05.005] [PMID: 28950945]
[16]
Kim JE, Han JM, Park CR, et al. Splicing variants of the orphan G-protein-coupled receptor GPR56 regulate the activity of transcription factors associated with tumorigenesis. J Cancer Res Clin Oncol 2010; 136(1): 47-53.
[http://dx.doi.org/10.1007/s00432-009-0635-z] [PMID: 19572147]
[17]
Singh AK, Lin HH. The role of GPR56/ADGRG1 in health and disease. Biomed J 2021; 44(5): 534-47.
[http://dx.doi.org/10.1016/j.bj.2021.04.012] [PMID: 34654683]
[18]
Hasan AM, Roy P, Dolan S, Martin PE, Patterson S, Bartholomew C. Adhesion G-protein coupled receptor 56 is required for 3T3-L1 adipogenesis. J Cell Physiol 2020; 235(2): 1601-14.
[http://dx.doi.org/10.1002/jcp.29079] [PMID: 31304602]
[19]
Zhang Y, Si Y, Ma N, Mei J. The RNA-binding protein PCBP2 inhibits Ang II-induced hypertrophy of cardiomyocytes though promoting GPR56 mRNA degeneration. Biochem Biophys Res Commun 2015; 464(3): 679-84.
[http://dx.doi.org/10.1016/j.bbrc.2015.06.139] [PMID: 26116532]
[20]
Singer K, Luo R, Jeong SJ, Piao X. GPR56 and the developing cerebral cortex: Cells, matrix, and neuronal migration. Mol Neurobiol 2013; 47(1): 186-96.
[http://dx.doi.org/10.1007/s12035-012-8343-0] [PMID: 23001883]
[21]
Belzeaux R, Gorgievski V, Fiori LM, et al. GPR56/ADGRG1 is associated with response to antidepressant treatment. Nat Commun 2020; 11(1): 1635.
[http://dx.doi.org/10.1038/s41467-020-15423-5] [PMID: 32242018]
[22]
Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 2018; 23(4): 801-11.
[http://dx.doi.org/10.1038/mp.2017.255] [PMID: 29532791]
[23]
Giera S, Luo R, Ying Y, et al. Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells. eLife 2018; 7: e33385.
[http://dx.doi.org/10.7554/eLife.33385] [PMID: 29809138]
[24]
Giera S, Deng Y, Luo R, et al. The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development. Nat Commun 2015; 6(1): 6121.
[http://dx.doi.org/10.1038/ncomms7121] [PMID: 25607655]
[25]
Mochida GH. Cortical malformation and pediatric epilepsy: A molecular genetic approach. J Child Neurol 2005; 20(4): 300-3.
[http://dx.doi.org/10.1177/08830738050200040501] [PMID: 15921229]
[26]
Jeong SJ, Luo R, Singer K, et al. GPR56 functions together with α3β1 integrin in regulating cerebral cortical development. PLoS One 2013; 8(7): e68781.
[http://dx.doi.org/10.1371/journal.pone.0068781] [PMID: 23874761]
[27]
Carneiro F, Duarte J, Laranjeira F, Gouveia BS, Couce ML, Fonseca MJ. Case Report: Diffuse Polymicrogyria Associated With a Novel ADGRG1 Variant. Front Pediatr 2021; 9: 728077.
[http://dx.doi.org/10.3389/fped.2021.728077] [PMID: 34513772]
[28]
Suzuki G, Kanda Y, Nibuya M, et al. Stress and electroconvulsive seizure differentially alter GPR56 expression in the adult rat brain. Brain Res 2007; 1183: 21-31.
[http://dx.doi.org/10.1016/j.brainres.2007.09.020] [PMID: 17945200]
[29]
Yamamoto T, Shimojima K, Yamazaki S, Ikeno K, Tohyama J. A 16q12.2q21 deletion identified in a patient with developmental delay, epilepsy, short stature, and distinctive features. Congenit Anom 2016; 56(6): 253-5.
[http://dx.doi.org/10.1111/cga.12172] [PMID: 27230627]
[30]
Borgatti R, Marelli S, Bernardini L, et al. Bilateral frontoparietal polymicrogyria (BFPP) syndrome secondary to a 16q12.1-q21 chromosome deletion involving GPR56 gene. Clin Genet 2009; 76(6): 573-6.
[http://dx.doi.org/10.1111/j.1399-0004.2009.01262.x] [PMID: 19807741]
[31]
Jansen A, Andermann E. Genetics of the polymicrogyria syndromes. J Med Genet 2005; 42(5): 369-78.
[http://dx.doi.org/10.1136/jmg.2004.023952] [PMID: 15863665]
[32]
Jain P, Sharma S, Buisson BN, Beldjord C, Aneja S. Bilateral frontoparietal polymicrogyria. Indian J Pediatr 2015; 82(4): 390-1.
[http://dx.doi.org/10.1007/s12098-014-1614-1] [PMID: 25416088]
[33]
Kuo CY, Tsai MH, Lin HH, et al. 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 2023; 8(1): 154-64.
[http://dx.doi.org/10.1002/epi4.12685] [PMID: 36524291]
[34]
Piao X, Chang BS, Bodell A, et al. Genotype–phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann Neurol 2005; 58(5): 680-7.
[http://dx.doi.org/10.1002/ana.20616] [PMID: 16240336]
[35]
Tchofo JP, Kara S, Barkovich AJ. Midbrain–hindbrain involvement in lissencephalies. Neurology 2009; 72(5): 410-8.
[http://dx.doi.org/10.1212/01.wnl.0000333256.74903.94] [PMID: 19020296]
[36]
Buisson BN, Poirier K, Boddaert N, et al. GPR56-related bilateral frontoparietal polymicrogyria: Further evidence for an overlap with the cobblestone complex. Brain 2010; 133(11): 3194-209.
[http://dx.doi.org/10.1093/brain/awq259] [PMID: 20929962]
[37]
Chang BS, Piao X, Bodell A, et al. Bilateral frontoparietal polymicrogyria: Clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol 2003; 53(5): 596-606.
[http://dx.doi.org/10.1002/ana.10520] [PMID: 12730993]
[38]
Parrini E, Ferrari AR, Dorn T, Walsh CA, Guerrini R. Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations. Epilepsia 2009; 50(6): 1344-53.
[http://dx.doi.org/10.1111/j.1528-1167.2008.01787.x] [PMID: 19016831]
[39]
Li S, Jin Z, Koirala S, et al. GPR56 regulates pial basement membrane integrity and cortical lamination. J Neurosci 2008; 28(22): 5817-26.
[http://dx.doi.org/10.1523/JNEUROSCI.0853-08.2008] [PMID: 18509043]
[40]
Luo R, Jeong SJ, Jin Z, Strokes N, Li S, Piao X. G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination. Proc Natl Acad Sci 2011; 108(31): 12925-30.
[http://dx.doi.org/10.1073/pnas.1104821108] [PMID: 21768377]
[41]
Janiszewska M, Primi MC, Izard T. Cell adhesion in cancer: Beyond the migration of single cells. J Biol Chem 2020; 295(8): 2495-505.
[http://dx.doi.org/10.1074/jbc.REV119.007759] [PMID: 31937589]
[42]
Biller LH, Schrag D. Diagnosis and Treatment of Metastatic Colorectal Cancer. JAMA 2021; 325(7): 669-85.
[http://dx.doi.org/10.1001/jama.2021.0106] [PMID: 33591350]
[43]
Yang L, Xu L. GPR56 in cancer progression: Current status and future perspective. Future Oncol 2012; 8(4): 431-40.
[http://dx.doi.org/10.2217/fon.12.27] [PMID: 22515446]
[44]
Xu L. GPR56 interacts with extracellular matrix and regulates cancer progression. Adv Exp Med Biol 2010; 706: 98-108.
[http://dx.doi.org/10.1007/978-1-4419-7913-1_8] [PMID: 21618829]
[45]
Luo R, Jin Z, Deng Y, Strokes N, Piao X. Disease-associated mutations prevent GPR56-collagen III interaction. PLoS One 2012; 7(1): e29818.
[http://dx.doi.org/10.1371/journal.pone.0029818] [PMID: 22238662]
[46]
Yang L, Chen G, Mohanty S, et al. GPR56 Regulates VEGF production and angiogenesis during melanoma progression. Cancer Res 2011; 71(16): 5558-68.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-4543] [PMID: 21724588]
[47]
Huang KY, Lin HH. The Activation and Signaling Mechanisms of GPR56/ADGRG1 in Melanoma Cell. Front Oncol 2018; 8: 304.
[http://dx.doi.org/10.3389/fonc.2018.00304] [PMID: 30135857]
[48]
Ji B, Feng Y, Sun Y, et al. GPR56 promotes proliferation of colorectal cancer cells and enhances metastasis via epithelial-mesenchymal transition through PI3K/AKT signaling activation. Oncol Rep 2018; 40(4): 1885-96.
[http://dx.doi.org/10.3892/or.2018.6582] [PMID: 30066935]
[49]
Jacob J, Francisco LE, Chatterjee T, et al. An antibody–drug conjugate targeting GPR56 demonstrates efficacy in preclinical models of colorectal cancer. Br J Cancer 2023; 128(8): 1592-602.
[http://dx.doi.org/10.1038/s41416-023-02192-3] [PMID: 36759728]
[50]
Nowicki A, Mrugalska SP, Jozkowiak M, et al. The Effect of 3′-Hydroxy-3,4,5,4′-Tetramethoxy -stilbene, the Metabolite of the Resveratrol Analogue DMU-212, on the Motility and Proliferation of Ovarian Cancer Cells. Int J Mol Sci 2020; 21(3): 1100.
[http://dx.doi.org/10.3390/ijms21031100] [PMID: 32046103]
[51]
Lim DR, Kang DH, Kuk JC, et al. Prognostic impact of GPR56 in patients with colorectal cancer. Neoplasma 2021; 68(3): 580-9.
[http://dx.doi.org/10.4149/neo_2021_201209N1333] [PMID: 33618521]
[52]
Liu Z, Huang Z, Yang W, et al. Expression of orphan GPR56 correlates with tumor progression in human epithelial ovarian cancer. Neoplasma 2017; 64(1): 32-9.
[http://dx.doi.org/10.4149/neo_2017_104] [PMID: 27881002]
[53]
Bilemjian V, Vlaming MR, Freile AJ, Huls G, De Bruyn M, Bremer E. The Novel Immune Checkpoint GPR56 Is Expressed on Tumor-Infiltrating Lymphocytes and Selectively Upregulated upon TCR Signaling. Cancers 2022; 14(13): 3164.
[http://dx.doi.org/10.3390/cancers14133164] [PMID: 35804934]
[54]
Wilkinson L, Gathani T. Understanding breast cancer as a global health concern. Br J Radiol 2022; 95(1130): 20211033.
[http://dx.doi.org/10.1259/bjr.20211033] [PMID: 34905391]
[55]
Kashyap D, Pal D, Sharma R, et al. Global Increase in Breast Cancer Incidence: Risk Factors and Preventive Measures. BioMed Res Int 2022; 2022: 1-16.
[http://dx.doi.org/10.1155/2022/9605439] [PMID: 35480139]
[56]
Sasaki S, Zhang D, Iwabuchi S, et al. Crucial contribution of GPR56/ADGRG1, expressed by breast cancer cells, to bone metastasis formation. Cancer Sci 2021; 112(12): 4883-93.
[http://dx.doi.org/10.1111/cas.15150] [PMID: 34632664]
[57]
Shashidhar S, Lorente G, Nagavarapu U, et al. GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion. Oncogene 2005; 24(10): 1673-82.
[http://dx.doi.org/10.1038/sj.onc.1208395] [PMID: 15674329]
[58]
Ohta S, Sakaguchi S, Kobayashi Y, Mizuno N, Tago K, Itoh H. Agonistic antibodies reveal the function of GPR56 in human glioma U87-MG cells. Biol Pharm Bull 2015; 38(4): 594-600.
[http://dx.doi.org/10.1248/bpb.b14-00752] [PMID: 25832639]
[59]
Moreno M, Pedrosa L, Paré L, et al. GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma. Cell Rep 2017; 21(8): 2183-97.
[http://dx.doi.org/10.1016/j.celrep.2017.10.083] [PMID: 29166609]
[60]
Millar MW, Corson N, Xu L. The Adhesion G-Protein-Coupled Receptor, GPR56/ADGRG1, Inhibits Cell–Extracellular Matrix Signaling to Prevent Metastatic Melanoma Growth. Front Oncol 2018; 8: 8.
[http://dx.doi.org/10.3389/fonc.2018.00008] [PMID: 29450192]
[61]
Zendman AJW, Cornelissen IMHA, Weidle UH, Ruiter DJ, van Muijen GNP. TM7XN1, a novel human EGF-TM7-like cDNA, detected with mRNA differential display using human melanoma cell lines with different metastatic potential. FEBS Lett 1999; 446(2-3): 292-8.
[http://dx.doi.org/10.1016/S0014-5793(99)00230-6] [PMID: 10100861]
[62]
Chiang NY, Peng YM, Juang HH, et al. GPR56/ADGRG1 Activation Promotes Melanoma Cell Migration via NTF Dissociation and CTF-Mediated Gα12/13/RhoA Signaling. J Invest Dermatol 2017; 137(3): 727-36.
[http://dx.doi.org/10.1016/j.jid.2016.10.031] [PMID: 27818281]
[63]
Fredriksson R, Lagerström MC, Lundin LG, Schiöth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 2003; 63(6): 1256-72.
[http://dx.doi.org/10.1124/mol.63.6.1256] [PMID: 12761335]
[64]
Hamann J, Aust G, Araç D, et al. International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors. Pharmacol Rev 2015; 67(2): 338-67.
[http://dx.doi.org/10.1124/pr.114.009647] [PMID: 25713288]
[65]
Ackerman SD, Garcia C, Piao X, Gutmann DH, Monk KR. The adhesion GPCR Gpr56 regulates oligodendrocyte development via interactions with Gα12/13 and RhoA. Nat Commun 2015; 6(1): 6122.
[http://dx.doi.org/10.1038/ncomms7122] [PMID: 25607772]
[66]
Chiang NY, Hsiao CC, Huang YS, et al. Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms. J Biol Chem 2011; 286(16): 14215-25.
[http://dx.doi.org/10.1074/jbc.M110.183830] [PMID: 21349848]
[67]
Zhang S, Chatterjee T, Godoy C, Wu L, Liu QJ, Carmon KS. GPR56 Drives Colorectal Tumor Growth and Promotes Drug Resistance through Upregulation of MDR1 Expression via a RhoA-Mediated Mechanism. Mol Cancer Res 2019; 17(11): 2196-207.
[http://dx.doi.org/10.1158/1541-7786.MCR-19-0436] [PMID: 31444231]
[68]
Chatterjee T, Zhang S, Posey TA, et al. Anti-GPR56 monoclonal antibody potentiates GPR56-mediated Src-Fak signaling to modulate cell adhesion. J Biol Chem 2021; 296: 100261.
[http://dx.doi.org/10.1016/j.jbc.2021.100261] [PMID: 33837725]
[69]
von Breitenbuch P, Kurz B, Wallner S, et al. Expression of pH-Sensitive GPCRs in Peritoneal Carcinomatosis of Colorectal Cancer—First Results. J Clin Med 2023; 12(5): 1803.
[http://dx.doi.org/10.3390/jcm12051803] [PMID: 36902589]
[70]
Ke N, Sundaram R, Liu G, et al. Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway. Mol Cancer Ther 2007; 6(6): 1840-50.
[http://dx.doi.org/10.1158/1535-7163.MCT-07-0066] [PMID: 17575113]
[71]
Verbovšek U, Motaln H, Rotter A, et al. Expression analysis of all protease genes reveals cathepsin K to be overexpressed in glioblastoma. PLoS One 2014; 9(10): e111819.
[http://dx.doi.org/10.1371/journal.pone.0111819] [PMID: 25356585]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy