Adhesion G protein-coupled receptors (aGPCRs) — one of the five main families in the GPCR superfamily — have several atypical characteristics, including large, multi-domain N termini and a highly conserved region that can be autoproteolytically cleaved. Although GPCRs overall have well-established pharmacological tractability, currently no therapies that target any of the 33 members of the aGPCR family are either approved or in clinical trials. However, human genetics and preclinical research have strengthened the links between aGPCRs and disease in recent years. This, together with a greater understanding of their functional complexity, has led to growing interest in aGPCRs as drug targets. A framework for prioritizing aGPCR targets and supporting approaches to develop aGPCR modulators could therefore be valuable in harnessing the untapped therapeutic potential of this family. With this in mind, here we discuss the unique opportunities and challenges for drug discovery in modulating aGPCR functions, including target identification, target validation, assay development and safety considerations, using ADGRG1 as an illustrative example.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hauser, A. S., Attwood, M. M., Rask-Andersen, M., Schioth, H. B. & Gloriam, D. E. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 16, 829–842 (2017).
Munk, C. et al. An online resource for GPCR structure determination and analysis. Nat. Methods 16, 151–162 (2019).
Wootten, D., Christopoulos, A., Marti-Solano, M., Babu, M. M. & Sexton, P. M. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nat. Rev. Mol. Cell Biol. 19, 638–653 (2018).
Isberg, V. et al. GPCRdb: an information system for G protein-coupled receptors. Nucleic Acids Res. 44, D356–D364 (2016).
Kolakowski, L. F., Jr. GCRDb: a G-protein-coupled receptor database. Receptors Channels 2, 1–7 (1994).
Munk, C. et al. GPCRdb: the G protein-coupled receptor database — an introduction. Br. J. Pharmacol. 173, 2195–2207 (2016).
Fredriksson, R., Lagerstrom, M. C., Lundin, L. G. & Schioth, H. B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 63, 1256–1272 (2003).
Baud, V. et al. EMR1, an unusual member in the family of hormone receptors with seven transmembrane segments. Genomics 26, 334–344 (1995).
Hamann, J. et al. Expression cloning and chromosomal mapping of the leukocyte activation antigen CD97, a new seven-span transmembrane molecule of the secretion receptor superfamily with an unusual extracellular domain. J. Immunol. 155, 1942–1950 (1995).
Hamann, J. et al. International union of basic and clinical pharmacology. XCIV. adhesion G protein-coupled receptors. Pharmacol. Rev. 67, 338–367 (2015).
Vallon, M. & Essler, M. Proteolytically processed soluble tumor endothelial marker (TEM) 5 mediates endothelial cell survival during angiogenesis by linking integrin α(v)β3 to glycosaminoglycans. J. Biol. Chem. 281, 34179–34188 (2006).
Koh, J. T. et al. Extracellular fragment of brain-specific angiogenesis inhibitor 1 suppresses endothelial cell proliferation by blocking αvβ5 integrin. Exp. Cell Res. 294, 172–184 (2004).
Kaur, B., Brat, D. J., Devi, N. S. & Van Meir, E. G. Vasculostatin, a proteolytic fragment of brain angiogenesis inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene 24, 3632–3642 (2005).
Gray, J. X. et al. CD97 is a processed, seven-transmembrane, heterodimeric receptor associated with inflammation. J. Immunol. 157, 5438–5447 (1996).
Leemans, J. C. et al. The epidermal growth factor-seven transmembrane (EGF-TM7) receptor CD97 is required for neutrophil migration and host defense. J. Immunol. 172, 1125–1131 (2004).
Davies, B. et al. Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility. Mol. Cell Biol. 24, 8642–8648 (2004).
Piao, X. et al. G protein-coupled receptor-dependent development of human frontal cortex. Science 303, 2033–2036 (2004).
Boyden, S. E. et al. Vibratory urticaria associated with a missense variant in ADGRE2. N. Engl. J. Med. 374, 656–663 (2016).
Bjarnadottir, T. K. et al. The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics 84, 23–33 (2004).
Nordstrom, K. J., Lagerstrom, M. C., Waller, L. M., Fredriksson, R. & Schioth, H. B. The Secretin GPCRs descended from the family of adhesion GPCRs. Mol Biol. Evol. 26, 71–84 (2009).
Arac, D. et al. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. EMBO J. 31, 1364–1378 (2012).
Hamilton, J. R. & Trejo, J. Challenges and opportunities in protease-activated receptor drug development. Annu. Rev. Pharmacol. Toxicol. 57, 349–373 (2017).
Liebscher, I. et al. A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133. Cell Rep. 9, 2018–2026 (2014).
Paavola, K. J., Stephenson, J. R., Ritter, S. L., Alter, S. P. & Hall, R. A. The N terminus of the adhesion G protein-coupled receptor GPR56 controls receptor signaling activity. J. Biol. Chem. 286, 28914–28921 (2011).
Stoveken, H. M., Hajduczok, A. G., Xu, L. & Tall, G. G. Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist. Proc. Natl Acad. Sci. USA 112, 6194–6199 (2015).
Promel, S., Langenhan, T. & Arac, D. Matching structure with function: the GAIN domain of adhesion-GPCR and PKD1-like proteins. Trends Pharmacol. Sci. 34, 470–478 (2013).
Hsiao, C. C., Chen, H. Y., Chang, G. W. & Lin, H. H. GPS autoproteolysis is required for CD97 to up-regulate the expression of N-cadherin that promotes homotypic cell-cell aggregation. FEBS Lett. 585, 313–318 (2011).
Hsiao, C. C. et al. The adhesion GPCR CD97/ADGRE5 inhibits apoptosis. Int. J. Biochem. Cell Biol. 65, 197–208 (2015).
Jin, Z. et al. Disease-associated mutations affect GPR56 protein trafficking and cell surface expression. Hum. Mol. Genet. 16, 1972–1985 (2007).
Promel, S. et al. The GPS motif is a molecular switch for bimodal activities of adhesion class G protein-coupled receptors. Cell Rep. 2, 321–331 (2012).
Scholz, N. et al. Mechano-dependent signaling by latrophilin/CIRL quenches cAMP in proprioceptive neurons. Elife 6, e28360 (2017).
Purcell, R. H., Hall, R. A. & Adhesion, G. Protein-coupled receptors as drug targets. Annu. Rev. Pharmacol. Toxicol. 58, 429–449 (2018).
Giera, S. et al. Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells. Elife 7, e33385 (2018).
Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430–434 (2007).
Posokhova, E. et al. GPR124 functions as a WNT7-specific coactivator of canonical β-catenin signaling. Cell Rep. 10, 123–130 (2015).
Stacey, M. et al. The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans. Blood 102, 2916–2924 (2003).
Luo, R. et al. G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination. Proc. Natl Acad. Sci. USA 108, 12925–12930 (2011).
Kuffer, A. et al. The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. Nature 536, 464–468 (2016).
Chen, H. et al. A forward chemical genetic screen reveals gut microbiota metabolites that modulate host physiology. Cell 177, 1217–1231 (2019).
Hamoud, N. et al. Spatiotemporal regulation of the GPCR activity of BAI3 by C1qL4 and Stabilin-2 controls myoblast fusion. Nat. Commun. 9, 4470 (2018).
Petersen, S. C. et al. The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211. Neuron 85, 755–769 (2015).
Paavola, K. J., Sidik, H., Zuchero, J. B., Eckart, M. & Talbot, W. S. Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126. Sci. Signal. 7, ra76 (2014).
Kaur, B. et al. Vasculostatin inhibits intracranial glioma growth and negatively regulates in vivo angiogenesis through a CD36-dependent mechanism. Cancer Res. 69, 1212–1220 (2009).
Silva, J. P. et al. Latrophilin 1 and its endogenous ligand Lasso/teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities. Proc. Natl Acad. Sci. USA 108, 12113–12118 (2011).
Hamann, J. et al. Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue. Arthritis Rheum. 42, 650–658 (1999).
Cork, S. M. et al. A proprotein convertase/MMP-14 proteolytic cascade releases a novel 40 kDa vasculostatin from tumor suppressor BAI1. Oncogene 31, 5144–5152 (2012).
Wang, T. et al. CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells. Blood 105, 2836–2844 (2005).
Boucard, A. A., Ko, J. & Sudhof, T. C. High affinity neurexin binding to cell adhesion G-protein-coupled receptor CIRL1/latrophilin-1 produces an intercellular adhesion complex. J. Biol. Chem. 287, 9399–9413 (2012).
Hamann, J., Vogel, B., van Schijndel, G. M. & van Lier, R. A. The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF). J. Exp. Med. 184, 1185–1189 (1996).
Wandel, E., Saalbach, A., Sittig, D., Gebhardt, C. & Aust, G. Thy-1 (CD90) is an interacting partner for CD97 on activated endothelial cells. J. Immunol. 188, 1442–1450 (2012).
Eubelen, M. et al. A molecular mechanism for Wnt ligand-specific signaling. Science 361, eaat1178 (2018).
Little, K. D., Hemler, M. E. & Stipp, C. S. Dynamic regulation of a GPCR-tetraspanin-G protein complex on intact cells: central role of CD81 in facilitating GPR56-Gα q/11 association. Mol. Biol. Cell 15, 2375–2387 (2004).
Ward, Y. et al. LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells. Cancer Res. 71, 7301–7311 (2011).
Becker, S. et al. Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions. PLoS ONE 5, e8507 (2010).
Hilbig, D. et al. The interaction of CD97/ADGRE5 with β-catenin in adherens junctions is lost during colorectal carcinogenesis. Front. Oncol. 8, 182 (2018).
Hamann, J. et al. EMR1, the human homolog of F4/80, is an eosinophil-specific receptor. Eur. J. Immunol. 37, 2797–2802 (2007).
Waddell, L. A. et al. ADGRE1 (EMR1, F4/80) is a rapidly-evolving gene expressed in mammalian monocyte-macrophages. Front. Immunol. 9, 2246 (2018).
Yona, S. et al. Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function. FASEB J. 22, 741–751 (2008).
Hsiao, C. C. et al. The adhesion g protein-coupled receptor GPR97/ADGRG3 Is expressed in human granulocytes and triggers antimicrobial effector functions. Front. Immunol. 9, 2830 (2018).
Fang, W. et al. Gpr97 exacerbates AKI by mediating Sema3A signaling. J. Am. Soc. Nephrol. 29, 1475–1489 (2018).
Wang, J. et al. Gpr97/Adgrg3 ameliorates experimental autoimmune encephalomyelitis by regulating cytokine expression. Acta Biochim. Biophys. Sin. 50, 666–675 (2018).
Bridges, J. P. et al. Orphan G protein-coupled receptor GPR116 regulates pulmonary surfactant pool size. Am. J. Respir. Cell Mol. Biol. 49, 348–357 (2013).
Niaudet, C. et al. Gpr116 Receptor regulates distinctive functions in pneumocytes and vascular endothelium. PLoS ONE 10, e0137949 (2015).
Lee, J. W. et al. Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function. Nat. Commun. 7, 13123 (2016).
Bhat, R. R. et al. GPCRs profiling and identification of GPR110 as a potential new target in HER2+ breast cancer. Breast Cancer Res. Treat. 170, 279–292 (2018).
Wang, X. J. et al. Understanding cadherin EGF LAG seven-pass G-type receptors. J. Neurochem. 131, 699–711 (2014).
Wang, L. et al. Digenic variants of planar cell polarity genes in human neural tube defect patients. Mol. Genet. Metab. 124, 94–100 (2018).
Lindenmaier, L. B., Parmentier, N., Guo, C., Tissir, F. & Wright, K. M. Dystroglycan is a scaffold for extracellular axon guidance decisions. Elife 8, e42143 (2019).
Karner, C. M., Long, F., Solnica-Krezel, L., Monk, K. R. & Gray, R. S. Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice. Hum. Mol. Genet. 24, 4365–4373 (2015).
Monk, K. R., Oshima, K., Jors, S., Heller, S. & Talbot, W. S. Gpr126 is essential for peripheral nerve development and myelination in mammals. Development 138, 2673–2680 (2011).
Mogha, A. et al. Gpr126/Adgrg6 Has schwann cell autonomous and nonautonomous functions in peripheral nerve injury and repair. J. Neurosci. 36, 12351–12367 (2016).
Cui, H. et al. GPR126 protein regulates developmental and pathological angiogenesis through modulation of VEGFR2 receptor signaling. J. Biol. Chem. 289, 34871–34885 (2014).
Favara, D. M., Banham, A. H. & Harris, A. L. A review of ELTD1, a pro-angiogenic adhesion GPCR. Biochem. Soc. Trans. 42, 1658–1664 (2014).
Cullen, M. et al. GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier. Proc. Natl Acad. Sci. USA 108, 5759–5764 (2011).
Kuhnert, F. et al. Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124. Science 330, 985–989 (2010).
Moon, S. Y., Shin, S. A., Oh, Y. S., Park, H. H. & Lee, C. S. Understanding the role of the BAI subfamily of adhesion G protein-coupled receptors (gpcrs) in pathological and physiological conditions. Genes (Basel) 9, E597 (2018).
Meza-Aguilar, D. G. & Boucard, A. A. Latrophilins updated. Biomol. Concepts 5, 457–478 (2014).
Rothe, J. et al. Involvement of the adhesion GPCRs latrophilins in the regulation of insulin release. Cell Rep. 26, 1573–1584 e1575 (2019).
Scholz, N. et al. The adhesion GPCR latrophilin/CIRL shapes mechanosensation. Cell Rep. 11, 866–874 (2015).
Pulley, J. M. et al. Accelerating precision drug development and drug repurposing by leveraging human genetics. Assay Drug Dev. Technol. 15, 113–119 (2017).
Nelson, M. R. et al. The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856–860 (2015).
Cazorla-Vazquez, S. & Engel, F. B. Adhesion GPCRs in kidney development and disease. Front. Cell Dev. Biol. 6, 9 (2018).
Lin, H. H. et al. Adhesion GPCRs in regulating immune responses and inflammation. Adv. Immunol. 136, 163–201 (2017).
White, J. P. Control of skeletal muscle cell growth and size through adhesion GPCRs. Handb. Exp. Pharmacol. 234, 299–308 (2016).
Aust, G., Zhu, D., Van Meir, E. G. & Xu, L. Adhesion GPCRs in tumorigenesis. Handb. Exp. Pharmacol. 234, 369–396 (2016).
Langenhan, T., Piao, X. & Monk, K. R. Adhesion G protein-coupled receptors in nervous system development and disease. Nat. Rev. Neurosci. 17, 550–561 (2016).
Ludwig, M. G., Seuwen, K. & Bridges, J. P. Adhesion GPCR Function in pulmonary development and disease. Handb. Exp. Pharmacol. 234, 309–327 (2016).
Musa, G., Engel, F. B. & Niaudet, C. Heart development, angiogenesis, and blood-brain barrier function is modulated by adhesion GPCRs. Handb. Exp. Pharmacol. 234, 351–368 (2016).
Kovacs, P. & Schoneberg, T. The relevance of genomic signatures at adhesion GPCR loci in humans. Handb. Exp. Pharmacol. 234, 179–217 (2016).
Huang, C. H. et al. Increased EMR2 expression on neutrophils correlates with disease severity and predicts overall mortality in cirrhotic patients. Sci. Rep. 6, 38250 (2016).
I, K. Y. et al. Activation of adhesion GPCR EMR2/ADGRE2 induces macrophage differentiation and inflammatory responses via Gα16/Akt/MAPK/NF-kappaB signaling pathways. Front. Immunol. 8, 373 (2017).
Chang, G. W. et al. The adhesion G protein-coupled receptor GPR56/ADGRG1 Is an inhibitory receptor on human NK cells. Cell Rep. 15, 1757–1770 (2016).
Kishore, A. & Hall, R. A. Disease-associated extracellular loop mutations in the adhesion G protein-coupled receptor G1 (ADGRG1; GPR56) differentially regulate downstream signaling. J. Biol. Chem. 292, 9711–9720 (2017).
Oncu-Oner, T. et al. GPR56 homozygous nonsense mutation p.R271* associated with phenotypic variability in bilateral frontoparietal polymicrogyria. Turk. J. Pediatr. 60, 229–237 (2018).
Zou, J. et al. The roles of USH1 proteins and PDZ domain-containing USH proteins in USH2 complex integrity in cochlear hair cells. Hum. Mol. Genet. 26, 624–636 (2017).
Scholz, N. Cancer cell mechanics: adhesion G protein-coupled receptors in action? Front. Oncol. 8, 59 (2018).
Millar, M. W., Corson, N. & Xu, L. The adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits cell-extracellular matrix signaling to prevent metastatic melanoma growth. Front. Oncol. 8, 8 (2018).
Yang, J. et al. G protein-coupled receptor 56 regulates matrix production and motility of lung fibroblasts. Exp. Biol. Med. (Maywood) 239, 686–696 (2014).
Yang, B. et al. Pathogenic role of ADGRG2 in CBAVD patients replicated in Chinese population. Andrology 5, 954–957 (2017).
Patat, O. et al. Truncating mutations in the adhesion G protein-coupled receptor G2 gene ADGRG2 cause an X-linked congenital bilateral absence of vas deferens. Am. J. Hum. Genet. 99, 437–442 (2016).
Khan, M. J. et al. X-linked ADGRG2 mutation and obstructive azoospermia in a large Pakistani family. Sci. Rep. 8, 16280 (2018).
Yuan, P. et al. Expanding the phenotypic and genetic spectrum of Chinese patients with congenital absence of vas deferens bearing CFTR and ADGRG2 alleles. Andrology 7, 329–340 (2019).
Liu, G. et al. Genetic polymorphisms of GPR126 are functionally associated with PUMC classifications of adolescent idiopathic scoliosis in a Northern Han population. J. Cell. Mol. Med. 22, 1964–1971 (2018).
Fischer, L., Wilde, C., Schoneberg, T. & Liebscher, I. Functional relevance of naturally occurring mutations in adhesion G protein-coupled receptor ADGRD1 (GPR133). BMC Genomics 17, 609 (2016).
Stäubert, C., Le Duc, D. & Schöneberg, T. in G Protein-Coupled Receptor Genetics 23–43 (ed. Stevens, C.) (Humana Press, 2014).
Luo, R., Jin, Z., Deng, Y., Strokes, N. & Piao, X. Disease-associated mutations prevent GPR56-collagen III interaction. PLoS ONE 7, e29818 (2012).
Chiang, N. Y. et al. Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms. J. Biol. Chem. 286, 14215–14225 (2011).
Hochreiter-Hufford, A. E. et al. Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion. Nature 497, 263–267 (2013).
Lee, C. S. et al. Boosting apoptotic cell clearance by colonic epithelial cells attenuates inflammation in vivo. Immunity 44, 807–820 (2016).
Billings, E. A. et al. The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against Gram-negative bacteria. Sci. Signal. 9, ra14 (2016).
Zhu, D. et al. BAI1 suppresses medulloblastoma formation by protecting p53 from Mdm2-mediated degradation. Cancer Cell 33, 1004–1016 e1005 (2018).
Haitina, T. et al. Expression profile of the entire family of adhesion G protein-coupled receptors in mouse and rat. BMC Neurosci. 9, 43 (2008).
Chiang, N. Y. et al. GPR56/ADGRG1 Activation promotes melanoma cell migration via NTF dissociation and CTF-mediated gα12/13/RhoA signaling. J. Invest. Dermatol. 137, 727–736 (2017).
Kishore, A., Purcell, R. H., Nassiri-Toosi, Z. & Hall, R. A. Stalk-dependent and Stalk-independent signaling by the adhesion G protein-coupled receptors GPR56 (ADGRG1) and BAI1 (ADGRB1). J. Biol. Chem. 291, 3385–3394 (2016).
Wilde, C. et al. The constitutive activity of the adhesion GPCR GPR114/ADGRG5 is mediated by its tethered agonist. FASEB J. 30, 666–673 (2016).
Boucard, A. A., Maxeiner, S. & Sudhof, T. C. Latrophilins function as heterophilic cell-adhesion molecules by binding to teneurins: regulation by alternative splicing. J. Biol. Chem. 289, 387–402 (2014).
Patra, C. et al. Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent. Proc. Natl Acad. Sci. USA 110, 16898–16903 (2013).
Scheel, H., Tomiuk, S. & Hofmann, K. A common protein interaction domain links two recently identified epilepsy genes. Hum. Mol. Genet. 11, 1757–1762 (2002).
Giera, S. et al. The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development. Nat. Commun. 6, 6121 (2015).
Ackerman, S. D., Garcia, C., Piao, X., Gutmann, D. H. & Monk, K. R. The adhesion GPCR Gpr56 regulates oligodendrocyte development via interactions with Gα12/13 and RhoA. Nat. Commun. 6, 6122 (2015).
Jeong, S. J. et al. GPR56 functions together with α3β1 integrin in regulating cerebral cortical development. PLoS ONE 8, e68781 (2013).
Li, S. et al. GPR56 regulates pial basement membrane integrity and cortical lamination. J. Neurosci. 28, 5817–5826 (2008).
Koirala, S., Jin, Z., Piao, X. & Corfas, G. GPR56-regulated granule cell adhesion is essential for rostral cerebellar development. J. Neurosci. 29, 7439–7449 (2009).
Daria, D. et al. GPR56 contributes to the development of acute myeloid leukemia in mice. Leukemia 30, 1734–1741 (2016).
Bostaille, N., Gauquier, A., Stainier, D. Y., Raible, D. W. & Vanhollebeke, B. Defective adgra2 (gpr124) splicing and function in zebrafish ouchless mutants. Development 144, 8–11 (2017).
Moffat, J. G., Vincent, F., Lee, J. A., Eder, J. & Prunotto, M. Opportunities and challenges in phenotypic drug discovery: an industry perspective. Nat. Rev. Drug Discov. 16, 531–543 (2017).
Demberg, L. M. et al. Activation of adhesion G protein-coupled receptors: agonist specificity of stachel sequence-derived peptides. J. Biol. Chem. 292, 4383–4394 (2017).
Monk, K. R. et al. A G protein-coupled receptor is essential for Schwann cells to initiate myelination. Science 325, 1402–1405 (2009).
Park, S. J. et al. Lysophosphatidylethanolamine utilizes LPA(1) and CD97 in MDA-MB-231 breast cancer cells. Cell Signal. 25, 2147–2154 (2013).
Peeters, M. C. et al. The adhesion G protein-coupled receptor G2 (ADGRG2/GPR64) constitutively activates SRE and NFkappaB and is involved in cell adhesion and migration. Cell Signal. 27, 2579–2588 (2015).
Balenga, N. et al. Orphan adhesion GPCR GPR64/ADGRG2 Is overexpressed in parathyroid tumors and attenuates calcium-sensing receptor-mediated signaling. J. Bone Min. Res. 32, 654–666 (2017).
Junge, H. J. Ligand-selective wnt receptor complexes in CNS blood vessels: RECK and GPR124 plugged In. Neuron 95, 983–985 (2017).
Woelfle, R., D'Aquila, A. L., Pavlovic, T., Husic, M. & Lovejoy, D. A. Ancient interaction between the teneurin C-terminal associated peptides (TCAP) and latrophilin ligand-receptor coupling: a role in behavior. Front. Neurosci. 9, 146 (2015).
Nishimura, T., Honda, H. & Takeichi, M. Planar cell polarity links axes of spatial dynamics in neural-tube closure. Cell 149, 1084–1097 (2012).
McLatchie, L. M. et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393, 333–339 (1998).
Mogha, A. et al. Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation. J. Neurosci. 33, 17976–17985 (2013).
Duner, P. et al. Adhesion G protein-coupled receptor G1 (ADGRG1/GPR56) and pancreatic β-cell function. J. Clin. Endocrinol. Metab. 101, 4637–4645 (2016).
Iguchi, T. et al. Orphan G protein-coupled receptor GPR56 regulates neural progenitor cell migration via a G α 12/13 and Rho pathway. J. Biol. Chem. 283, 14469–14478 (2008).
Flock, T. et al. Selectivity determinants of GPCR-G-protein binding. Nature 545, 317–322 (2017).
Nazarko, O. et al. A comprehensive mutagenesis screen of the adhesion GPCR latrophilin-1/ADGRL1. iScience 3, 264–278 (2018).
Kroeze, W. K. et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol. 22, 362–369 (2015).
Stoveken, H. M. et al. Dihydromunduletone is a small-molecule selective adhesion G protein-coupled receptor antagonist. Mol. Pharmacol. 90, 214–224 (2016).
Stoveken, H. M., Larsen, S. D., Smrcka, A. V. & Tall, G. G. Gedunin- and khivorin-derivatives are small-molecule partial agonists for adhesion G protein-coupled receptors GPR56/ADGRG1 and GPR114/ADGRG5. Mol. Pharmacol. 93, 477–488 (2018).
Gupte, J. et al. Signaling property study of adhesion G-protein-coupled receptors. FEBS Lett. 586, 1214–1219 (2012).
Southern, C. et al. Screening β-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors. J. Biomol. Screen. 18, 599–609 (2013).
Luo, R. et al. Mechanism for adhesion G protein-coupled receptor GPR56-mediated RhoA activation induced by collagen III stimulation. PLoS ONE 9, e100043 (2014).
Salzman, G. S. et al. Structural basis for regulation of GPR56/ADGRG1 by its alternatively spliced extracellular domains. Neuron 91, 1292–1304 (2016).
Salzman, G. S. et al. Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region. Proc. Natl Acad. Sci. USA 114, 10095–10100 (2017).
Ackerman, S. D. et al. GPR56/ADGRG1 regulates development and maintenance of peripheral myelin. J. Exp. Med. 215, 941–961 (2018).
Hernandez-Vasquez, M. N. et al. Cell adhesion controlled by adhesion G protein-coupled receptor GPR124/ADGRA2 is mediated by a protein complex comprising intersectins and Elmo-Dock. J. Biol. Chem. 292, 12178–12191 (2017).
Chai, G. et al. Celsr3 is required in motor neurons to steer their axons in the hindlimb. Nat. Neurosci. 17, 1171–1179 (2014).
Moreno, M. et al. GPR56/ADGRG1 inhibits mesenchymal differentiation and radioresistance in glioblastoma. Cell Rep. 21, 2183–2197 (2017).
Alok, A. et al. Wnt proteins synergize to activate β-catenin signaling. J. Cell Sci. 130, 1532–1544 (2017).
Demberg, L. M., Rothemund, S., Schoneberg, T. & Liebscher, I. Identification of the tethered peptide agonist of the adhesion G protein-coupled receptor GPR64/ADGRG2. Biochem. Biophys. Res. Commun. 464, 743–747 (2015).
Chackalamannil, S. et al. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J. Med. Chem. 51, 3061–3064 (2008).
Hoffman, B. D., Grashoff, C. & Schwartz, M. A. Dynamic molecular processes mediate cellular mechanotransduction. Nature 475, 316–323 (2011).
Hilbig, D. et al. Mechano-dependent phosphorylation of the PDZ-Binding Motif of CD97/ADGRE5 modulates cellular detachment. Cell Rep. 24, 1986–1995 (2018).
Scholz, N., Monk, K. R., Kittel, R. J. & Langenhan, T. Adhesion GPCRs as a putative class of metabotropic mechanosensors. Handb. Exp. Pharmacol. 234, 221–247 (2016).
White, J. P. et al. G protein-coupled receptor 56 regulates mechanical overload-induced muscle hypertrophy. Proc. Natl Acad. Sci. USA 111, 15756–15761 (2014).
Brown, K. et al. Epithelial Gpr116 regulates pulmonary alveolar homeostasis via Gq/11 signaling. JCI Insight 2, 93700 (2017).
Tang, X. et al. GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Gαq-p63RhoGEF-Rho GTPase pathway. Cancer Res. 73, 6206–6218 (2013).
Martino, F., Perestrelo, A. R., Vinarsky, V., Pagliari, S. & Forte, G. Cellular mechanotransduction: from tension to function. Front. Physiol. 9, 824 (2018).
Olaniru, O. E. et al. The adhesion receptor GPR56 is activated by extracellular matrix collagen III to improve β-cell function. Cell Mol. Life Sci. 75, 4007–4019 (2018).
Yang, L., Friedland, S., Corson, N. & Xu, L. GPR56 inhibits melanoma growth by internalizing and degrading its ligand TG2. Cancer Res. 74, 1022–1031 (2014).
Yang, L. et al. GPR56 Regulates VEGF production and angiogenesis during melanoma progression. Cancer Res. 71, 5558–5568 (2011).
Kwakkenbos, M. J. et al. Expression of the largest CD97 and EMR2 isoforms on leukocytes facilitates a specific interaction with chondroitin sulfate on B cells. J. Leukoc. Biol. 77, 112–119 (2005).
Sigoillot, S. M., Monk, K. R., Piao, X., Selimi, F. & Harty, B. L. Adhesion GPCRs as novel actors in neural and glial cell functions: from synaptogenesis to myelination. Handb. Exp. Pharmacol. 234, 275–298 (2016).
Stephenson, J. R. et al. Brain-specific angiogenesis inhibitor-1 signaling, regulation, and enrichment in the postsynaptic density. J. Biol. Chem. 288, 22248–22256 (2013).
Shiratsuchi, T. et al. Cloning and characterization of BAI-associated protein 1: a PDZ domain-containing protein that interacts with BAI1. Biochem. Biophys. Res. Commun. 247, 597–604 (1998).
Mathema, V. B. & Na-Bangchang, K. Regulatory roles of brain-specific angiogenesis inhibitor 1(BAI1) protein in inflammation, tumorigenesis and phagocytosis: A brief review. Crit. Rev. Oncol. Hematol. 111, 81–86 (2017).
Stucki, J. D. & Guenat, O. T. A microfluidic bubble trap and oscillator. Lab Chip 15, 4393–4397 (2015).
Hammerschmidt, S., Kuhn, H., Gessner, C., Seyfarth, H. J. & Wirtz, H. Stretch-induced alveolar type II cell apoptosis: role of endogenous bradykinin and PI3K-Akt signaling. Am J. Respir. Cell Mol. Biol. 37, 699–705 (2007).
Wells, R. G. Tissue mechanics and fibrosis. Biochim. Biophys. Acta 1832, 884–890 (2013).
Barnes, J. M., Przybyla, L. & Weaver, V. M. Tissue mechanics regulate brain development, homeostasis and disease. J. Cell Sci. 130, 71–82 (2017).
Xu, J. et al. GPR68 Senses flow and is essential for vascular physiology. Cell 173, 762–775 e716 (2018).
Mih, J. D. et al. A multiwell platform for studying stiffness-dependent cell biology. PLoS ONE 6, e19929 (2011).
Karpus, O. N. et al. Shear stress-dependent downregulation of the adhesion-G protein-coupled receptor CD97 on circulating leukocytes upon contact with its ligand CD55. J. Immunol. 190, 3740–3748 (2013).
Raftopoulou, M. & Hall, A. Cell migration: Rho GTPases lead the way. Dev. Biol. 265, 23–32 (2004).
Ohashi, K., Fujiwara, S. & Mizuno, K. Roles of the cytoskeleton, cell adhesion and rho signalling in mechanosensing and mechanotransduction. J. Biochem. 161, 245–254 (2017).
Herrick, W. G. et al. Smooth muscle stiffness sensitivity is driven by soluble and insoluble ECM chemistry. Cell Mol. Bioeng. 8, 333–348 (2015).
Yin, Y. et al. CD97 Promotes tumor aggressiveness through the traditional g protein-coupled receptor-mediated signaling in hepatocellular carcinoma. Hepatology 68, 1865–1878 (2018).
Gupta, A., Heimann, A. S., Gomes, I. & Devi, L. A. Antibodies against G-protein coupled receptors: novel uses in screening and drug development. Comb. Chem. High Throughput Screen. 11, 463–467 (2008).
Gupta, A. et al. Conformation state-sensitive antibodies to G-protein-coupled receptors. J. Biol. Chem. 282, 5116–5124 (2007).
Li, J. et al. Structural basis for teneurin function in circuit-wiring: a toxin motif at the synapse. Cell 173, 735–748 e715 (2018).
de Groot, D. M. et al. Therapeutic antibody targeting of CD97 in experimental arthritis: the role of antigen expression, shedding, and internalization on the pharmacokinetics of anti-CD97 monoclonal antibody 1B2. J. Immunol. 183, 4127–4134 (2009).
Wobus, M., Vogel, B., Schmucking, E., Hamann, J. & Aust, G. N-glycosylation of CD97 within the EGF domains is crucial for epitope accessibility in normal and malignant cells as well as CD55 ligand binding. Int. J. Cancer 112, 815–822 (2004).
Lin, H. H. et al. Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif. J. Biol. Chem. 279, 31823–31832 (2004).
Huang, Y. S. et al. Activation of myeloid cell-specific adhesion class G protein-coupled receptor EMR2 via ligation-induced translocation and interaction of receptor subunits in lipid raft microdomains. Mol. Cell Biol. 32, 1408–1420 (2012).
Abe, J., Fukuzawa, T. & Hirose, S. Cleavage of Ig-Hepta at a "SEA" module and at a conserved G protein-coupled receptor proteolytic site. J. Biol. Chem. 277, 23391–23398 (2002).
Moriguchi, T. et al. DREG, a developmentally regulated G protein-coupled receptor containing two conserved proteolytic cleavage sites. Genes Cells 9, 549–560 (2004).
Patra, C., Monk, K. R. & Engel, F. B. The multiple signaling modalities of adhesion G protein-coupled receptor GPR126 in development. Receptors Clin. Invest. 1, 79 (2014).
Renaud, J. P. et al. Cryo-EM in drug discovery: achievements, limitations and prospects. Nat. Rev. Drug Discov. 17, 471–492 (2018).
Liang, Y. L. et al. Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature 555, 121–125 (2018).
Zhang, Y. et al. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546, 248–253 (2017).
Liang, Y. L. et al. Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. Nature 561, 492–497 (2018).
Lu, Y. C. et al. Structural basis of latrophilin-FLRT-UNC5 interaction in cell adhesion. Structure 23, 1678–1691 (2015).
Jackson, V. A. et al. Super-complexes of adhesion GPCRs and neural guidance receptors. Nat. Commun. 7, 11184 (2016).
Cho, C., Smallwood, P. M. & Nathans, J. Reck and Gpr124 Are essential receptor cofactors for Wnt7a/Wnt7b-specific signaling in mammalian CNS angiogenesis and blood-brain barrier regulation. Neuron 95, 1221–1225 (2017).
Schaarschmidt, J. et al. Rearrangement of the extracellular domain/extracellular loop 1 interface is critical for thyrotropin receptor activation. J. Biol. Chem. 291, 14095–14108 (2016).
Saha, H. R. et al. Suppression of GPR56 expression by pyrrole-imidazole polyamide represents a novel therapeutic drug for AML with high EVI1 expression. Sci. Rep. 8, 13741 (2018).
Hanrahan, J. W., Matthes, E., Carlile, G. & Thomas, D. Y. Corrector combination therapies for F508del-CFTR. Curr. Opin. Pharmacol. 34, 105–111 (2017).
Fukuda, R. & Okiyoneda, T. Peripheral protein quality control as a novel drug target for CFTR stabilizer. Front. Pharmacol. 9, 1100 (2018).
Bostaille, N., Gauquier, A., Twyffels, L. & Vanhollebeke, B. Molecular insights into Adgra2/Gpr124 and Reck intracellular trafficking. Biol. Open 5, 1874–1881 (2016).
Ramachandran, R., Altier, C., Oikonomopoulou, K. & Hollenberg, M. D. Proteinases, their extracellular targets, and inflammatory signaling. Pharmacol. Rev. 68, 1110–1142 (2016).
Oller-Salvia, B., Sanchez-Navarro, M., Giralt, E. & Teixido, M. Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery. Chem. Soc. Rev. 45, 4690–4707 (2016).
Allouche, S., Noble, F. & Marie, N. Opioid receptor desensitization: mechanisms and its link to tolerance. Front. Pharmacol. 5, 280 (2014).
Zhang, D. L. et al. Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility. Elife 7, e33432 (2018).
Ji, B. et al. GPR56 promotes proliferation of colorectal cancer cells and enhances metastasis via epithelialmesenchymal transition through PI3K/AKT signaling activation. Oncol. Rep. 40, 1885–1896 (2018).
Veninga, H. et al. Analysis of CD97 expression and manipulation: antibody treatment but not gene targeting curtails granulocyte migration. J. Immunol. 181, 6574–6583 (2008).
Huang, Y. S., Chiang, N. Y., Chang, G. W. & Lin, H. H. Membrane-association of EMR2/ADGRE2-NTF is regulated by site-specific N-glycosylation. Sci. Rep. 8, 4532 (2018).
Hamann, J. et al. Molecular cloning and characterization of mouse CD97. Int. Immunol. 12, 439–448 (2000).
Tseng, W. Y. et al. High levels of soluble GPR56/ADGRG1 are associated with positive rheumatoid factor and elevated tumor necrosis factor in patients with rheumatoid arthritis. J. Microbiol. Immunol. Infect. 51, 485–491 (2017).
Jacobson, K. A. New paradigms in GPCR drug discovery. Biochem. Pharmacol. 98, 541–555 (2015).
Shepherd, C. A., Hopkins, A. L. & Navratilova, I. Fragment screening by SPR and advanced application to GPCRs. Prog. Biophys. Mol. Biol. 116, 113–123 (2014).
Jin, G. et al. The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis. Oncotarget 8, 40606–40619 (2017).
Ribases, M. et al. Contribution of LPHN3 to the genetic susceptibility to ADHD in adulthood: a replication study. Genes Brain Behav. 10, 149–157 (2011).
Orsini, C. A. et al. Behavioral and transcriptomic profiling of mice null for Lphn3, a gene implicated in ADHD and addiction. Mol. Genet. Genomic Med. 4, 322–343 (2016).
O'Sullivan, M. L. et al. FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development. Neuron 73, 903–910 (2012).
Ravenscroft, G. et al. Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita. Am. J. Hum. Genet. 96, 955–961 (2015).
Tu, Y. K., Duman, J. G. & Tolias, K. F. The Adhesion-GPCR BAI1 Promotes excitatory synaptogenesis by coordinating bidirectional trans-synaptic signaling. J. Neurosci. 38, 8388–8406 (2018).
Zhu, D. et al. BAI1 regulates spatial learning and synaptic plasticity in the hippocampus. J. Clin. Invest. 125, 1497–1508 (2015).
Wang, T. et al. Improved antibacterial host defense and altered peripheral granulocyte homeostasis in mice lacking the adhesion class G protein receptor CD97. Infect. Immun. 75, 1144–1153 (2007).
Safaee, M. et al. CD97 is a multifunctional leukocyte receptor with distinct roles in human cancers (Review). Int. J. Oncol. 43, 1343–1350 (2013).
Xie, K. et al. Polymorphisms in genes related to epithelial-mesenchymal transition and risk of non-small cell lung cancer. Carcinogenesis 38, 1029–1035 (2017).
Ma, B. et al. Gpr110 deficiency decelerates carcinogen-induced hepatocarcinogenesis via activation of the IL-6/STAT3 pathway. Am. J. Cancer Res. 7, 433–447 (2017).
Austyn, J. M. & Gordon, S. F4/80, a monoclonal antibody directed specifically against the mouse macrophage. Eur. J. Immunol. 11, 805–815 (1981).
Tissir, F., Bar, I., Jossin, Y., De Backer, O. & Goffinet, A. M. Protocadherin Celsr3 is crucial in axonal tract development. Nat. Neurosci. 8, 451–457 (2005).
Vanhollebeke, B. et al. Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis. Elife 4, e6489 (2015).
F.B., M.-G.L. and M.N. are employees of Novartis Institutes for Biomedical Research and hold Novartis shares.
About this article
Cite this article
Bassilana, F., Nash, M. & Ludwig, MG. Adhesion G protein-coupled receptors: opportunities for drug discovery. Nat Rev Drug Discov 18, 869–884 (2019). https://doi.org/10.1038/s41573-019-0039-y
Progress in Neuro-Psychopharmacology and Biological Psychiatry (2021)
Trends in Biochemical Sciences (2020)
Cellular Signalling (2020)
Cellular Signalling (2020)