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Abstract

The adhesion G protein–coupled receptors (aGPCRs) are an evolutionarily ancient family of receptors that play key roles in many different physiological processes. These receptors are notable for their exceptionally long ectodomains, which span several hundred to several thousand amino acids and contain various adhesion-related domains, as well as a GPCR autoproteolysis–inducing (GAIN) domain. The GAIN domain is conserved throughout almost the entire family and undergoes autoproteolysis to cleave the receptors into two noncovalently-associated protomers. Recent studies have revealed that the signaling activity of aGPCRs is largely determined by changes in the interactions among these protomers. We review recent advances in understanding aGPCR activation mechanisms and discuss the physiological roles and pharmacological properties of aGPCRs, with an eye toward the potential utility of these receptors as drug targets.

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2018-01-06
2024-06-25
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Literature Cited

  1. Roth BL, Kroeze WK. 1.  2015. Integrated approaches for genome-wide interrogation of the druggable non-olfactory G protein–coupled receptor superfamily. J. Biol. Chem. 290:19471–77 [Google Scholar]
  2. Hamann J, Aust G, Araç D, Engel FB, Formstone C. 2.  et al. 2015. International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein–coupled receptors. Pharmacol. Rev. 67:338–67 [Google Scholar]
  3. Baud V, Chissoe SL, Viegas-Pequignot E, Diriong S, N'Guyen VC. 3.  et al. 1995. EMR1, an unusual member in the family of hormone receptors with seven transmembrane segments. Genomics 26:334–44 [Google Scholar]
  4. Hamann J, Eichler W, Hamann D, Kerstens HM, Poddighe PJ. 4.  et al. 1995. 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. 155:1942–50 [Google Scholar]
  5. Stacey M, Lin HH, Gordon S, McKnight AJ. 5.  2000. LNB-TM7, a group of seven-transmembrane proteins related to family-B G-protein-coupled receptors. Trends Biochem. Sci. 25:284–89 [Google Scholar]
  6. Bjarnadottir TK, Fredriksson R, Hoglund PJ, Gloriam DE, Lagerstrom MC, Schioth HB. 6.  2004. The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics 84:23–33 [Google Scholar]
  7. Arac D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM. 7.  et al. 2012. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. EMBO J 31:1364–78 [Google Scholar]
  8. Krasnoperov V, Lu Y, Buryanovsky L, Neubert TA, Ichtchenko K, Petrenko AG. 8.  2002. Post-translational proteolyses processing of the calcium-independent receptor of α-latrotoxin (CIRL), a natural chimera of the cell adhesion protein and the G protein–coupled receptor: role of the G protein–coupled receptor proteolysis site (GPS) motif. J. Biol. Chem. 277:46518–26 [Google Scholar]
  9. McKnight AJ, Gordon S. 9.  1998. The EGF-TM7 family: unusual structures at the leukocyte surface. J. Leukoc. Biol. 63:271–80 [Google Scholar]
  10. Krishnan A, Nijmeijer S, de Graaf C, Schiöth HB. 10.  2016. Classification, nomenclature, and structural aspects of adhesion GPCRs. See Ref. 162 15–41
  11. Lin HH, Chang GW, Davies JQ, Stacey M, Harris J, Gordon S. 11.  2004. Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein–coupled receptor proteolytic site motif. J. Biol. Chem. 279:31823–32 [Google Scholar]
  12. Kishore A, Purcell RH, Nassiri-Toosi Z, Hall RA. 12.  2016. Stalk-dependent and stalk-independent signaling by the adhesion G protein–coupled receptors GPR56 (ADGRG1) and BAI1 (ADGRB1). J. Biol. Chem. 291:3385–94 [Google Scholar]
  13. Promel S, Waller-Evans H, Dixon J, Zahn D, Colledge WH. 13.  et al. 2012. Characterization and functional study of a cluster of four highly conserved orphan adhesion-GPCR in mouse. Dev. Dyn. 241:1591–602 [Google Scholar]
  14. Peeters MC, Fokkelman M, Boogaard B, Egerod KL, van de Water B. 14.  et al. 2015. The adhesion G protein–coupled receptor G2 (ADGRG2/GPR64) constitutively activates SRE and NFκB and is involved in cell adhesion and migration. Cell. Signal. 27:2579–88 [Google Scholar]
  15. de Graaf C, Nijmeijer S, Wolf S, Ernst OP. 15.  2016. 7TM domain structure of adhesion GPCRs. See Ref. 162 43–66
  16. Rovati GE, Capra V, Neubig RR. 16.  2007. The highly conserved DRY motif of class A G protein–coupled receptors: beyond the ground state. Mol. Pharmacol. 71:959–64 [Google Scholar]
  17. Pin JP, Galvez T, Prezeau L. 17.  2003. Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol. Ther. 98:325–54 [Google Scholar]
  18. Paavola KJ, Stephenson JR, Ritter SL, Alter SP, Hall RA. 18.  2011. The N terminus of the adhesion G protein–coupled receptor GPR56 controls receptor signaling activity. J. Biol. Chem. 286:28914–21 [Google Scholar]
  19. Stephenson JR, Paavola KJ, Schaefer SA, Kaur B, Van Meir EG Hall RA. 19.  2013. Brain-specific angiogenesis inhibitor-1 signaling, regulation, and enrichment in the postsynaptic density. J. Biol. Chem. 288:22248–56 [Google Scholar]
  20. Ward Y, Lake R, Yin JJ, Heger CD, Raffeld M. 20.  et al. 2011. LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells. Cancer Res 71:7301–11 [Google Scholar]
  21. Okajima D, Kudo G, Yokota H. 21.  2010. Brain-specific angiogenesis inhibitor 2 (BAI2) may be activated by proteolytic processing. J. Recept. Signal Transduct. Res. 30:143–53 [Google Scholar]
  22. Paavola KJ, Hall RA. 22.  2012. Adhesion G protein–coupled receptors: signaling, pharmacology, and mechanisms of activation. Mol. Pharmacol. 82:777–83 [Google Scholar]
  23. Demberg LM, Rothemund S, Schoneberg T, Liebscher I. 23.  2015. Identification of the tethered peptide agonist of the adhesion G protein–coupled receptor GPR64/ADGRG2. Biochem. Biophys. Res. Commun. 464:743–7 [Google Scholar]
  24. Balenga N, Azimzadeh P, Hogue JA, Staats PN, Shi Y. 24.  et al. 2017. Orphan adhesion GPCR GPR64/ADGRG2 is overexpressed in parathyroid tumors and attenuates calcium-sensing receptor-mediated signaling. J. Bone Miner. Res. 32:654–66 [Google Scholar]
  25. Paavola KJ, Sidik H, Zuchero JB, Eckart M, Talbot WS. 25.  2014. Type IV collagen is an activating ligand for the adhesion G protein–coupled receptor GPR126. Sci. Signal. 7:ra76 [Google Scholar]
  26. Liebscher I, Schon J, Petersen SC, Fischer L, Auerbach N. 26.  et al. 2014. A tethered agonist within the ectodomain activates the adhesion G protein–coupled receptors GPR126 and GPR133. Cell Rep 9:2018–26 [Google Scholar]
  27. Stoveken HM, Hajduczok AG, Xu L, Tall GG. 27.  2015. Adhesion G protein–coupled receptors are activated by exposure of a cryptic tethered agonist. PNAS 112:6194–99 [Google Scholar]
  28. Hu QX, Dong JH, Du HB, Zhang DL, Ren HZ. 28.  et al. 2014. Constitutive Gαi coupling activity of very large G protein–coupled receptor 1 (VLGR1) and its regulation by PDZD7 protein. J. Biol. Chem. 289:24215–25 [Google Scholar]
  29. Liebscher I, Schoneberg T. 29.  2016. Tethered agonism: a common activation mechanism of adhesion GPCRs. See Ref. 162 111–25
  30. Scholz N, Monk KR, Kittel RJ, Langenhan T. 30.  2016. Adhesion GPCRs as a putative class of metabotropic mechanosensors. See Ref. 162 221–47
  31. Wilde C, Fischer L, Lede V, Kirchberger J, Rothemund S. 31.  et al. 2016. The constitutive activity of the adhesion GPCR GPR114/ADGRG5 is mediated by its tethered agonist. FASEB J 30:666–73 [Google Scholar]
  32. Petersen SC, Luo R, Liebscher I, Giera S, Jeong SJ. 32.  et al. 2015. The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211. Neuron 85:755–69 [Google Scholar]
  33. Scholz N, Gehring J, Guan C, Ljaschenko D, Fischer R. 33.  et al. 2015. The adhesion GPCR latrophilin/CIRL shapes mechanosensation. Cell Rep 11:866–74 [Google Scholar]
  34. Demberg LM, Winkler J, Wilde C, Simon KU, Schon J. 34.  et al. 2017. Activation of adhesion G protein–coupled receptors: agonist specificity of Stachel sequence–derived peptides. J. Biol. Chem. 292:4383–94 [Google Scholar]
  35. Lelianova VG, Davletov BA, Sterling A, Rahman MA, Grishin EV. 35.  et al. 1997. α-Latrotoxin receptor, latrophilin, is a novel member of the secretin family of G protein–coupled receptors. J. Biol. Chem. 272:21504–8 [Google Scholar]
  36. Rahman MA, Ashton AC, Meunier FA, Davletov BA, Dolly JO, Ushkaryov YA. 36.  1999. Norepinephrine exocytosis stimulated by α-latrotoxin requires both external and stored Ca2+ and is mediated by latrophilin, G proteins and phospholipase C. Philos. Trans. R. Soc. B 354:379–86 [Google Scholar]
  37. Iguchi T, Sakata K, Yoshizaki K, Tago K, Mizuno N, Itoh H. 37.  2008. Orphan G protein–coupled receptor GPR56 regulates neural progenitor cell migration via a Gα12/13 and Rho pathway. J. Biol. Chem. 283:14469–78 [Google Scholar]
  38. Little KD, Hemler ME, Stipp CS. 38.  2004. Dynamic regulation of a GPCR–tetraspanin–G protein complex on intact cells: central role of CD81 in facilitating GPR56–Gαq/11 association. Mol. Biol. Cell 15:2375–87 [Google Scholar]
  39. Mogha A, Benesh AE, Patra C, Engel FB, Schoneberg T. 39.  et al. 2013. Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation. J. Neurosci. 33:17976–85 [Google Scholar]
  40. Daaka Y, Luttrell LM, Lefkowitz RJ. 40.  1997. Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A. Nature 390:88–91 [Google Scholar]
  41. Mahon MJ, Donowitz M, Yun CC, Segre GV. 41.  2002. Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. Nature 417:858–61 [Google Scholar]
  42. Gupte J, Swaminath G, Danao J, Tian H, Li Y, Wu X. 42.  2012. Signaling property study of adhesion G-protein-coupled receptors. FEBS Lett 586:1214–19 [Google Scholar]
  43. Valtcheva N, Primorac A, Jurisic G, Hollmen M, Detmar M. 43.  2013. The orphan adhesion G protein–coupled receptor GPR97 regulates migration of lymphatic endothelial cells via the small GTPases RhoA and Cdc42. J. Biol. Chem. 288:35736–48 [Google Scholar]
  44. Peeters MC, Mos I, Lenselink EB, Lucchesi M, AP IJ, Schwartz TW. 44.  2016. Getting from A to B—exploring the activation motifs of the class B adhesion G protein–coupled receptor subfamily G member 4/GPR112. FASEB J 30:1836–48 [Google Scholar]
  45. Park D, Tosello-Trampont AC, Elliott MR, Lu M, Haney LB. 45.  et al. 2007. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450:430–34 [Google Scholar]
  46. Duman JG, Tzeng CP, Tu YK, Munjal T, Schwechter B. 46.  et al. 2013. The adhesion-GPCR BAI1 regulates synaptogenesis by controlling the recruitment of the Par3/Tiam1 polarity complex to synaptic sites. J. Neurosci. 33:6964–78 [Google Scholar]
  47. Posokhova E, Shukla A, Seaman S, Volate S, Hilton MB. 47.  et al. 2015. GPR124 functions as a WNT7-specific coactivator of canonical β-catenin signaling. Cell Rep 10:123–30 [Google Scholar]
  48. Shima Y, Kawaguchi SY, Kosaka K, Nakayama M, Hoshino M. 48.  et al. 2007. Opposing roles in neurite growth control by two seven-pass transmembrane cadherins. Nat. Neurosci. 10:963–69 [Google Scholar]
  49. Morgan R, El-Kadi AM, Theokli C. 49.  2003. Flamingo, a cadherin-type receptor involved in the Drosophila planar polarity pathway, can block signaling via the canonical wnt pathway in Xenopus laevis. Int. J. Dev. Biol. 47:245–52 [Google Scholar]
  50. Usui T, Shima Y, Shimada Y, Hirano S, Burgess RW. 50.  et al. 1999. Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of Frizzled. Cell 98:585–95 [Google Scholar]
  51. Nishimura T, Honda H, Takeichi M. 51.  2012. Planar cell polarity links axes of spatial dynamics in neural-tube closure. Cell 149:1084–97 [Google Scholar]
  52. Yates LL, Schnatwinkel C, Murdoch JN, Bogani D, Formstone CJ. 52.  et al. 2010. The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis. Hum. Mol. Genet. 19:2251–67 [Google Scholar]
  53. Shin D, Lin ST, Fu YH, Ptacek LJ. 53.  2013. Very large G protein–coupled receptor 1 regulates myelin-associated glycoprotein via Gαs/Gαq-mediated protein kinases A/C. PNAS 110:19101–6 [Google Scholar]
  54. Krasnoperov VG, Bittner MA, Beavis R, Kuang Y, Salnikow KV. 54.  et al. 1997. α-Latrotoxin stimulates exocytosis by the interaction with a neuronal G-protein-coupled receptor. Neuron 18:925–37 [Google Scholar]
  55. Sugita S, Ichtchenko K, Khvotchev M, Sudhof TC. 55.  1998. α-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors: G-protein coupling not required for triggering exocytosis. J. Biol. Chem. 273:32715–24 [Google Scholar]
  56. Boucard AA, Ko J, Sudhof TC. 56.  2012. High affinity neurexin binding to cell adhesion G-protein-coupled receptor CIRL1/latrophilin-1 produces an intercellular adhesion complex. J. Biol. Chem. 287:9399–413 [Google Scholar]
  57. O'Sullivan ML, de Wit J, Savas JN, Comoletti D, Otto-Hitt S. 57.  et al. 2012. FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development. Neuron 73:903–10 [Google Scholar]
  58. Boucard AA, Maxeiner S, Sudhof TC. 58.  2014. Latrophilins function as heterophilic cell-adhesion molecules by binding to teneurins: regulation by alternative splicing. J. Biol. Chem. 289:387–402 [Google Scholar]
  59. Silva JP, Lelianova VG, Ermolyuk YS, Vysokov N, Hitchen PG. 59.  et al. 2011. Latrophilin 1 and its endogenous ligand Lasso/teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities. PNAS 108:12113–18 [Google Scholar]
  60. Jackson VA, Mehmood S, Chavent M, Roversi P, Carrasquero M. 60.  et al. 2016. Super-complexes of adhesion GPCRs and neural guidance receptors. Nat. Commun. 7:11184 [Google Scholar]
  61. Billings EA, Lee CS, Owen KA, D'Souza RS, Ravichandran KS, Casanova JE. 61.  2016. The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against Gram-negative bacteria. Sci. Signal. 9:ra14 [Google Scholar]
  62. Das S, Owen KA, Ly KT, Park D, Black SG. 62.  et al. 2011. Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria. PNAS 108:2136–41 [Google Scholar]
  63. Koh JT, Kook H, Kee HJ, Seo YW, Jeong BC. 63.  et al. 2004. Extracellular fragment of brain-specific angiogenesis inhibitor 1 suppresses endothelial cell proliferation by blocking αvβ5 integrin. Exp. Cell Res. 294:172–84 [Google Scholar]
  64. Bolliger MF, Martinelli DC, Sudhof TC. 64.  2011. The cell-adhesion G protein–coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins. PNAS 108:2534–39 [Google Scholar]
  65. Sigoillot SM, Iyer K, Binda F, Gonzalez-Calvo I, Talleur M. 65.  et al. 2015. The secreted protein C1QL1 and its receptor BAI3 control the synaptic connectivity of excitatory inputs converging on cerebellar Purkinje cells. Cell Rep 10:820–32 [Google Scholar]
  66. Hamann J, Vogel B, van Schijndel GM, van Lier RA. 66.  1996. The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF). J. Exp. Med. 184:1185–89 [Google Scholar]
  67. Lin HH, Stacey M, Saxby C, Knott V, Chaudhry Y. 67.  et al. 2001. Molecular analysis of the epidermal growth factor–like short consensus repeat domain-mediated protein–protein interactions: dissection of the CD97–CD55 complex. J. Biol. Chem. 276:24160–69 [Google Scholar]
  68. Stacey M, Chang GW, Davies JQ, Kwakkenbos MJ, Sanderson RD. 68.  et al. 2003. The epidermal growth factor–like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans. Blood 102:2916–24 [Google Scholar]
  69. Wandel E, Saalbach A, Sittig D, Gebhardt C, Aust G. 69.  2012. Thy-1 (CD90) is an interacting partner for CD97 on activated endothelial cells. J. Immunol. 188:1442–50 [Google Scholar]
  70. Wang T, Ward Y, Tian L, Lake R, Guedez L. 70.  et al. 2005. CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells. Blood 105:2836–44 [Google Scholar]
  71. Vallon M, Essler M. 71.  2006. Proteolytically processed soluble tumor endothelial marker (TEM) 5 mediates endothelial cell survival during angiogenesis by linking integrin αvβ3 to glycosaminoglycans. J. Biol. Chem. 281:34179–88 [Google Scholar]
  72. Xu L, Begum S, Hearn JD, Hynes RO. 72.  2006. GPR56, an atypical G protein–coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. PNAS 103:9023–28 [Google Scholar]
  73. Yang L, Friedland S, Corson N, Xu L. 73.  2014. GPR56 inhibits melanoma growth by internalizing and degrading its ligand TG2. Cancer Res 74:1022–31 [Google Scholar]
  74. Luo R, Jeong SJ, Jin Z, Strokes N, Li S, Piao X. 74.  2011. G protein–coupled receptor 56 and collagen III, a receptor–ligand pair, regulates cortical development and lamination. PNAS 108:12925–30 [Google Scholar]
  75. Luo R, Jeong SJ, Yang A, Wen M, Saslowsky DE. 75.  et al. 2014. Mechanism for adhesion G protein–coupled receptor GPR56-mediated RhoA activation induced by collagen III stimulation. PLOS ONE 9:e100043 [Google Scholar]
  76. Kuffer A, Lakkaraju AK, Mogha A, Petersen SC, Airich K. 76.  et al. 2016. The prion protein is an agonistic ligand of the G protein–coupled receptor Adgrg6. Nature 536:464–68 [Google Scholar]
  77. Lee JW, Huang BX, Kwon H, Rashid MA, Kharebava G. 77.  et al. 2016. Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function. Nat. Commun. 7:13123 [Google Scholar]
  78. Ludwig MG, Seuwen K, Bridges JP. 78.  2016. Adhesion GPCR function in pulmonary development and disease. See Ref. 162 309–27
  79. Fukuzawa T, Ishida J, Kato A, Ichinose T, Ariestanti DM. 79.  et al. 2013. Lung surfactant levels are regulated by Ig-Hepta/GPR116 by monitoring surfactant protein D. PLOS ONE 8:e69451 [Google Scholar]
  80. Overington JP, Al-Lazikani B, Hopkins AL. 80.  2006. How many drug targets are there?. Nat. Rev. Drug Discov. 5:993–96 [Google Scholar]
  81. Piao X, Hill RS, Bodell A, Chang BS, Basel-Vanagaite L. 81.  et al. 2004. G protein–coupled receptor–dependent development of human frontal cortex. Science 303:2033–36 [Google Scholar]
  82. Chiang NY, Hsiao CC, Huang YS, Chen HY, Hsieh IJ. 82.  et al. 2011. Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms. J. Biol. Chem. 286:14215–25 [Google Scholar]
  83. Jin Z, Tietjen I, Bu L, Liu-Yesucevitz L, Gaur SK. 83.  et al. 2007. Disease-associated mutations affect GPR56 protein trafficking and cell surface expression. Hum. Mol. Genet. 16:1972–85 [Google Scholar]
  84. Piao X, Chang BS, Bodell A, Woods K, Benzeev B. 84.  et al. 2005. Genotype–phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann. Neurol. 58:680–87 [Google Scholar]
  85. Ackerman SD, Garcia C, Piao X, Gutmann DH, Monk KR. 85.  2015. The adhesion GPCR Gpr56 regulates oligodendrocyte development via interactions with Gα12/13 and RhoA. Nat. Commun. 6:6122 [Google Scholar]
  86. Giera S, Deng Y, Luo R, Ackerman SD, Mogha A. 86.  et al. 2015. The adhesion G protein–coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development. Nat. Commun. 6:6121 [Google Scholar]
  87. McMillan DR, White PC. 87.  2010. Studies on the very large G protein–coupled receptor: from initial discovery to determining its role in sensorineural deafness in higher animals. Adhesion-GPCRs: Structure to Function 706 S Yona, M Stacey 76–86 Dordrecht, Neth.: Springer [Google Scholar]
  88. McGee J, Goodyear RJ, McMillan DR, Stauffer EA, Holt JR. 88.  et al. 2006. The very large G-protein-coupled receptor VLGR1: a component of the ankle link complex required for the normal development of auditory hair bundles. J. Neurosci. 26:6543–53 [Google Scholar]
  89. van Wijk E, van der Zwaag B, Peters T, Zimmermann U, Te Brinke H. 89.  et al. 2006. The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1. Hum. Mol. Genet. 15:751–65 [Google Scholar]
  90. Weston MD, Luijendijk MW, Humphrey KD, Moller C, Kimberling WJ. 90.  2004. Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II. Am. J. Hum. Genet. 74:357–66 [Google Scholar]
  91. Curtin JA, Quint E, Tsipouri V, Arkell RM, Cattanach B. 91.  et al. 2003. Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr. Biol. 13:1129–33 [Google Scholar]
  92. Robinson A, Escuin S, Doudney K, Vekemans M, Stevenson RE. 92.  et al. 2012. Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis. Hum. Mutat. 33:440–47 [Google Scholar]
  93. Tissir F, Goffinet AM. 93.  2013. Shaping the nervous system: role of the core planar cell polarity genes. Nat. Rev. Neurosci. 14:525–35 [Google Scholar]
  94. Thakar S, Wang L, Yu T, Ye M, Onishi K. 94.  et al. 2017. Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation. PNAS 114:E610–18 [Google Scholar]
  95. Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR. 95.  et al. 2009. A G protein–coupled receptor is essential for Schwann cells to initiate myelination. Science 325:1402–5 [Google Scholar]
  96. Monk KR, Oshima K, Jors S, Heller S, Talbot WS. 96.  2011. Gpr126 is essential for peripheral nerve development and myelination in mammals. Development 138:2673–80 [Google Scholar]
  97. Anderson KD, Pan L, Yang XM, Hughes VC, Walls JR. 97.  et al. 2011. Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein–coupled receptor. PNAS 108:2807–12 [Google Scholar]
  98. Cullen M, Elzarrad MK, Seaman S, Zudaire E, Stevens J. 98.  et al. 2011. GPR124, an orphan G protein–coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier. PNAS 108:5759–64 [Google Scholar]
  99. Kuhnert F, Mancuso MR, Shamloo A, Wang HT, Choksi V. 99.  et al. 2010. Essential regulation of CNS angiogenesis by the orphan G protein–coupled receptor GPR124. Science 330:985–89 [Google Scholar]
  100. Vanhollebeke B, Stone OA, Bostaille N, Cho C, Zhou Y. 100.  et al. 2015. Tip cell–specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis. eLife 4:e06489 [Google Scholar]
  101. Zhou Y, Nathans J. 101.  2014. Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical Wnt signaling. Dev. Cell 31:248–56 [Google Scholar]
  102. Chang J, Mancuso MR, Maier C, Liang X, Yuki K. 102.  et al. 2017. Gpr124 is essential for blood-brain barrier integrity in central nervous system disease. Nat. Med. 23:450–60 [Google Scholar]
  103. Meza-Aguilar DG, Boucard AA. 103.  2014. Latrophilins updated. Biomol. Concepts 5:457–78 [Google Scholar]
  104. Arcos-Burgos M, Jain M, Acosta MT, Shively S, Stanescu H. 104.  et al. 2010. A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Mol. Psychiatry 15:1053–66 [Google Scholar]
  105. Ribases M, Ramos-Quiroga JA, Sanchez-Mora C, Bosch R, Richarte V. 105.  et al. 2011. Contribution of LPHN3 to the genetic susceptibility to ADHD in adulthood: a replication study. Genes Brain Behav 10:149–57 [Google Scholar]
  106. Wallis D, Hill DS, Mendez IA, Abbott LC, Finnell RH. 106.  et al. 2012. Initial characterization of mice null for Lphn3, a gene implicated in ADHD and addiction. Brain Res 1463:85–92 [Google Scholar]
  107. O'Sullivan ML, Martini F, von Daake S, Comoletti D, Ghosh A. 107.  2014. LPHN3, a presynaptic adhesion-GPCR implicated in ADHD, regulates the strength of neocortical layer 2/3 synaptic input to layer 5. Neural. Dev. 9:7 [Google Scholar]
  108. Lange M, Norton W, Coolen M, Chaminade M, Merker S. 108.  et al. 2012. The ADHD-linked gene Lphn3.1 controls locomotor activity and impulsivity in zebrafish. Mol. Psychiatry 17:855 [Google Scholar]
  109. Zhu D, Li C, Swanson AM, Villalba RM, Guo J. 109.  et al. 2015. BAI1 regulates spatial learning and synaptic plasticity in the hippocampus. J. Clin. Investig. 125:1497–508 [Google Scholar]
  110. DeRosse P, Lencz T, Burdick KE, Siris SG, Kane JM, Malhotra AK. 110.  2008. The genetics of symptom-based phenotypes: toward a molecular classification of schizophrenia. Schizophr. Bull. 34:1047–53 [Google Scholar]
  111. Lanoue V, Usardi A, Sigoillot SM, Talleur M, Iyer K. 111.  et al. 2013. The adhesion-GPCR BAI3, a gene linked to psychiatric disorders, regulates dendrite morphogenesis in neurons. Mol. Psychiatry 18:943–50 [Google Scholar]
  112. Kee HJ, Ahn KY, Choi KC, Won Song J, Heo T. 112.  et al. 2004. Expression of brain-specific angiogenesis inhibitor 3 (BAI3) in normal brain and implications for BAI3 in ischemia-induced brain angiogenesis and malignant glioma. FEBS Lett 569:307–16 [Google Scholar]
  113. Shiratsuchi T, Nishimori H, Ichise H, Nakamura Y, Tokino T. 113.  1997. Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1). Cytogenet. Cell Genet. 79:103–8 [Google Scholar]
  114. Okajima D, Kudo G, Yokota H. 114.  2011. Antidepressant-like behavior in brain-specific angiogenesis inhibitor 2–deficient mice. J. Physiol. Sci. 61:47–54 [Google Scholar]
  115. Aust G, Zhu D, Van Meir EG Xu L. 115.  2016. Adhesion GPCRs in tumorigenesis. See Ref. 162 369–96
  116. O'Hayre M, Vazquez-Prado J, Kufareva I, Stawiski EW, Handel TM. 116.  et al. 2013. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. Nat. Rev. Cancer 13:412–24 [Google Scholar]
  117. Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D. 117.  et al. 2010. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466:869–73 [Google Scholar]
  118. Zendman AJ, Cornelissen IM, Weidle UH, Ruiter DJ, van Muijen GN. 118.  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 446:292–98 [Google Scholar]
  119. Aust G, Eichler W, Laue S, Lehmann I, Heldin NE. 119.  et al. 1997. CD97: a dedifferentiation marker in human thyroid carcinomas. Cancer Res 57:1798–806 [Google Scholar]
  120. Yang L, Chen G, Mohanty S, Scott G, Fazal F. 120.  et al. 2011. GPR56 regulates VEGF production and angiogenesis during melanoma progression. Cancer Res 71:5558–68 [Google Scholar]
  121. Weis SM, Cheresh DA. 121.  2011. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat. Med. 17:1359–70 [Google Scholar]
  122. Cork SM, Kaur B, Devi NS, Cooper L, Saltz JH. 122.  et al. 2012. A proprotein convertase/MMP-14 proteolytic cascade releases a novel 40 kDa vasculostatin from tumor suppressor BAI1. Oncogene 31:5144–52 [Google Scholar]
  123. Kaur B, Brat DJ, Devi NS, Van Meir EG. 123.  2005. Vasculostatin, a proteolytic fragment of brain angiogenesis inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene 24:3632–42 [Google Scholar]
  124. Kaur B, Cork SM, Sandberg EM, Devi NS, Zhang Z. 124.  et al. 2009. Vasculostatin inhibits intracranial glioma growth and negatively regulates in vivo angiogenesis through a CD36-dependent mechanism. Cancer Res 69:1212–20 [Google Scholar]
  125. Zhu D, Hunter SB, Vertino PM, Van Meir EG. 125.  2011. Overexpression of MBD2 in glioblastoma maintains epigenetic silencing and inhibits the antiangiogenic function of the tumor suppressor gene BAI1. Cancer Res 71:5859–70 [Google Scholar]
  126. Safaee M, Clark AJ, Oh MC, Ivan ME, Bloch O. 126.  et al. 2013. Overexpression of CD97 confers an invasive phenotype in glioblastoma cells and is associated with decreased survival of glioblastoma patients. PLOS ONE 8:e62765 [Google Scholar]
  127. Ward Y, Lake R, Martin PL, Killian K, Salerno P. 127.  et al. 2013. CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model. Oncogene 32:2726–38 [Google Scholar]
  128. Tang X, Jin R, Qu G, Wang X, Li Z. 128.  et al. 2013. GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Gaαq–p63RhoGEF–Rho GTPase pathway. Cancer Res 73:6206–18 [Google Scholar]
  129. Dieterich LC, Mellberg S, Langenkamp E, Zhang L, Zieba A. 129.  et al. 2012. Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization. J. Pathol. 228:378–90 [Google Scholar]
  130. Masiero M, Simoes FC, Han HD, Snell C, Peterkin T. 130.  et al. 2013. A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis. Cancer Cell 24:229–41 [Google Scholar]
  131. Towner RA, Jensen RL, Colman H, Vaillant B, Smith N. 131.  et al. 2013. ELTD1, a potential new biomarker for gliomas. Neurosurgery 72:77–90 [Google Scholar]
  132. Bayin NS, Frenster JD, Kane JR, Rubenstein J, Modrek AS. 132.  et al. 2016. GPR133 (ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth. Oncogenesis 5:e263 [Google Scholar]
  133. Hamann J, Hsiao CC, Lee CS, Ravichandran KS, Lin HH. 133.  2016. Adhesion GPCRs as modulators of immune cell function. See Ref. 162 329–50
  134. Boyden SE, Desai A, Cruse G, Young ML, Bolan HC. 134.  et al. 2016. Vibratory urticaria associated with a missense variant in ADGRE2. N. Engl. J. Med. 374:656–63 [Google Scholar]
  135. Capasso M, Durrant LG, Stacey M, Gordon S, Ramage J, Spendlove I. 135.  2006. Costimulation via CD55 on human CD4+ T cells mediated by CD97. J. Immunol. 177:1070–77 [Google Scholar]
  136. Waller-Evans H, Promel S, Langenhan T, Dixon J, Zahn D. 136.  et al. 2010. The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse. PLOS ONE 5:e14047 [Google Scholar]
  137. Patra C, van Amerongen MJ, Ghosh S, Ricciardi F, Sajjad A. 137.  et al. 2013. Organ-specific function of adhesion G protein–coupled receptor GPR126 is domain-dependent. PNAS 110:16898–903 [Google Scholar]
  138. Xiao J, Jiang H, Zhang R, Fan G, Zhang Y. 138.  et al. 2012. Augmented cardiac hypertrophy in response to pressure overload in mice lacking ELTD1. PLOS ONE 7:e35779 [Google Scholar]
  139. Musa G, Engel FB, Niaudet C. 139.  2016. Heart development, angiogenesis, and blood-brain barrier function is modulated by adhesion GPCRs. See Ref. 162 351–68
  140. Doyle SE, Scholz MJ, Greer KA, Hubbard AD, Darnell DK. 140.  et al. 2006. Latrophilin-2 is a novel component of the epithelial–mesenchymal transition within the atrioventricular canal of the embryonic chicken heart. Dev. Dyn. 235:3213–21 [Google Scholar]
  141. Bridges JP, Ludwig MG, Mueller M, Kinzel B, Sato A. 141.  et al. 2013. Orphan G protein–coupled receptor GPR116 regulates pulmonary surfactant pool size. Am. J. Respir. Cell Mol. Biol. 49:348–57 [Google Scholar]
  142. Yang MY, Hilton MB, Seaman S, Haines DC, Nagashima K. 142.  et al. 2013. Essential regulation of lung surfactant homeostasis by the orphan G protein–coupled receptor GPR116. Cell Rep 3:1457–64 [Google Scholar]
  143. Hochreiter-Hufford AE, Lee CS, Kinchen JM, Sokolowski JD, Arandjelovic S. 143.  et al. 2013. Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion. Nature 497:263–67 [Google Scholar]
  144. Hamoud N, Tran V, Croteau LP, Kania A, Cote JF. 144.  2014. G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates. PNAS 111:3745–50 [Google Scholar]
  145. White JP, Wrann CD, Rao RR, Nair SK, Jedrychowski MP. 145.  et al. 2014. G protein–coupled receptor 56 regulates mechanical overload–induced muscle hypertrophy. PNAS 111:15756–61 [Google Scholar]
  146. Ravenscroft G, Nolent F, Rajagopalan S, Meireles AM, Paavola KJ. 146.  et al. 2015. Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita. Am. J. Hum. Genet. 96:955–61 [Google Scholar]
  147. Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L. 147.  et al. 2013. Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat. Genet. 45:676–79 [Google Scholar]
  148. Xu JF, Yang GH, Pan XH, Zhang SJ, Zhao C. 148.  et al. 2015. Association of GPR126 gene polymorphism with adolescent idiopathic scoliosis in Chinese populations. Genomics 105:101–7 [Google Scholar]
  149. Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R. 149.  et al. 2004. Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility. Mol. Cell Biol. 24:8642–48 [Google Scholar]
  150. Stoveken HM, Bahr LL, Anders MW, Wojtovich AP, Smrcka AV, Tall GG. 150.  2016. Dihydromunduletone is a small-molecule selective adhesion G protein–coupled receptor antagonist. Mol. Pharmacol. 90:214–24 [Google Scholar]
  151. Huang YS, Chiang NY, Hu CH, Hsiao CC, Cheng KF. 151.  et al. 2012. 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. 32:1408–20 [Google Scholar]
  152. Yona S, Lin HH, Dri P, Davies JQ, Hayhoe RP. 152.  et al. 2008. Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function. FASEB J 22:741–51 [Google Scholar]
  153. Zolot RS, Basu S, Million RP. 153.  2013. Antibody–drug conjugates. Nat. Rev. Drug Discov. 12:259–60 [Google Scholar]
  154. Arkin MR, Tang Y, Wells JA. 154.  2014. Small-molecule inhibitors of protein–protein interactions: progressing toward the reality. Chem. Biol. 21:1102–14 [Google Scholar]
  155. Salzman GS, Ackerman SD, Ding C, Koide A, Leon K. 155.  et al. 2016. Structural basis for regulation of GPR56/ADGRG1 by its alternatively spliced extracellular domains. Neuron 91:1292–304 [Google Scholar]
  156. Tobaben S, Sudhof TC, Stahl B. 156.  2000. The G protein–coupled receptor CL1 interacts directly with proteins of the Shank family. J. Biol. Chem. 275:36204–10 [Google Scholar]
  157. Kreienkamp HJ, Zitzer H, Gundelfinger ED, Richter D, Bockers TM. 157.  2000. The calcium-independent receptor for α-latrotoxin from human and rodent brains interacts with members of the ProSAP/SSTRIP/Shank family of multidomain proteins. J. Biol. Chem. 275:32387–90 [Google Scholar]
  158. Blazer LL, Neubig RR. 158.  2009. Small molecule protein–protein interaction inhibitors as CNS therapeutic agents: current progress and future hurdles. Neuropsychopharmacology 34:126–41 [Google Scholar]
  159. Wang NX, Lee HJ, Zheng JJ. 159.  2008. Therapeutic use of PDZ protein–protein interaction antagonism. Drug News Perspect 21:137–41 [Google Scholar]
  160. Drag M, Salvesen GS. 160.  2010. Emerging principles in protease-based drug discovery. Nat. Rev. Drug Discov. 9:690–701 [Google Scholar]
  161. Bohnekamp J, Schoneberg T. 161.  2011. Cell adhesion receptor GPR133 couples to Gs protein. J. Biol. Chem. 286:41912–16 [Google Scholar]
  162. Langenhan T, Schöneberg T. 162.  2016. Adhesion G Protein–Coupled Receptors: Molecular, Physiological and Pharmacological Principles in Health and Disease 234 Dordrecht, Neth.: Springer [Google Scholar]
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