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ADGRA2

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Target not currently curated in GtoImmuPdb

Target id: 198

Nomenclature: ADGRA2

Family: Adhesion Class GPCRs

Contents:

Gene and Protein Information Click here for help
Adhesion G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 1338 8p11.23 ADGRA2 adhesion G protein-coupled receptor A2 6
Mouse 7 1336 8 A2 Adgra2 adhesion G protein-coupled receptor A2 6
Rat 7 - 16q12.4 Adgra2 adhesion G protein-coupled receptor A2
Previous and Unofficial Names Click here for help
GPR124 (G protein-coupled receptor 124)
Database Links Click here for help
Specialist databases
GPCRdb gp124_human (Hs), agra2_mouse (Mm)
Other databases
Alphafold Q96PE1 (Hs), Q91ZV8 (Mm)
CATH/Gene3D 2.60.40.10, 4.10.1240.10, 3.80.10.10
ChEMBL Target CHEMBL4523909 (Hs)
Ensembl Gene ENSG00000020181 (Hs), ENSMUSG00000031486 (Mm)
Entrez Gene 25960 (Hs), 78560 (Mm), 306543 (Rn)
Human Protein Atlas ENSG00000020181 (Hs)
KEGG Gene hsa:25960 (Hs), mmu:78560 (Mm), rno:306543 (Rn)
OMIM 606823 (Hs)
Pharos Q96PE1 (Hs)
RefSeq Nucleotide NM_032777 (Hs), NM_054044 (Mm)
RefSeq Protein NP_116166 (Hs), NP_473385 (Mm)
UniProtKB Q96PE1 (Hs), Q91ZV8 (Mm)
Wikipedia ADGRA2 (Hs)
Agonist Comments
ADGRA2 has been shown to bind several GAGs (glycosaminoglycans) found in the extracellular membrane [22].
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
G protein (identity unknown)
Comments:  Predicted to transduce signal through G proteins based on sequence signatures [8]. However, studies on several different adhesion GPCRs have provided evidence that these receptors are in fact authentic G protein-coupled receptors. Adhesion GPCRs with experimentally verified G-protein coupling includes ADGRG1 [12], ADGRD1 [5] and ADGRG6 [15]. Recent reviews [17] and adhesion GPCR consortium meeting report [2] addressed the issues to unravel the signal transduction of adhesion GPCRs and provided further preliminary evidences [9] for other adhesion GPCRs to transduce signal through G proteins.
References: 
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
G protein (identity unknown)
References: 
Tissue Distribution Click here for help
Placenta, prostate, ovary > heart, skeletal muscle, small intestine, colon > lung, liver, kidney, pancreas, spleen, testis. Not detected in the brain, thymus or white blood cells.
Species:  Human
Technique:  Northern blotting.
References:  24
Tumor endothelial cells and cell lines
Species:  Human
Technique:  RT-PCR, SAGE and immunohistochemistry
References:  20,22-23
Heart, placenta, prostate, ovary, small intestine and colon, present in tumors of breast, uterus and liver
Species:  Human
Technique:  Northern blot and RT-PCR
References:  24
Expressed in brain, heart, intestine, lung, skeletal muscle, pancreas and in melanoma, not found in adrenal gland, kidney cortex, kidney medulla, liver, spleen and stomach
Species:  Mouse
Technique:  in situ hybridisation and RT-PCR
References:  6,10
Branchial arches, limb bud, somite of early embryo
Species:  Mouse
Technique:  In situ hybridisation
References:  11
Expressed during embryogenesis in both endothelial cells and pericytes, most prominently in brain and neural tube, and to lesser degrees in non-CNS embryonic organs, including liver, heart and kidney, also expressed in embryonic epithelium of lung and esophagus and in mesenchyme. Adult expression exclusively vascular, with endothelial expression in CNS including the brain and retina, and more widespread pericyte expression in the brain and organs, including the kidney, pancreas and corpus luteum
Species:  Mouse
Technique:  Immunohistochemistry, RT-PCR and hybridisation
References:  1,7,14
Expression Datasets Click here for help

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

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Functional Assays Click here for help
ADGRA2+ bEND3 display collective cell migration and robust formation of stable sprouts toward forebrain CM gradients, but no sprout formation was observed in hindbrain
Species:  Mouse
Tissue:  Embryonic forebrain and hindbrain endothelial cells
Response measured:  Sprout formation
References:  14
ADGRA2-overexpressing bEND3 cells exhibit directed migration toward gradients of forebrain cortical cells but migrate randomly to equivalent hindbrain
Species:  Mouse
Tissue:  Embryonic forebrain and hindbrain endothelial cells
Response measured:  Endothelial cell migration
References:  14
Physiological Functions Click here for help
Directs brain-specific angiogenesis
Species:  Mouse
Tissue:  Endothelial cells
References:  14
Required for proper angiogenic sprouting into the developing neural tube in mammals
Species:  Mouse
Tissue:  Fore brain and spinal cord
References:  1
Required for invasion and migration of blood vessels into neuroepithelium, establishment of blood brain barrier properties, and expansion of the cerebral cortex
Species:  Mouse
Tissue:  Endothelial cells, astrocytes, pericytes, embryonic stem cells
References:  7
Physiological Consequences of Altering Gene Expression Click here for help
Knockout results in embryonic lethality: CNS-specific angiogenesis arrest in forebrain and neural tube, and CNS-specific vascular patterning defects with markedly reduced angiogenic sprouting into the forebrain telencephalon. These angiogenic phenotypes are highly restricted to the CNS vasculature
Species:  Mouse
Tissue:  Full-body and tissue-specific (PDGFB promotor-driven) knockouts
Technique:  Gene knockouts
References:  14
Brain-specific vascular phenotype; CNS-specific hyperproliferative vascular malformations
Species:  Mouse
Tissue:  Tissue-specific Tie2 promotor-driven overexpression
Technique:  Gene over-expression
References:  14
Abnormal vascular phenotype. Vascular defects characterized by delayed vascular penetration, formation of pathological glomeruloid tufts within the CNS, and hemorrhage, in addition, defects in palate and lung development, knockout results in perturbed TGF-β pathway activation
Species:  Mouse
Tissue:  Full body knockout
Technique:  Gene knockouts
References:  1
Intracranial hemorrhage in the forebrain. Embryonic lethality associated with abnormal angiogenesis of the forebrain and spinal cord
Species:  Mouse
Tissue:  Full-body knockout
Technique:  Gene knockouts
References:  7
Biologically Significant Variants Click here for help
Type:  Splice variant
Species:  Human
Description:  The physiological effect of this variant is unknown.
Amino acids:  1338
Nucleotide accession:  ENST00000412232
Protein accession:  ENSP00000406367
References:  4
General Comments
ADGRA2 (formerly GPR124) is a receptor that belongs to Family III Adhesion-GPCRs together with ADGRA1 and 3 [3]. The gene is localized on human chromosome 8 and mouse chromosome 8. Phylogenetic analysis suggests that ADGRA1-3 share a common ancestor suggesting the evolution from an ancestral gene through gene duplication [3]. Deuterostome invertebrates like ciona, amphioxus, sea urchin and acorn worms contain a single copy that is very similar to ADGRA1-3 [13,16,18] indicating a gene duplication event at the emergence of vertebrates. ADGRA2 in human is 1338 amino acids long and has a GPCR proteolysis site (GPS), Ig-like domain and leucin-rich repeats (LRR) in the N terminus. Human ADGRA2 has a functional splice variant that lacks the GPS [4]. Furthermore, ADGRA2 has a RGD motif in the N terminus, which is found in several proteins of the ECM and mediates cell adhesion by binding to specific integrins on the cell surface [21]. Some RGD motifs found in ECM proteins are cryptic and become exposed upon proteolytic processing of the protein [19]. Similarly, ADGRA2 has a cryptic RGD motif, which is shed by thrombin (a "trypsin-like" serine protease). This shedding of ADGRA2 is regulated by protein disulfide-isomerase [21].

References

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1. Anderson KD, Pan L, Yang XM, Hughes VC, Walls JR, Dominguez MG, Simmons MV, Burfeind P, Xue Y, Wei Y et al.. (2011) Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor. Proc Natl Acad Sci USA, 108 (7): 2807-12. [PMID:21282641]

2. Araç D, Aust G, Calebiro D, Engel FB, Formstone C, Goffinet A, Hamann J, Kittel RJ, Liebscher I, Lin HH et al.. (2012) Dissecting signaling and functions of adhesion G protein-coupled receptors. Ann N Y Acad Sci, 1276: 1-25. [PMID:23215895]

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

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

5. Bohnekamp J, Schöneberg T. (2011) Cell adhesion receptor GPR133 couples to Gs protein. J Biol Chem, 286 (49): 41912-6. [PMID:22025619]

6. Carson-Walter EB, Watkins DN, Nanda A, Vogelstein B, Kinzler KW, St Croix B. (2001) Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res, 61 (18): 6649-55. [PMID:11559528]

7. Cullen M, Elzarrad MK, Seaman S, Zudaire E, Stevens J, Yang MY, Li X, Chaudhary A, Xu L, Hilton MB et al.. (2011) 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 (14): 5759-64. [PMID:21421844]

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

9. Gupte J, Swaminath G, Danao J, Tian H, Li Y, Wu X. (2012) Signaling property study of adhesion G-protein-coupled receptors. FEBS Lett, 586 (8): 1214-9. [PMID:22575658]

10. Haitina T, Olsson F, Stephansson O, Alsiö J, Roman E, Ebendal T, Schiöth HB, Fredriksson R. (2008) Expression profile of the entire family of Adhesion G protein-coupled receptors in mouse and rat. BMC Neurosci, 9: 43. [PMID:18445277]

11. Homma S, Shimada T, Hikake T, Yaginuma H. (2009) Expression pattern of LRR and Ig domain-containing protein (LRRIG protein) in the early mouse embryo. Gene Expr Patterns, 9 (1): 1-26. [PMID:18848646]

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

13. Kamesh N, Aradhyam GK, Manoj N. (2008) The repertoire of G protein-coupled receptors in the sea squirt Ciona intestinalis. BMC Evol Biol, 8: 129. [PMID:18452600]

14. Kuhnert F, Mancuso MR, Shamloo A, Wang HT, Choksi V, Florek M, Su H, Fruttiger M, Young WL, Heilshorn SC et al.. (2010) Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124. Science, 330 (6006): 985-9. [PMID:21071672]

15. Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, Moens CB, Talbot WS. (2009) A G protein-coupled receptor is essential for Schwann cells to initiate myelination. Science, 325 (5946): 1402-5. [PMID:19745155]

16. Nordström KJ, Fredriksson R, Schiöth HB. (2008) The amphioxus (Branchiostoma floridae) genome contains a highly diversified set of G protein-coupled receptors. BMC Evol Biol, 8: 9. [PMID:18199322]

17. Paavola KJ, Hall RA. (2012) Adhesion G protein-coupled receptors: signaling, pharmacology, and mechanisms of activation. Mol Pharmacol, 82 (5): 777-83. [PMID:22821233]

18. Raible F, Tessmar-Raible K, Arboleda E, Kaller T, Bork P, Arendt D, Arnone MI. (2006) Opsins and clusters of sensory G-protein-coupled receptors in the sea urchin genome. Dev Biol, 300 (1): 461-75. [PMID:17067569]

19. Senger DR, Perruzzi CA, Papadopoulos-Sergiou A, Van de Water L. (1994) Adhesive properties of osteopontin: regulation by a naturally occurring thrombin-cleavage in close proximity to the GRGDS cell-binding domain. Mol Biol Cell, 5 (5): 565-74. [PMID:7522656]

20. St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, Lal A, Riggins GJ, Lengauer C, Vogelstein B et al.. (2000) Genes expressed in human tumor endothelium. Science, 289 (5482): 1197-202. [PMID:10947988]

21. Vallon M, Aubele P, Janssen KP, Essler M. (2012) Thrombin-induced shedding of tumour endothelial marker 5 and exposure of its RGD motif are regulated by cell-surface protein disulfide-isomerase. Biochem J, 441 (3): 937-44. [PMID:22013897]

22. Vallon M, Essler M. (2006) Proteolytically processed soluble tumor endothelial marker (TEM) 5 mediates endothelial cell survival during angiogenesis by linking integrin alpha(v)beta3 to glycosaminoglycans. J Biol Chem, 281 (45): 34179-88. [PMID:16982628]

23. Vallon M, Rohde F, Janssen KP, Essler M. (2010) Tumor endothelial marker 5 expression in endothelial cells during capillary morphogenesis is induced by the small GTPase Rac and mediates contact inhibition of cell proliferation. Exp Cell Res, 316 (3): 412-21. [PMID:19853600]

24. Yamamoto Y, Irie K, Asada M, Mino A, Mandai K, Takai Y. (2004) Direct binding of the human homologue of the Drosophila disc large tumor suppressor gene to seven-pass transmembrane proteins, tumor endothelial marker 5 (TEM5), and a novel TEM5-like protein. Oncogene, 23 (22): 3889-97. [PMID:15021905]

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