Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBT4W36)

• DOT Name: Adhesion G protein-coupled receptor A2 (ADGRA2)
• Synonyms: G-protein coupled receptor 124; Tumor endothelial marker 5
• Gene Name: ADGRA2
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Colorectal carcinoma
  Lung adenocarcinoma
  Multiple sclerosis
  Neoplasm
  Non-small-cell lung cancer
  Vascular dementia
  High blood pressure
  Adult glioblastoma
  Glioblastoma multiforme
• UniProt ID: AGRA2_HUMAN
• Pfam ID: PF00002 ; PF01825 ; PF13855
• Sequence:
  MGAGGRRMRGAPARLLLPLLPWLLLLLAPEARGAPGCPLSIRSCKCSGERPKGLSGGVPG
  PARRRVVCSGGDLPEPPEPGLLPNGTVTLLLSNNKITGLRNGSFLGLSLLEKLDLRNNII
  STVQPGAFLGLGELKRLDLSNNRIGCLTSETFQGLPRLLRLNISGNIFSSLQPGVFDELP
  ALKVVDLGTEFLTCDCHLRWLLPWAQNRSLQLSEHTLCAYPSALHAQALGSLQEAQLCCE
  GALELHTHHLIPSLRQVVFQGDRLPFQCSASYLGNDTRIRWYHNRAPVEGDEQAGILLAE
  SLIHDCTFITSELTLSHIGVWASGEWECTVSMAQGNASKKVEIVVLETSASYCPAERVAN
  NRGDFRWPRTLAGITAYQSCLQYPFTSVPLGGGAPGTRASRRCDRAGRWEPGDYSHCLYT
  NDITRVLYTFVLMPINASNALTLAHQLRVYTAEAASFSDMMDVVYVAQMIQKFLGYVDQI
  KELVEVMVDMASNLMLVDEHLLWLAQREDKACSRIVGALERIGGAALSPHAQHISVNARN
  VALEAYLIKPHSYVGLTCTAFQRREGGVPGTRPGSPGQNPPPEPEPPADQQLRFRCTTGR
  PNVSLSSFHIKNSVALASIQLPPSLFSSLPAALAPPVPPDCTLQLLVFRNGRLFHSHSNT
  SRPGAAGPGKRRGVATPVIFAGTSGCGVGNLTEPVAVSLRHWAEGAEPVAAWWSQEGPGE
  AGGWTSEGCQLRSSQPNVSALHCQHLGNVAVLMELSAFPREVGGAGAGLHPVVYPCTALL
  LLCLFATIITYILNHSSIRVSRKGWHMLLNLCFHIAMTSAVFAGGITLTNYQMVCQAVGI
  TLHYSSLSTLLWMGVKARVLHKELTWRAPPPQEGDPALPTPSPMLRFYLIAGGIPLIICG
  ITAAVNIHNYRDHSPYCWLVWRPSLGAFYIPVALILLITWIYFLCAGLRLRGPLAQNPKA
  GNSRASLEAGEELRGSTRLRGSGPLLSDSGSLLATGSARVGTPGPPEDGDSLYSPGVQLG
  ALVTTHFLYLAMWACGALAVSQRWLPRVVCSCLYGVAASALGLFVFTHHCARRRDVRASW
  RACCPPASPAAPHAPPRALPAAAEDGSPVFGEGPPSLKSSPSGSSGHPLALGPCKLTNLQ
  LAQSQVCEAGAAAGGEGEPEPAGTRGNLAHRHPNNVHHGRRAHKSRAKGHRAGEACGKNR
  LKALRGGAAGALELLSSESGSLHNSPTDSYLGSSRNSPGAGLQLEGEPMLTPSEGSDTSA
  APLSEAGRAGQRRSASRDSLKGGGALEKESHRRSYPLNAASLNGAPKGGKYDDVTLMGAE
  VASGGCMKTGLWKSETTV
• Function: Endothelial receptor which functions together with RECK to enable brain endothelial cells to selectively respond to Wnt7 signals (WNT7A or WNT7B). Plays a key role in Wnt7-specific responses, such as endothelial cell sprouting and migration in the forebrain and neural tube, and establishment of the blood-brain barrier. Acts as a Wnt7-specific coactivator of canonical Wnt signaling: required to deliver RECK-bound Wnt7 to frizzled by assembling a higher-order RECK-ADGRA2-Fzd-LRP5-LRP6 complex. ADGRA2-tethering function does not rely on its G-protein coupled receptor (GPCR) structure but instead on its combined capacity to interact with RECK extracellularly and recruit the Dishevelled scaffolding protein intracellularly. Binds to the glycosaminoglycans heparin, heparin sulfate, chondroitin sulfate and dermatan sulfate.
• Tissue Specificity: Expressed in endothelial cells (at protein level) . Abundantly expressed in heart, placenta, ovary, small intestine, and colon .

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Genetic Variation	[1]
Prostate carcinoma	DISMJPLE	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Vascular dementia	DISVO82H	Strong	Biomarker	[7]
High blood pressure	DISY2OHH	moderate	Biomarker	[8]
Adult glioblastoma	DISVP4LU	Disputed	Altered Expression	[9]
Glioblastoma multiforme	DISK8246	Disputed	Altered Expression	[9]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Adhesion G protein-coupled receptor A2 (ADGRA2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Adhesion G protein-coupled receptor A2 (ADGRA2).	[16]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Adhesion G protein-coupled receptor A2 (ADGRA2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adhesion G protein-coupled receptor A2 (ADGRA2).	[12]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Adhesion G protein-coupled receptor A2 (ADGRA2).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Adhesion G protein-coupled receptor A2 (ADGRA2).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Adhesion G protein-coupled receptor A2 (ADGRA2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Adhesion G protein-coupled receptor A2 (ADGRA2).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Adhesion G protein-coupled receptor A2 (ADGRA2).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Adhesion G protein-coupled receptor A2 (ADGRA2).	[19]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Adhesion G protein-coupled receptor A2 (ADGRA2).	[20]

References

• [1] Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer.Urol Oncol. 2016 Mar;34(3):120.e9-16. doi: 10.1016/j.urolonc.2015.10.009. Epub 2015 Nov 14.
• [2] Serum TEM5 and TEM7 concentrations correlate with clinicopathologic features and poor prognosis of colorectal cancer patients.Adv Med Sci. 2019 Sep;64(2):402-408. doi: 10.1016/j.advms.2019.07.001. Epub 2019 Jul 25.
• [3] Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation.Cell Physiol Biochem. 2018;45(2):547-557. doi: 10.1159/000487032. Epub 2018 Jan 25.
• [4] miR-138-5p reverses gefitinib resistance in non-small cell lung cancer cells via negatively regulating G protein-coupled receptor 124.Biochem Biophys Res Commun. 2014 Mar 28;446(1):179-86. doi: 10.1016/j.bbrc.2014.02.073. Epub 2014 Feb 28.
• [5] The role of orphan G protein-coupled receptors in the pathophysiology of multiple sclerosis: A review.Life Sci. 2019 May 1;224:33-40. doi: 10.1016/j.lfs.2019.03.045. Epub 2019 Mar 20.
• [6] G-protein coupled receptor 124 (GPR124) in endothelial cells regulates vascular endothelial growth factor (VEGF)-induced tumor angiogenesis.Curr Mol Med. 2014 May;14(4):543-54. doi: 10.2174/1566524014666140414205943.
• [7] A Novel Octapeptide Derived From G Protein-Coupled Receptor 124 Improves Cognitive Function Via Pro-Angiogenesis In A Rat Model Of Chronic Cerebral Hypoperfusion-Induced Vascular Dementia.Drug Des Devel Ther. 2019 Oct 23;13:3669-3682. doi: 10.2147/DDDT.S226473. eCollection 2019.
• [8] Possible involvement of orphan receptors GPR88 and GPR124 in the development of hypertension in spontaneously hypertensive rat.Clin Exp Hypertens. 2017;39(6):513-519. doi: 10.1080/10641963.2016.1273949. Epub 2017 Jul 5.
• [9] GPR124 regulates microtubule assembly, mitotic progression, and glioblastoma cell proliferation.Glia. 2019 Aug;67(8):1558-1570. doi: 10.1002/glia.23628. Epub 2019 May 6.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [13] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [14] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation. J Clin Med. 2020 Feb 3;9(2):405. doi: 10.3390/jcm9020405.
• [18] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [19] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [20] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.