Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTSB84Q)

• DOT Name: Adhesion G protein-coupled receptor E5 (ADGRE5)
• Synonyms: Leukocyte antigen CD97; CD antigen CD97
• Gene Name: ADGRE5
• Related Disease:
  Acute undifferentiated leukemia
  Acute myelogenous leukaemia
  Adenocarcinoma
  Adult glioblastoma
  Anaplastic astrocytoma
  B-cell lymphoma
  Brain cancer
  Breast cancer
  Breast carcinoma
  Burkitt lymphoma
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Epithelial ovarian cancer
  Fibrosarcoma
  Glioma
  Intrahepatic cholangiocarcinoma
  Malignant glioma
  Metastatic malignant neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pancreatitis
  Pulmonary fibrosis
  Stomach cancer
  Prostate cancer
  Prostate carcinoma
  Thyroid cancer
  Undifferentiated carcinoma
  Thyroid gland carcinoma
  Thyroid tumor
  Advanced cancer
  Arthritis
  Digestive system neoplasm
  Gastric cancer
  Hepatocellular carcinoma
  Neoplasm
  Pulmonary disease
  Rheumatoid arthritis
  Type-1/2 diabetes
• UniProt ID: AGRE5_HUMAN
• PDB ID: 2BOU; 7DO4; 7YDH; 7YDJ; 7YDM; 7YDP
• Pfam ID: PF00002 ; PF07645 ; PF01825
• Sequence:
  MGGRVFLAFCVWLTLPGAETQDSRGCARWCPQNSSCVNATACRCNPGFSSFSEIITTPTE
  TCDDINECATPSKVSCGKFSDCWNTEGSYDCVCSPGYEPVSGAKTFKNESENTCQDVDEC
  QQNPRLCKSYGTCVNTLGSYTCQCLPGFKFIPEDPKVCTDVNECTSGQNPCHSSTHCLNN
  VGSYQCRCRPGWQPIPGSPNGPNNTVCEDVDECSSGQHQCDSSTVCFNTVGSYSCRCRPG
  WKPRHGIPNNQKDTVCEDMTFSTWTPPPGVHSQTLSRFFDKVQDLGRDSKTSSAEVTIQN
  VIKLVDELMEAPGDVEALAPPVRHLIATQLLSNLEDIMRILAKSLPKGPFTYISPSNTEL
  TLMIQERGDKNVTMGQSSARMKLNWAVAAGAEDPGPAVAGILSIQNMTTLLANASLNLHS
  KKQAELEEIYESSIRGVQLRRLSAVNSIFLSHNNTKELNSPILFAFSHLESSDGEAGRDP
  PAKDVMPGPRQELLCAFWKSDSDRGGHWATEGCQVLGSKNGSTTCQCSHLSSFAILMAHY
  DVEDWKLTLITRVGLALSLFCLLLCILTFLLVRPIQGSRTTIHLHLCICLFVGSTIFLAG
  IENEGGQVGLRCRLVAGLLHYCFLAAFCWMSLEGLELYFLVVRVFQGQGLSTRWLCLIGY
  GVPLLIVGVSAAIYSKGYGRPRYCWLDFEQGFLWSFLGPVTFIILCNAVIFVTTVWKLTQ
  KFSEINPDMKKLKKARALTITAIAQLFLLGCTWVFGLFIFDDRSLVLTYVFTILNCLQGA
  FLYLLHCLLNKKVREEYRKWACLVAGGSKYSEFTSTTSGTGHNQTRALRASESGI
• Function: Receptor potentially involved in both adhesion and signaling processes early after leukocyte activation. Plays an essential role in leukocyte migration.
• Tissue Specificity: Broadly expressed, found on most hematopoietic cells, including activated lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. Expressed also abundantly by smooth muscle cells. Expressed in thyroid, colorectal, gastric, esophageal and pancreatic carcinomas too. Expression are increased under inflammatory conditions in the CNS of multiple sclerosis and in synovial tissue of patients with rheumatoid arthritis. Increased expression of CD97 in the synovium is accompanied by detectable levels of soluble CD97 in the synovial fluid.
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute undifferentiated leukemia	DISJ4SSG	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Anaplastic astrocytoma	DISSBE0K	Strong	Biomarker	[3]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[4]
Brain cancer	DISBKFB7	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Burkitt lymphoma	DIS9D5XU	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[6]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[9]
Fibrosarcoma	DISWX7MU	Strong	Altered Expression	[10]
Glioma	DIS5RPEH	Strong	Altered Expression	[11]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[12]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[13]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[14]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[9]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[9]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[15]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[16]
Stomach cancer	DISKIJSX	Strong	Biomarker	[17]
Prostate cancer	DISF190Y	moderate	Altered Expression	[18]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[18]
Thyroid cancer	DIS3VLDH	moderate	Altered Expression	[19]
Undifferentiated carcinoma	DISIAZST	moderate	Altered Expression	[19]
Thyroid gland carcinoma	DISMNGZ0	Disputed	Altered Expression	[19]
Thyroid tumor	DISLVKMD	Disputed	Biomarker	[19]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[20]
Arthritis	DIST1YEL	Limited	Biomarker	[21]
Digestive system neoplasm	DISPOJCT	Limited	Biomarker	[22]
Gastric cancer	DISXGOUK	Limited	Biomarker	[17]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[23]
Neoplasm	DISZKGEW	Limited	Biomarker	[4]
Pulmonary disease	DIS6060I	Limited	Biomarker	[24]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[21]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[28]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[29]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[30]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[31]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[32]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[33]
Marinol	DM70IK5	Approved	Marinol increases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[34]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[35]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[36]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[37]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[38]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[39]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[40]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[30]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[30]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[44]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[45]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Adhesion G protein-coupled receptor E5 (ADGRE5).	[46]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Adhesion G protein-coupled receptor E5 (ADGRE5).	[41]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Adhesion G protein-coupled receptor E5 (ADGRE5).	[43]

References

• [1] CD97 is a critical regulator of acute myeloid leukemia stem cell function.J Exp Med. 2019 Oct 7;216(10):2362-2377. doi: 10.1084/jem.20190598. Epub 2019 Aug 1.
• [2] The invasion and metastasis promotion role of CD97 small isoform in gastric carcinoma.PLoS One. 2012;7(6):e39989. doi: 10.1371/journal.pone.0039989. Epub 2012 Jun 29.
• [3] Proportional upregulation of CD97 isoforms in glioblastoma and glioblastoma-derived brain tumor initiating cells.PLoS One. 2015 Feb 25;10(2):e0111532. doi: 10.1371/journal.pone.0111532. eCollection 2015.
• [4] Identification of ADGRE5 as discriminating MYC target between Burkitt lymphoma and diffuse large B-cell lymphoma.BMC Cancer. 2019 Apr 5;19(1):322. doi: 10.1186/s12885-019-5537-0.
• [5] Effects of targeted CD97 immune epitopes small interference RNA on cellular biological behaviors in MDA-MB231 malignant breast cancer cell line.Am J Transl Res. 2017 Oct 15;9(10):4640-4651. eCollection 2017.
• [6] Role of CD97 small isoform in human cervical carcinoma.Int J Exp Pathol. 2019 Feb;100(1):19-24. doi: 10.1111/iep.12303. Epub 2019 Mar 18.
• [7] The Interaction of CD97/ADGRE5 With -Catenin in Adherens Junctions Is Lost During Colorectal Carcinogenesis.Front Oncol. 2018 May 25;8:182. doi: 10.3389/fonc.2018.00182. eCollection 2018.
• [8] CD97 overexpression in tumor cells at the invasion front in colorectal cancer (CC) is independently regulated of the canonical Wnt pathway.Mol Carcinog. 2006 Nov;45(11):881-6. doi: 10.1002/mc.20262.
• [9] MicroRNA-503-5p Inhibits the CD97-Mediated JAK2/STAT3 Pathway in Metastatic or Paclitaxel-Resistant Ovarian Cancer Cells.Neoplasia. 2019 Feb;21(2):206-215. doi: 10.1016/j.neo.2018.12.005. Epub 2019 Jan 9.
• [10] CD97 inhibits cell migration in human fibrosarcoma cells by modulating TIMP-2/MT1- MMP/MMP-2 activity--role of GPS autoproteolysis and functional cooperation between the N- and C-terminal fragments.FEBS J. 2014 Nov;281(21):4878-91. doi: 10.1111/febs.13027. Epub 2014 Sep 22.
• [11] Overexpression of CD97 confers an invasive phenotype in glioblastoma cells and is associated with decreased survival of glioblastoma patients.PLoS One. 2013 Apr 26;8(4):e62765. doi: 10.1371/journal.pone.0062765. Print 2013.
• [12] Expression and prognostic value of soluble CD97 and its ligand CD55 in intrahepatic cholangiocarcinoma.Tumour Biol. 2017 Mar;39(3):1010428317694319. doi: 10.1177/1010428317694319.
• [13] Novel report of expression and function of CD97 in malignant gliomas: correlation with Wilms tumor 1 expression and glioma cell invasiveness.J Neurosurg. 2012 Apr;116(4):843-53. doi: 10.3171/2011.11.JNS111455. Epub 2012 Feb 7.
• [14] The epigenetic factor BORIS (CTCFL) controls the androgen receptor regulatory network in ovarian cancer.Oncogenesis. 2019 Aug 12;8(8):41. doi: 10.1038/s41389-019-0150-2.
• [15] CD97, CD95 and Fas-L clearly discriminate between chronic pancreatitis and pancreatic ductal adenocarcinoma in perioperative evaluation of cryocut sections.Pathol Int. 2002 Feb;52(2):83-8. doi: 10.1046/j.1440-1827.2002.01324.x.
• [16] Cell-surface phenotyping identifies CD36 and CD97 as novel markers of fibroblast quiescence in lung fibrosis.Am J Physiol Lung Cell Mol Physiol. 2018 Nov 1;315(5):L682-L696. doi: 10.1152/ajplung.00439.2017. Epub 2018 Jun 28.
• [17] CD97 promotion of gastric carcinoma lymphatic metastasis is exosome dependent.Gastric Cancer. 2016 Jul;19(3):754-66. doi: 10.1007/s10120-015-0523-y. Epub 2015 Aug 2.
• [18] LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells.Cancer Res. 2011 Dec 1;71(23):7301-11. doi: 10.1158/0008-5472.CAN-11-2381. Epub 2011 Oct 6.
• [19] CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model.Oncogene. 2013 May 30;32(22):2726-38. doi: 10.1038/onc.2012.301. Epub 2012 Jul 16.
• [20] A-to-I-edited miRNA-379-5p inhibits cancer cell proliferation through CD97-induced apoptosis.J Clin Invest. 2019 Dec 2;129(12):5343-5356. doi: 10.1172/JCI123396.
• [21] Deletion of either CD55 or CD97 ameliorates arthritis in mouse models.Arthritis Rheum. 2010 Apr;62(4):1036-42. doi: 10.1002/art.27347.
• [22] 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. 2004 Dec 10;112(5):815-22. doi: 10.1002/ijc.20483.
• [23] CD97 Promotes Tumor Aggressiveness Through the Traditional G Protein-Coupled Receptor-Mediated Signaling in Hepatocellular Carcinoma.Hepatology. 2018 Nov;68(5):1865-1878. doi: 10.1002/hep.30068. Epub 2018 Sep 22.
• [24] Blood gene expression profiling detects silica exposure and toxicity.Toxicol Sci. 2011 Aug;122(2):253-64. doi: 10.1093/toxsci/kfr125. Epub 2011 May 19.
• [25] Lentivirusmediated overexpression of CD97/ADGRE5 reverses dysregulated high glucoseinduced endothelial cell migration.Mol Med Rep. 2017 May;15(5):3048-3054. doi: 10.3892/mmr.2017.6417. Epub 2017 Mar 30.
• [26] 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.
• [27] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [29] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [30] Antiproliferation and redifferentiation in thyroid cancer cell lines by polyphenol phytochemicals. J Korean Med Sci. 2011 Jul;26(7):893-9. doi: 10.3346/jkms.2011.26.7.893. Epub 2011 Jun 20.
• [31] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [32] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [33] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [34] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [35] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [36] 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.
• [37] Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines. Thyroid. 2005 Mar;15(3):222-31. doi: 10.1089/thy.2005.15.222.
• [38] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [39] Ultradian cortisol pulsatility encodes a distinct, biologically important signal. PLoS One. 2011 Jan 18;6(1):e15766.
• [40] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [41] 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.
• [42] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [43] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [44] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [45] 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.
• [46] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.