Details of Drug Off-Target (DOT)

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

• DOT Name: Adhesion G protein-coupled receptor E2 (ADGRE2)
• Synonyms: EGF-like module receptor 2; EGF-like module-containing mucin-like hormone receptor-like 2; CD antigen CD312
• Gene Name: ADGRE2
• Related Disease:
  Acute undifferentiated leukemia
  Acute myelogenous leukaemia
  Adenocarcinoma
  Anaplastic astrocytoma
  B-cell lymphoma
  Brain cancer
  Burkitt lymphoma
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Epithelial ovarian cancer
  Fibrosarcoma
  Glioma
  Intrahepatic cholangiocarcinoma
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Malignant glioma
  Metastatic malignant neoplasm
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pancreatitis
  Pulmonary fibrosis
  Stomach cancer
  Vibratory urticaria
  Prostate cancer
  Prostate carcinoma
  Thyroid cancer
  Undifferentiated carcinoma
  Autosomal dominant vibratory urticaria
  Ductal breast carcinoma in situ
  Invasive breast carcinoma
  Thyroid gland carcinoma
  Thyroid tumor
  Advanced cancer
  Arthritis
  Breast cancer
  Breast carcinoma
  Digestive system neoplasm
  Gastric cancer
  Hepatocellular carcinoma
  Rheumatoid arthritis
• UniProt ID: AGRE2_HUMAN
• PDB ID: 2BO2; 2BOU; 2BOX
• Pfam ID: PF00002 ; PF07645 ; PF01825
• Sequence:
  MGGRVFLVFLAFCVWLTLPGAETQDSRGCARWCPQDSSCVNATACRCNPGFSSFSEIITT
  PMETCDDINECATLSKVSCGKFSDCWNTEGSYDCVCSPGYEPVSGAKTFKNESENTCQDV
  DECQQNPRLCKSYGTCVNTLGSYTCQCLPGFKLKPEDPKLCTDVNECTSGQNPCHSSTHC
  LNNVGSYQCRCRPGWQPIPGSPNGPNNTVCEDVDECSSGQHQCDSSTVCFNTVGSYSCRC
  RPGWKPRHGIPNNQKDTVCEDMTFSTWTPPPGVHSQTLSRFFDKVQDLGRDYKPGLANNT
  IQSILQALDELLEAPGDLETLPRLQQHCVASHLLDGLEDVLRGLSKNLSNGLLNFSYPAG
  TELSLEVQKQVDRSVTLRQNQAVMQLDWNQAQKSGDPGPSVVGLVSIPGMGKLLAEAPLV
  LEPEKQMLLHETHQGLLQDGSPILLSDVISAFLSNNDTQNLSSPVTFTFSHRSVIPRQKV
  LCVFWEHGQNGCGHWATTGCSTIGTRDTSTICRCTHLSSFAVLMAHYDVQEEDPVLTVIT
  YMGLSVSLLCLLLAALTFLLCKAIQNTSTSLHLQLSLCLFLAHLLFLVAIDQTGHKVLCS
  IIAGTLHYLYLATLTWMLLEALYLFLTARNLTVVNYSSINRFMKKLMFPVGYGVPAVTVA
  ISAASRPHLYGTPSRCWLQPEKGFIWGFLGPVCAIFSVNLVLFLVTLWILKNRLSSLNSE
  VSTLRNTRMLAFKATAQLFILGCTWCLGILQVGPAARVMAYLFTIINSLQGVFIFLVYCL
  LSQQVREQYGKWSKGIRKLKTESEMHTLSSSAKADTSKPSTVN
• Function: Cell surface receptor that binds to the chondroitin sulfate moiety of glycosaminoglycan chains and promotes cell attachment. Promotes granulocyte chemotaxis, degranulation and adhesion. In macrophages, promotes the release of inflammatory cytokines, including IL8 and TNF. Signals probably through G-proteins. Is a regulator of mast cell degranulation.
• Tissue Specificity: Expression is restricted to myeloid cells. Highest expression was found in peripheral blood leukocytes, followed by spleen and lymph nodes, with intermediate to low levels in thymus, bone marrow, fetal liver, placenta, and lung, and no expression in heart, brain, skeletal muscle, kidney, or pancreas. Expression is also detected in monocyte/macrophage and Jurkat cell lines but not in other cell lines tested. High expression in mast cells .
• Reactome Pathway: Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

44 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]
Anaplastic astrocytoma	DISSBE0K	Strong	Biomarker	[3]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[4]
Brain cancer	DISBKFB7	Strong	Biomarker	[3]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[8]
Fibrosarcoma	DISWX7MU	Strong	Altered Expression	[9]
Glioma	DIS5RPEH	Strong	Altered Expression	[10]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[2]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[2]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[12]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[13]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[8]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[8]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[15]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[16]
Stomach cancer	DISKIJSX	Strong	Biomarker	[17]
Vibratory urticaria	DIS22GGG	Strong	Genetic Variation	[18]
Prostate cancer	DISF190Y	moderate	Altered Expression	[19]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[19]
Thyroid cancer	DIS3VLDH	moderate	Altered Expression	[20]
Undifferentiated carcinoma	DISIAZST	moderate	Altered Expression	[20]
Autosomal dominant vibratory urticaria	DISPGJPH	Supportive	Autosomal dominant	[21]
Ductal breast carcinoma in situ	DISLCJY7	Disputed	Altered Expression	[22]
Invasive breast carcinoma	DISANYTW	Disputed	Biomarker	[22]
Thyroid gland carcinoma	DISMNGZ0	Disputed	Altered Expression	[20]
Thyroid tumor	DISLVKMD	Disputed	Biomarker	[20]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[23]
Arthritis	DIST1YEL	Limited	Biomarker	[24]
Breast cancer	DIS7DPX1	Limited	Biomarker	[25]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[25]
Digestive system neoplasm	DISPOJCT	Limited	Biomarker	[26]
Gastric cancer	DISXGOUK	Limited	Biomarker	[17]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[27]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Adhesion G protein-coupled receptor E2 (ADGRE2).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Adhesion G protein-coupled receptor E2 (ADGRE2).	[29]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Adhesion G protein-coupled receptor E2 (ADGRE2).	[30]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Adhesion G protein-coupled receptor E2 (ADGRE2).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Adhesion G protein-coupled receptor E2 (ADGRE2).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Adhesion G protein-coupled receptor E2 (ADGRE2).	[33]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Adhesion G protein-coupled receptor E2 (ADGRE2).	[34]
Octanal	DMTN0OK	Investigative	Octanal increases the expression of Adhesion G protein-coupled receptor E2 (ADGRE2).	[35]

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] miR-99a reveals two novel oncogenic proteins E2F2 and EMR2 and represses stemness in lung cancer.Cell Death Dis. 2017 Oct 26;8(10):e3141. doi: 10.1038/cddis.2017.544.
• [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] 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.
• [6] 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.
• [7] Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues.Am J Pathol. 2002 Nov;161(5):1657-67. doi: 10.1016/S0002-9440(10)64443-4.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] The PHF21B gene is associated with major depression and modulates the stress response.Mol Psychiatry. 2017 Jul;22(7):1015-1025. doi: 10.1038/mp.2016.174. Epub 2016 Oct 25.
• [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] Mast cells signal their importance in health and disease.J Allergy Clin Immunol. 2018 Aug;142(2):381-393. doi: 10.1016/j.jaci.2018.01.034. Epub 2018 Feb 15.
• [19] 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.
• [20] 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.
• [21] Vibratory Urticaria Associated with a Missense Variant in ADGRE2. N Engl J Med. 2016 Feb 18;374(7):656-63. doi: 10.1056/NEJMoa1500611. Epub 2016 Feb 3.
• [22] Leukocyte adhesion-GPCR EMR2 is aberrantly expressed in human breast carcinomas and is associated with patient survival.Oncol Rep. 2011 Mar;25(3):619-27. doi: 10.3892/or.2010.1117. Epub 2010 Dec 21.
• [23] 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.
• [24] Deletion of either CD55 or CD97 ameliorates arthritis in mouse models.Arthritis Rheum. 2010 Apr;62(4):1036-42. doi: 10.1002/art.27347.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [29] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [30] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [31] 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.
• [32] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [33] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [34] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [35] 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.