Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSE3TRP)

• DOT Name: RalBP1-associated Eps domain-containing protein 2 (REPS2)
• Synonyms: Partner of RalBP1; RalBP1-interacting protein 2
• Gene Name: REPS2
• Related Disease:
  Esophageal squamous cell carcinoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Synovial sarcoma
  Advanced cancer
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
• UniProt ID: REPS2_HUMAN
• PDB ID: 1IQ3
• Pfam ID: PF12763
• Sequence:
  MEAAAAAAAAAAAAAAAGGGCGSGPPPLLLSEGEQQCYSELFARCAGAAGGGPGSGPPEA
  ARVAPGTATAAAGPVADLFRASQLPAETLHQITELCGAKRVGYFGPTQFYIALKLIAAAQ
  SGLPVRIESIKCELPLPRFMMSKNDGEIRFGNPAELHGTKVQIPYLTTEKNSFKRMDDED
  KQQETQSPTMSPLASPPSSPPHYQRVPLSHGYSKLRSSAEQMHPAPYEARQPLVQPEGSS
  SGGPGTKPLRHQASLIRSFSVERELQDNSSYPDEPWRITEEQREYYVNQFRSLQPDPSSF
  ISGSVAKNFFTKSKLSIPELSYIWELSDADCDGALTLPEFCAAFHLIVARKNGYPLPEGL
  PPTLQPEYLQAAFPKPKWDCQLFDSYSESLPANQQPRDLNRMEKTSVKDMADLPVPNQDV
  TSDDKQALKSTINEALPKDVSEDPATPKDSNSLKARPRSRSYSSTSIEEAMKRGEDPPTP
  PPRPQKTHSRASSLDLNKVFQPSVPATKSGLLPPPPALPPRPCPSQSEQVSEAELLPQLS
  RAPSQAAESSPAKKDVLYSQPPSKPIRRKFRPENQATENQEPSTAASGPASAATMKPHPT
  VQKQSSKQKKAIQTAIRKNKEANAVLARLNSELQQQLKEVHQERIALENQLEQLRPVTVL
• Function: Involved in ligand-dependent receptor mediated endocytosis of the EGF and insulin receptors as part of the Ral signaling pathway. By controlling growth factor receptors endocytosis may regulate cell survival. Through ASAP1 may regulate cell adhesion and migration.
• Tissue Specificity: Expressed at high levels in the cerebrum, cerebellum, lung, kidney, and testis. Weakly expressed in the kidney. Isoform 2 is down-regulated during progression of prostate cancer.
• Reactome Pathway:
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Synovial sarcoma	DISEZJS7	Strong	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[5]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]
Prostate cancer	DISF190Y	Limited	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[6]
Prostate neoplasm	DISHDKGQ	Limited	Altered Expression	[6]

1 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 RalBP1-associated Eps domain-containing protein 2 (REPS2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[10]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[11]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[12]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[17]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of RalBP1-associated Eps domain-containing protein 2 (REPS2).	[19]

References

• [1] miR-675-5p enhances tumorigenesis and metastasis of esophageal squamous cell carcinoma by targeting REPS2.Oncotarget. 2016 May 24;7(21):30730-47. doi: 10.18632/oncotarget.8950.
• [2] Expression and clinical significance of REPS2 in human esophageal squamous cell carcinoma.Asian Pac J Cancer Prev. 2013;14(5):2851-7. doi: 10.7314/apjcp.2013.14.5.2851.
• [3] TMEM25, REPS2 and Meis 1: favourable prognostic and predictive biomarkers for breast cancer.Tumour Biol. 2009;30(4):200-9. doi: 10.1159/000239795. Epub 2009 Sep 21.
• [4] Recurrent and novel SS18-SSX fusion transcripts in synovial sarcoma: description of three new cases.Tumour Biol. 2012 Dec;33(6):2245-53. doi: 10.1007/s13277-012-0486-0. Epub 2012 Sep 14.
• [5] Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer.Oncotarget. 2015 Mar 20;6(8):5903-17. doi: 10.18632/oncotarget.3464.
• [6] EGF signalling in prostate cancer cell lines is inhibited by a high expression level of the endocytosis protein REPS2.Int J Cancer. 2005 Feb 10;113(4):561-7. doi: 10.1002/ijc.20612.
• [7] 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.
• [8] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [12] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [13] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [18] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.