Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD2NDQP)

• DOT Name: Ras-related protein Rap-2b (RAP2B)
• Synonyms: EC 3.6.5.2
• Gene Name: RAP2B
• Related Disease:
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Capillary malformation-arteriovenous malformation syndrome
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Epithelial neoplasm
  Glioma
  Melanoma
  Myotonic dystrophy
  Neoplasm
  Non-small-cell lung cancer
  Renal cell carcinoma
  Testicular germ cell tumor
  Urinary bladder cancer
  Urinary bladder neoplasm
  Advanced cancer
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Neuroblastoma
  Bone osteosarcoma
  Osteosarcoma
  Parkinson disease
• UniProt ID: RAP2B_HUMAN
• PDB ID: 1N4P; 1N4Q; 1N4R
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MREYKVVVLGSGGVGKSALTVQFVTGSFIEKYDPTIEDFYRKEIEVDSSPSVLEILDTAG
  TEQFASMRDLYIKNGQGFILVYSLVNQQSFQDIKPMRDQIIRVKRYERVPMILVGNKVDL
  EGEREVSYGEGKALAEEWSCPFMETSAKNKASVDELFAEIVRQMNYAAQPNGDEGCCSAC
  VIL
• Function: Small GTP-binding protein which cycles between a GDP-bound inactive and a GTP-bound active form. Involved in EGFR and CHRM3 signaling pathways through stimulation of PLCE1. May play a role in cytoskeletal rearrangements and regulate cell spreading through activation of the effector TNIK. May regulate membrane vesiculation in red blood cells.
• Tissue Specificity: Expressed in red blood cells (at protein level).
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Capillary malformation-arteriovenous malformation syndrome	DISMN03Q	Strong	Genetic Variation	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Epithelial neoplasm	DIS0T594	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[8]
Melanoma	DIS1RRCY	Strong	Altered Expression	[9]
Myotonic dystrophy	DISNBEMX	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[11]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[6]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[12]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[13]
Lung cancer	DISCM4YA	moderate	Altered Expression	[14]
Lung carcinoma	DISTR26C	moderate	Biomarker	[14]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[15]
Bone osteosarcoma	DIST1004	Disputed	Biomarker	[16]
Osteosarcoma	DISLQ7E2	Disputed	Biomarker	[16]
Parkinson disease	DISQVHKL	Limited	Biomarker	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ras-related protein Rap-2b (RAP2B).	[18]

16 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 Ras-related protein Rap-2b (RAP2B).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras-related protein Rap-2b (RAP2B).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related protein Rap-2b (RAP2B).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras-related protein Rap-2b (RAP2B).	[22]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Ras-related protein Rap-2b (RAP2B).	[23]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Ras-related protein Rap-2b (RAP2B).	[22]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Ras-related protein Rap-2b (RAP2B).	[22]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Ras-related protein Rap-2b (RAP2B).	[22]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Ras-related protein Rap-2b (RAP2B).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ras-related protein Rap-2b (RAP2B).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ras-related protein Rap-2b (RAP2B).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras-related protein Rap-2b (RAP2B).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ras-related protein Rap-2b (RAP2B).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ras-related protein Rap-2b (RAP2B).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ras-related protein Rap-2b (RAP2B).	[29]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Ras-related protein Rap-2b (RAP2B).	[30]

References

• [1] MiR-194 inhibits cell proliferation and invasion via repression of RAP2B in bladder cancer.Biomed Pharmacother. 2016 May;80:268-275. doi: 10.1016/j.biopha.2016.03.026. Epub 2016 Apr 1.
• [2] Phospholipase Cgamma1 is required for metastasis development and progression.Cancer Res. 2008 Dec 15;68(24):10187-96. doi: 10.1158/0008-5472.CAN-08-1181.
• [3] RASA1 regulates the function of lymphatic vessel valves in mice.J Clin Invest. 2017 Jun 30;127(7):2569-2585. doi: 10.1172/JCI89607. Epub 2017 May 22.
• [4] Rap2B promotes migration and invasion of human suprarenal epithelioma.Tumour Biol. 2014 Sep;35(9):9387-94. doi: 10.1007/s13277-014-2174-8. Epub 2014 Jun 21.
• [5] Knockdown of Rap2B, a Ras Superfamily Protein, Inhibits Proliferation, Migration, and Invasion in Cervical Cancer Cells via Regulating the ERK1/2 Signaling Pathway.Oncol Res. 2018 Jan 19;26(1):123-130. doi: 10.3727/096504017X14912172235777. Epub 2017 Apr 3.
• [6] Rap2B promotes angiogenesis via PI3K/AKT/VEGF signaling pathway in human renal cell carcinoma.Tumour Biol. 2017 Jul;39(7):1010428317701653. doi: 10.1177/1010428317701653.
• [7] MicroRNA-147b Promotes Proliferation and Invasion of Human Colorectal Cancer by Targeting RAS Oncogene Family (RAP2B).Pathobiology. 2019;86(4):173-181. doi: 10.1159/000495253. Epub 2019 May 23.
• [8] Rap2B promotes cell adhesion, proliferation, migration and invasion of human glioma.J Neurooncol. 2019 Jun;143(2):221-229. doi: 10.1007/s11060-019-03163-6. Epub 2019 Apr 17.
• [9] Gene expression changes and signaling events associated with the direct antimelanoma effect of IFN-gamma.Cancer Res. 2005 Oct 1;65(19):8869-77. doi: 10.1158/0008-5472.CAN-05-1387.
• [10] The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase.EMBO J. 1996 Apr 15;15(8):1885-93.
• [11] miR-342-3p targets RAP2B to suppress proliferation and invasion of non-small cell lung cancer cells.Tumour Biol. 2015 Jul;36(7):5031-8. doi: 10.1007/s13277-015-3154-3. Epub 2015 Feb 9.
• [12] Overexpression of RhoA mRNA is associated with advanced stage in testicular germ cell tumour.BJU Int. 2001 Feb;87(3):227-31. doi: 10.1046/j.1464-410x.2001.02030.x.
• [13] Knockdown of Rap2B Inhibits the Proliferation and Invasion in Hepatocellular Carcinoma Cells.Oncol Res. 2017 Jan 2;25(1):19-27. doi: 10.3727/096504016X14685034103914.
• [14] Expression and DNA methylation status of the Rap2B gene in human bronchial epithelial cells treated by cigarette smoke condensate.Inhal Toxicol. 2015;27(10):502-9. doi: 10.3109/08958378.2015.1076546. Epub 2015 Aug 26.
• [15] HaRas activates the NADPH oxidase complex in human neuroblastoma cells via extracellular signal-regulated kinase 1/2 pathway.J Neurochem. 2004 Nov;91(3):613-22. doi: 10.1111/j.1471-4159.2004.02754.x.
• [16] Long Noncoding RNA XIST Promotes Osteosarcoma Progression by Targeting Ras-Related Protein RAP2B via miR-320b.Oncol Res. 2018 Jul 5;26(6):837-846. doi: 10.3727/096504017X14920318811721. Epub 2017 Apr 12.
• [17] GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease.Biochemistry. 2007 Feb 6;46(5):1380-8. doi: 10.1021/bi061960m.
• [18] 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.
• [19] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [20] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [23] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [26] 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.
• [27] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [28] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [30] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.