Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0JB5S4)

• DOT Name: Ras-related protein Rap-2a (RAP2A)
• Synonyms: EC 3.6.5.2; RbBP-30
• Gene Name: RAP2A
• Related Disease:
  Breast cancer
  Breast carcinoma
  Cerebral cavernous malformation 3
  Glioma
  Neoplasm
  Peripheral arterial disease
  Prostate neoplasm
  Rheumatoid arthritis
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Thyroid tumor
  Prostate cancer
  Prostate carcinoma
• UniProt ID: RAP2A_HUMAN
• PDB ID: 1KAO; 2RAP; 3RAP
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MREYKVVVLGSGGVGKSALTVQFVTGTFIEKYDPTIEDFYRKEIEVDSSPSVLEILDTAG
  TEQFASMRDLYIKNGQGFILVYSLVNQQSFQDIKPMRDQIIRVKRYEKVPVILVGNKVDL
  ESEREVSSSEGRALAEEWGCPFMETSAKSKTMVDELFAEIVRQMNYAAQPDKDDPCCSAC
  NIQ
• Function: Small GTP-binding protein which cycles between a GDP-bound inactive and a GTP-bound active form. In its active form interacts with and regulates several effectors including MAP4K4, MINK1 and TNIK. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. More generally, it is part of several signaling cascades and may regulate cytoskeletal rearrangements, cell migration, cell adhesion and cell spreading.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Cerebral cavernous malformation 3	DISHAV0P	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[5]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[6]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[7]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Altered Expression	[8]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[8]
Prostate cancer	DISF190Y	moderate	Genetic Variation	[9]
Prostate carcinoma	DISMJPLE	moderate	Genetic Variation	[9]

13 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 Ras-related protein Rap-2a (RAP2A).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ras-related protein Rap-2a (RAP2A).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ras-related protein Rap-2a (RAP2A).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras-related protein Rap-2a (RAP2A).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related protein Rap-2a (RAP2A).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ras-related protein Rap-2a (RAP2A).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ras-related protein Rap-2a (RAP2A).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ras-related protein Rap-2a (RAP2A).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Ras-related protein Rap-2a (RAP2A).	[18]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Ras-related protein Rap-2a (RAP2A).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ras-related protein Rap-2a (RAP2A).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Ras-related protein Rap-2a (RAP2A).	[21]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Ras-related protein Rap-2a (RAP2A).	[23]

1 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 decreases the methylation of Ras-related protein Rap-2a (RAP2A).	[22]

References

• [1] Expression of RPIP9 (Rap2 interacting protein 9) is activated in breast carcinoma and correlates with a poor prognosis.Int J Cancer. 2005 Dec 20;117(6):934-41. doi: 10.1002/ijc.21252.
• [2] Sporadic cerebral cavernous malformations: report of further mutations of CCM genes in 40 Italian patients.Biomed Res Int. 2013;2013:459253. doi: 10.1155/2013/459253. Epub 2013 Aug 22.
• [3] Regulation of glioma migration and invasion via modification of Rap2a activity by the ubiquitin ligase Nedd4-1.Oncol Rep. 2017 May;37(5):2565-2574. doi: 10.3892/or.2017.5572. Epub 2017 Apr 11.
• [4] Histone deacetylase inhibitors upregulate Rap1GAP and inhibit Rap activity in thyroid tumor cells.Endocr Relat Cancer. 2011 Apr 2;18(3):301-10. doi: 10.1530/ERC-10-0320. Print 2011 Jun.
• [5] Genome-Wide Association Study of Peripheral Arterial Disease in a Japanese Population.PLoS One. 2015 Oct 21;10(10):e0139262. doi: 10.1371/journal.pone.0139262. eCollection 2015.
• [6] Rap2 regulates androgen sensitivity in human prostate cancer cells.Prostate. 2007 Oct 1;67(14):1590-9. doi: 10.1002/pros.20644.
• [7] From transcriptome to proteome: differentially expressed proteins identified in synovial tissue of patients suffering from rheumatoid arthritis and osteoarthritis by an initial screen with a panel of 791 antibodies.Proteomics. 2003 Jun;3(6):991-1002. doi: 10.1002/pmic.200300412.
• [8] RAP1GAP inhibits cytoskeletal remodeling and motility in thyroid cancer cells.Endocr Relat Cancer. 2012 Jul 22;19(4):575-88. doi: 10.1530/ERC-12-0086. Print 2012 Aug.
• [9] HNF1b is involved in prostate cancer risk via modulating androgenic hormone effects and coordination with other genes.Genet Mol Res. 2013 Apr 25;12(2):1327-35. doi: 10.4238/2013.April.25.4.
• [10] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] 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.
• [15] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [16] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [19] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [22] 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.
• [23] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.