Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC31ONQ)

• DOT Name: Rap1 GTPase-activating protein 1 (RAP1GAP)
• Synonyms: Rap1GAP; Rap1GAP1
• Gene Name: RAP1GAP
• Related Disease:
  Acute myelogenous leukaemia
  Ductal breast carcinoma in situ
  Invasive breast carcinoma
  Myelodysplastic syndrome
  Pancreatic cancer
  Thyroid cancer
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Advanced cancer
  Behavioral variant of frontotemporal dementia
  Chronic myelomonocytic leukaemia
  Clear cell renal carcinoma
  Differentiated thyroid carcinoma
  Focal segmental glomerulosclerosis
  Gastric cancer
  Head-neck squamous cell carcinoma
  leukaemia
  Leukemia
  Myelodysplastic syndrome with multilineage dysplasia
  Myelodysplastic/myeloproliferative neoplasm
  Neoplasm
  Oropharyngeal squamous cell carcinoma
  Pancreatic tumour
  Promyelocytic leukaemia
  Renal carcinoma
  Renal cell carcinoma
  Squamous cell carcinoma
  Stomach cancer
  Thyroid tumor
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Familial multiple trichoepithelioma
  Tuberous sclerosis
  Adenoma
  Benign neoplasm
  Kidney cancer
  Melanoma
  Metastatic malignant neoplasm
  Thyroid gland papillary carcinoma
  Tuberous sclerosis 2
• UniProt ID: RPGP1_HUMAN
• PDB ID: 1SRQ; 3BRW
• Pfam ID: PF02188 ; PF21022 ; PF02145
• Sequence:
  MIEKMQGSRMDEQRCSFPPPLKTEEDYIPYPSVHEVLGREGPFPLILLPQFGGYWIEGTN
  HEITSIPETEPLQSPTTKVKLECNPTARIYRKHFLGKEHFNYYSLDAALGHLVFSLKYDV
  IGDQEHLRLLLRTKCRTYHDVIPISCLTEFPNVVQMAKLVCEDVNVDRFYPVLYPKASRL
  IVTFDEHVISNNFKFGVIYQKLGQTSEEELFSTNEESPAFVEFLEFLGQKVKLQDFKGFR
  GGLDVTHGQTGTESVYCNFRNKEIMFHVSTKLPYTEGDAQQLQRKRHIGNDIVAVVFQDE
  NTPFVPDMIASNFLHAYVVVQAEGGGPDGPLYKVSVTARDDVPFFGPPLPDPAVFRKGPE
  FQEFLLTKLINAEYACYKAEKFAKLEERTRAALLETLYEELHIHSQSMMGLGGDEDKMEN
  GSGGGGFFESFKRVIRSRSQSMDAMGLSNKKPNTVSTSHSGSFAPNNPDLAKAAGISLIV
  PGKSPTRKKSGPFGSRRSSAIGIENIQEVQEKRESPPAGQKTPDSGHVSQEPKSENSSTQ
  SSPEMPTTKNRAETAAQRAEALKDFSRSSSSASSFASVVEETEGVDGEDTGLESVSSSGT
  PHKRDSFIYSTWLEDSVSTTSGGSSPGPSRSPHPDAGKLGDPACPEIKIQLEASEQHMPQ
  LGC
• Function: GTPase activator for the nuclear Ras-related regulatory protein RAP-1A (KREV-1), converting it to the putatively inactive GDP-bound state.
• Tissue Specificity: Significant expression seen in the brain, kidney and pancreas. Abundant in the cerebral cortex and expressed at much lower levels in the spinal cord. Not detected in the lymphoid tissues.
• KEGG Pathway: Rap1 sig.ling pathway (hsa04015)
• Reactome Pathway:
  RET signaling (R-HSA-8853659)
  Rap1 signalling (R-HSA-392517)

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 myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
Ductal breast carcinoma in situ	DISLCJY7	Definitive	Biomarker	[2]
Invasive breast carcinoma	DISANYTW	Definitive	Altered Expression	[2]
Myelodysplastic syndrome	DISYHNUI	Definitive	Biomarker	[1]
Pancreatic cancer	DISJC981	Definitive	Biomarker	[3]
Thyroid cancer	DIS3VLDH	Definitive	Biomarker	[3]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Definitive	Altered Expression	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Behavioral variant of frontotemporal dementia	DISQHX2V	Strong	Altered Expression	[6]
Chronic myelomonocytic leukaemia	DISDN5P7	Strong	Genetic Variation	[7]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[8]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Altered Expression	[9]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Altered Expression	[10]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[11]
leukaemia	DISS7D1V	Strong	Biomarker	[3]
Leukemia	DISNAKFL	Strong	Biomarker	[3]
Myelodysplastic syndrome with multilineage dysplasia	DISFFCP3	Strong	Biomarker	[1]
Myelodysplastic/myeloproliferative neoplasm	DISDHXQ4	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Oropharyngeal squamous cell carcinoma	DIS7D7QV	Strong	Biomarker	[12]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[3]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[3]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[13]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[8]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[11]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[14]
Endometrial cancer	DISW0LMR	moderate	Biomarker	[15]
Endometrial carcinoma	DISXR5CY	moderate	Biomarker	[15]
Familial multiple trichoepithelioma	DISKZAUY	moderate	Altered Expression	[15]
Tuberous sclerosis	DISEMUGZ	moderate	Genetic Variation	[16]
Adenoma	DIS78ZEV	Limited	Altered Expression	[17]
Benign neoplasm	DISDUXAD	Limited	Altered Expression	[17]
Kidney cancer	DISBIPKM	Limited	Altered Expression	[8]
Melanoma	DIS1RRCY	Limited	Altered Expression	[18]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[19]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[17]
Tuberous sclerosis 2	DISR6GKZ	Limited	Genetic Variation	[20]

19 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 Rap1 GTPase-activating protein 1 (RAP1GAP).	[21]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[25]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[27]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[25]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[28]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[29]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[30]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[32]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[34]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[36]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[37]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Rap1 GTPase-activating protein 1 (RAP1GAP).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Rap1 GTPase-activating protein 1 (RAP1GAP).	[35]

References

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• [3] Rap1GAP alters leukemia cell differentiation, apoptosis and invasion invitro.Oncol Rep. 2012 Aug;28(2):622-8. doi: 10.3892/or.2012.1825. Epub 2012 May 18.
• [4] 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.
• [5] Reduced expression of Rap1GAP as a prognostic biomarker for primary gastric cancer patients.Cancer Biomark. 2018;22(3):375-384. doi: 10.3233/CBM-170832.
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• [9] 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.
• [10] Podocyte-specific RAP1GAP expression contributes to focal segmental glomerulosclerosis-associated glomerular injury.J Clin Invest. 2014 Apr;124(4):1757-69. doi: 10.1172/JCI67846. Epub 2014 Mar 18.
• [11] The tumor suppressor gene rap1GAP is silenced by miR-101-mediated EZH2 overexpression in invasive squamous cell carcinoma.Oncogene. 2011 Oct 20;30(42):4339-49. doi: 10.1038/onc.2011.141. Epub 2011 May 2.
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• [13] Prostaglandin E2 regulates renal cell carcinoma invasion through the EP4 receptor-Rap GTPase signal transduction pathway.J Biol Chem. 2011 Sep 30;286(39):33954-62. doi: 10.1074/jbc.M110.187344. Epub 2011 Aug 10.
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• [16] Rap1 activity is elevated in malignant astrocytomas independent of tuberous sclerosis complex-2 gene expression.Int J Oncol. 2003 Jan;22(1):195-200.
• [17] Loss of Rap1GAP in papillary thyroid cancer.J Clin Endocrinol Metab. 2009 Mar;94(3):1026-32. doi: 10.1210/jc.2008-1042. Epub 2008 Dec 9.
• [18] Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma.Oncotarget. 2012 Sep;3(9):1011-25. doi: 10.18632/oncotarget.622.
• [19] Low expression of Rap1GAP is associated with epithelial-mesenchymal transition (EMT) and poor prognosis in gastric cancer.Oncotarget. 2017 Jan 31;8(5):8057-8068. doi: 10.18632/oncotarget.14074.
• [20] Identification of tuberous sclerosis 2 messenger RNA splice variants that are conserved and differentially expressed in rat and human tissues.Cell Growth Differ. 1995 Sep;6(9):1185-91.
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• [26] Down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration. Cancer Res. 2009 Jan 15;69(2):449-57. doi: 10.1158/0008-5472.CAN-08-2399.
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• [33] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [34] 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.
• [35] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [36] 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.
• [37] 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.
• [38] 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.