Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT84ATF5)

• DOT Name: Rho GTPase-activating protein 10 (ARHGAP10)
• Synonyms: GTPase regulator associated with focal adhesion kinase 2; GRAF2; Graf-related protein 2; Rho-type GTPase-activating protein 10
• Gene Name: ARHGAP10
• Related Disease:
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Neoplasm
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Familial atrial fibrillation
  Advanced cancer
  Lung cancer
  Lung carcinoma
• UniProt ID: RHG10_HUMAN
• PDB ID: 2MIO
• Pfam ID: PF16746 ; PF00169 ; PF00620 ; PF14604
• Sequence:
  MGLQPLEFSDCYLDSPWFRERIRAHEAELERTNKFIKELIKDGKNLIAATKSLSVAQRKF
  AHSLRDFKFEFIGDAVTDDERCIDASLREFSNFLKNLEEQREIMALSVTETLIKPLEKFR
  KEQLGAVKEEKKKFDKETEKNYSLIDKHLNLSAKKKDSHLQEADIQVEQNRQHFYELSLE
  YVCKLQEIQERKKFEFVEPMLSFFQGMFTFYHQGHELAKDFNHYKMELQINIQNTRNRFE
  GTRSEVEELMNKIRQNPKDHKRASQFTAEGYLYVQEKRPAPFGSSWVKHYCMYRKAAKKF
  NMIPFEHRSGGKLGDGEVFFLKECTKRHTDSIDRRFCFDIEAADRPGVSLTMQAFSEEER
  KQWLEALGGKEALSHSFNTAIIPRPEGNAQLDKMGFTIIRKCISAVETRGINDQGLYRVV
  GVSSKVQRLLSMLMDVKTCNEVDLENSADWEVKTITSALKQYLRSLPEPLMTYELHGDFI
  VPAKSGSPESRVNAIHFLVHKLPEKNKEMLDILVKHLTNVSNHSKQNLMTVANLGVVFGP
  TLMRPQEETVAALMDLKFQNIVVEILIENHEKIFRTPPDTTFPEPTCLSASPPNAPPRQS
  KRQGQRTKRPVAVYNLCLELEDGDNPYPSKEDTPTSSLDSLSSPSPVTTAVPGPPGPDKN
  HLLADGGSFGDWASTIPGQTRSSMVQWLNPQSPTTTSSNSAVTPLSPGSSPFPFSPPATV
  ADKPPESIRSRKARAVYPCEAEHSSELSFEIGAIFEDVQTSREPGWLEGTLNGKRGLIPQ
  NYVKLL
• Function: GTPase-activating protein that catalyzes the conversion of active GTP-bound Rho GTPases to their inactive GDP-bound form, thus suppressing various Rho GTPase-mediated cellular processes. Also converts Cdc42 to an inactive GDP-bound state. Essential for PTKB2 regulation of cytoskeletal organization via Rho family GTPases. Inhibits PAK2 proteolytic fragment PAK-2p34 kinase activity and changes its localization from the nucleus to the perinuclear region. Stabilizes PAK-2p34 thereby increasing stimulation of cell death. Associates with MICAL1 on the endosomal membrane to promote Rab8-Rab10-dependent tubule extension. After dissociation with MICAL1, recruits WDR44 which connects the endoplasmic reticulum (ER) with the endosomal tubule, thereby participating in the export of a subset of neosynthesized proteins.
• Tissue Specificity: High levels of expression in heart and skeletal muscle.
• KEGG Pathway: Bacterial invasion of epithelial cells (hsa05100)
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  Regulation of PAK-2p34 activity by PS-GAP/RHG10 (R-HSA-211728)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[4]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[3]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[1]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[5]
Lung cancer	DISCM4YA	Limited	Biomarker	[6]
Lung carcinoma	DISTR26C	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho GTPase-activating protein 10 (ARHGAP10).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Rho GTPase-activating protein 10 (ARHGAP10).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Rho GTPase-activating protein 10 (ARHGAP10).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Rho GTPase-activating protein 10 (ARHGAP10).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Rho GTPase-activating protein 10 (ARHGAP10).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Rho GTPase-activating protein 10 (ARHGAP10).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Rho GTPase-activating protein 10 (ARHGAP10).	[13]

References

• [1] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [2] Downregulated expression of ARHGAP10 correlates with advanced stage and high Ki-67 index in breast cancer.PeerJ. 2019 Aug 1;7:e7431. doi: 10.7717/peerj.7431. eCollection 2019.
• [3] CXCL12 promotes human ovarian cancer cell invasion through suppressing ARHGAP10 expression.Biochem Biophys Res Commun. 2019 Oct 20;518(3):416-422. doi: 10.1016/j.bbrc.2019.07.098. Epub 2019 Aug 22.
• [4] Upregulated circRNA ARHGAP10 Predicts an Unfavorable Prognosis in NSCLC through Regulation of the miR-150-5p/GLUT-1 Axis.Mol Ther Nucleic Acids. 2019 Dec 6;18:219-231. doi: 10.1016/j.omtn.2019.08.016. Epub 2019 Aug 21.
• [5] ARHGAP10, downregulated in ovarian cancer, suppresses tumorigenicity of ovarian cancer cells.Cell Death Dis. 2016 Mar 24;7(3):e2157. doi: 10.1038/cddis.2015.401.
• [6] The roles of ARHGAP10 in the proliferation, migration and invasion of lung cancer cells.Oncol Lett. 2017 Oct;14(4):4613-4618. doi: 10.3892/ol.2017.6729. Epub 2017 Aug 7.
• [7] 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.
• [8] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] 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.