Details of Drug Off-Target (DOT)

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

• DOT Name: Rho GTPase-activating protein 6 (ARHGAP6)
• Synonyms: Rho-type GTPase-activating protein 6; Rho-type GTPase-activating protein RhoGAPX-1
• Gene Name: ARHGAP6
• Related Disease:
  Amelogenesis imperfecta
  Familial prostate carcinoma
  High blood pressure
  Lung cancer
  Lung carcinoma
  Neoplasm
  Prostate cancer, hereditary, 1
  Prostate carcinoma
• UniProt ID: RHG06_HUMAN
• Pfam ID: PF00620
• Sequence:
  MSAQSLLHSVFSCSSPASSSAASAKGFSKRKLRQTRSLDPALIGGCGSDEAGAEGSARGA
  TAGRLYSPSLPAESLGPRLASSSRGPPPRATRLPPPGPLCSSFSTPSTPQEKSPSGSFHF
  DYEVPLGRGGLKKSMAWDLPSVLAGPASSRSASSILCSSGGGPNGIFASPRRWLQQRKFQ
  SPPDSRGHPYVVWKSEGDFTWNSMSGRSVRLRSVPIQSLSELERARLQEVAFYQLQQDCD
  LSCQITIPKDGQKRKKSLRKKLDSLGKEKNKDKEFIPQAFGMPLSQVIANDRAYKLKQDL
  QRDEQKDASDFVASLLPFGNKRQNKELSSSNSSLSSTSETPNESTSPNTPEPAPRARRRG
  AMSVDSITDLDDNQSRLLEALQLSLPAEAQSKKEKARDKKLSLNPIYRQVPRLVDSCCQH
  LEKHGLQTVGIFRVGSSKKRVRQLREEFDRGIDVSLEEEHSVHDVAALLKEFLRDMPDPL
  LTRELYTAFINTLLLEPEEQLGTLQLLIYLLPPCNCDTLHRLLQFLSIVARHADDNISKD
  GQEVTGNKMTSLNLATIFGPNLLHKQKSSDKEFSVQSSARAEESTAIIAVVQKMIENYEA
  LFMVPPDLQNEVLISLLETDPDVVDYLLRRKASQSSSPDMLQSEVSFSVGGRHSSTDSNK
  ASSGDISPYDNNSPVLSERSLLAMQEDAAPGGSEKLYRVPGQFMLVGHLSSSKSRESSPG
  PRLGKDLSEEPFDIWGTWHSTLKSGSKDPGMTGSSGDIFESSSLRAGPCSLSQGNLSPNW
  PRWQGSPAELDSDTQGARRTQAAAPATEGRAHPAVSRACSTPHVQVAGKAERPTARSEQY
  LTLSGAHDLSESELDVAGLQSRATPQCQRPHGSGRDDKRPPPPYPGPGKPAAAAAWIQGP
  PEGVETPTDQGGQAAEREQQVTQKKLSSANSLPAGEQDSPRLGDAGWLDWQRERWQIWEL
  LSTDNPDALPETLV
• Function: GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state. Could regulate the interactions of signaling molecules with the actin cytoskeleton. Promotes continuous elongation of cytoplasmic processes during cell motility and simultaneous retraction of the cell body changing the cell morphology.
• Tissue Specificity: Highly expressed in kidney, heart and skeletal muscle followed by retina, lymphoblast, placenta, lung, brain, pancreas and liver.
• Reactome Pathway:
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amelogenesis imperfecta	DISGYR9E	Strong	Genetic Variation	[1]
Familial prostate carcinoma	DISL9KNO	Strong	Biomarker	[2]
High blood pressure	DISY2OHH	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Prostate cancer, hereditary, 1	DISE2P4L	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[2]

10 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 Rho GTPase-activating protein 6 (ARHGAP6).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho GTPase-activating protein 6 (ARHGAP6).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho GTPase-activating protein 6 (ARHGAP6).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Rho GTPase-activating protein 6 (ARHGAP6).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Rho GTPase-activating protein 6 (ARHGAP6).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Rho GTPase-activating protein 6 (ARHGAP6).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Rho GTPase-activating protein 6 (ARHGAP6).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Rho GTPase-activating protein 6 (ARHGAP6).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho GTPase-activating protein 6 (ARHGAP6).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rho GTPase-activating protein 6 (ARHGAP6).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rho GTPase-activating protein 6 (ARHGAP6).	[14]

References

• [1] Amelogenesis imperfecta in two families with defined AMELX deletions in ARHGAP6. PLoS One. 2012;7(12):e52052. doi: 10.1371/journal.pone.0052052. Epub 2012 Dec 14.
• [2] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [3] Regulation of phospholipase C-delta1 by ARGHAP6, a GTPase-activating protein for RhoA: possible role for enhanced activity of phospholipase C in hypertension.Int J Biochem Cell Biol. 2008;40(10):2264-73. doi: 10.1016/j.biocel.2008.03.007. Epub 2008 Mar 16.
• [4] ARHGAP6 regulates the proliferation, migration and invasion of lung cancer cells.Oncol Rep. 2019 Apr;41(4):2281-2888. doi: 10.3892/or.2019.7031. Epub 2019 Feb 25.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [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 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] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] 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.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.