Details of Drug Off-Target (DOT)

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

• DOT Name: Rho GTPase-activating protein 22 (ARHGAP22)
• Synonyms: Rho-type GTPase-activating protein 22
• Gene Name: ARHGAP22
• Related Disease:
  Diabetic retinopathy
  Melanoma
  Non-insulin dependent diabetes
  Spinal muscular atrophy
• UniProt ID: RHG22_HUMAN
• Pfam ID: PF00169 ; PF00620
• Sequence:
  MLSPKIRQARRARSKSLVMGEQSRSPGRMPCPHRLGPVLKAGWLKKQRSIMKNWQQRWFV
  LRGDQLFYYKDKDEIKPQGFISLQGTQVTELPPGPEDPGKHLFEISPGGAGEREKVPANP
  EALLLMASSQRDMEDWVQAIRRVIWAPLGGGIFGQRLEETVHHERKYGPRLAPLLVEQCV
  DFIRERGLTEEGLFRMPGQANLVRDLQDSFDCGEKPLFDSTTDVHTVASLLKLYLRELPE
  PVVPFARYEDFLSCAQLLTKDEGEGTLELAKQVSNLPQANYNLLRYICKFLDEVQAYSNV
  NKMSVQNLATVFGPNILRPQVEDPVTIMEGTSLVQHLMTVLIRKHSQLFTAPVPEGPTSP
  RGGLQCAVGWGSEEVTRDSQGEPGGPGLPAHRTSSLDGAAVAVLSRTAPTGPGSRCSPGK
  KVQTLPSWKSSFRQPRSLSGSPKGGGSSLEVPIISSGGNWLMNGLSSLRGHRRASSGDRL
  KDSGSVQRLSTYDNVPAPGLVPGIPSVASMAWSGASSSESSVGGSLSSCTACRASDSSAR
  SSLHTDWALEPSPLPSSSEDPKSLDLDHSMDEAGAGASNSEPSEPDSPTREHARRSEALQ
  GLVTELRAELCRQRTEYERSVKRIEEGSADLRKRMSRLEEELDQEKKKYIMLEIKLRNSE
  RAREDAERRNQLLQREMEEFFSTLGSLTVGAKGARAPK
• Function: Rho GTPase-activating protein involved in the signal transduction pathway that regulates endothelial cell capillary tube formation during angiogenesis. Acts as a GTPase activator for the RAC1 by converting it to an inactive GDP-bound state. Inhibits RAC1-dependent lamellipodia formation. May also play a role in transcription regulation via its interaction with VEZF1, by regulating activity of the endothelin-1 (EDN1) promoter.
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic retinopathy	DISHGUJM	Strong	Altered Expression	[1]
Melanoma	DIS1RRCY	Strong	Posttranslational Modification	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[1]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Rho GTPase-activating protein 22 (ARHGAP22).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Rho GTPase-activating protein 22 (ARHGAP22).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rho GTPase-activating protein 22 (ARHGAP22).	[17]

12 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 Rho GTPase-activating protein 22 (ARHGAP22).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho GTPase-activating protein 22 (ARHGAP22).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Rho GTPase-activating protein 22 (ARHGAP22).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Rho GTPase-activating protein 22 (ARHGAP22).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Rho GTPase-activating protein 22 (ARHGAP22).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Rho GTPase-activating protein 22 (ARHGAP22).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Rho GTPase-activating protein 22 (ARHGAP22).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Rho GTPase-activating protein 22 (ARHGAP22).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Rho GTPase-activating protein 22 (ARHGAP22).	[13]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Rho GTPase-activating protein 22 (ARHGAP22).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho GTPase-activating protein 22 (ARHGAP22).	[16]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Rho GTPase-activating protein 22 (ARHGAP22).	[18]

References

• [1] High levels of circulating endothelial progenitor cells in patients with diabetic retinopathy are positively associated with ARHGAP22 expression.Oncotarget. 2018 Apr 3;9(25):17858-17866. doi: 10.18632/oncotarget.24909. eCollection 2018 Apr 3.
• [2] DNA hypermethylation is associated with invasive phenotype of malignant melanoma.Exp Dermatol. 2020 Jan;29(1):39-50. doi: 10.1111/exd.14047. Epub 2019 Nov 14.
• [3] Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity.Eur J Hum Genet. 2013 Sep;21(9):988-93. doi: 10.1038/ejhg.2012.293. Epub 2013 Jan 9.
• [4] 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.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] 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.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] 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.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [15] 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.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [17] 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.
• [18] 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.