Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKD9XY9)

• DOT Name: Rho guanine nucleotide exchange factor 19 (ARHGEF19)
• Synonyms: Ephexin-2
• Gene Name: ARHGEF19
• Related Disease:
  Lung cancer
  Lung carcinoma
  Metabolic disorder
  Non-small-cell lung cancer
• UniProt ID: ARHGJ_HUMAN
• Pfam ID: PF00621 ; PF07653
• Sequence:
  MDCGPPATLQPHLTGPPGTAHHPVAVCQQESLSFAELPALKPPSPVCLDLFPVAPEELRA
  PGSRWSLGTPAPLQGLLWPLSPGGSDTEITSGGMRPSRAGSWPHCPGAQPPALEGPWSPR
  HTQPQRRASHGSEKKSAWRKMRVYQREEVPGCPEAHAVFLEPGQVVQEQALSTEEPRVEL
  SGSTRVSLEGPERRRFSASELMTRLHSSLRLGRNSAARALISGSGTGAAREGKASGMEAR
  SVEMSGDRVSRPAPGDSREGDWSEPRLDTQEEPPLGSRSTNERRQSRFLLNSVLYQEYSD
  VASARELRRQQREEEGPGDEAEGAEEGPGPPRANLSPSSSFRAQRSARGSTFSLWQDIPD
  VRGSGVLATLSLRDCKLQEAKFELITSEASYIHSLSVAVGHFLGSAELSECLGAQDKQWL
  FSKLPEVKSTSERFLQDLEQRLEADVLRFSVCDVVLDHCPAFRRVYLPYVTNQAYQERTY
  QRLLLENPRFPGILARLEESPVCQRLPLTSFLILPFQRITRLKMLVENILKRTAQGSEDE
  DMATKAFNALKELVQECNASVQSMKRTEELIHLSKKIHFEGKIFPLISQARWLVRHGELV
  ELAPLPAAPPAKLKLSSKAVYLHLFNDCLLLSRRKELGKFAVFVHAKMAELQVRDLSLKL
  QGIPGHVFLLQLLHGQHMKHQFLLRARTESEKQRWISALCPSSPQEDKEVISEGEDCPQV
  QCVRTYKALHPDELTLEKTDILSVRTWTSDGWLEGVRLADGEKGWVPQAYVEEISSLSAR
  LRNLRENKRVTSATSKLGEAPV
• Function: Acts as a guanine nucleotide exchange factor (GEF) for RhoA GTPase.
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  RHOA GTPase cycle (R-HSA-8980692)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Strong	Altered Expression	[1]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[1]
Metabolic disorder	DIS71G5H	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[1]

2 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 guanine nucleotide exchange factor 19 (ARHGEF19).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Rho guanine nucleotide exchange factor 19 (ARHGEF19).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Rho guanine nucleotide exchange factor 19 (ARHGEF19).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Rho guanine nucleotide exchange factor 19 (ARHGEF19).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Rho guanine nucleotide exchange factor 19 (ARHGEF19).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rho guanine nucleotide exchange factor 19 (ARHGEF19).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Rho guanine nucleotide exchange factor 19 (ARHGEF19).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rho guanine nucleotide exchange factor 19 (ARHGEF19).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Rho guanine nucleotide exchange factor 19 (ARHGEF19).	[11]

References

• [1] ARHGEF19 interacts with BRAF to activate MAPK signaling during the tumorigenesis of non-small cell lung cancer.Int J Cancer. 2018 Apr 1;142(7):1379-1391. doi: 10.1002/ijc.31169. Epub 2017 Dec 4.
• [2] In Utero Exposure to a High-Fat Diet Programs Hepatic Hypermethylation and Gene Dysregulation and Development of Metabolic Syndrome in Male Mice.Endocrinology. 2017 Sep 1;158(9):2860-2872. doi: 10.1210/en.2017-00334.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [7] 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.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] 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.
• [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.