Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR2VG0W)

• DOT Name: Rho guanine nucleotide exchange factor 4 (ARHGEF4)
• Synonyms: APC-stimulated guanine nucleotide exchange factor 1; Asef; Asef1
• Gene Name: ARHGEF4
• Related Disease:
  Adenoma
  Advanced cancer
  Breast neoplasm
  Familial adenomatous polyposis
  Metastatic malignant neoplasm
  Pancreatic cancer
• UniProt ID: ARHG4_HUMAN
• PDB ID: 2DX1; 2PZ1; 3NMX; 3NMZ
• Pfam ID: PF00169 ; PF00621 ; PF00018
• Sequence:
  MPWEEPAGEKPSCSHSQKAFHMEPAQKPCFTTDMVTWALLCISAETVRGEAPSQPRGIPH
  RSPVSVDDLWLEKTQRKKLQKQAHVERRLHIGAVHKDGVKCWRKTIITSPESLNLPRRSH
  PLSQSAPTGLNHMGWPEHTPGTAMPDGALDTAVCADEVGSEEDLYDDLHSSSHHYSHPGG
  GGEQLAINELISDGSVVCAEALWDHVTMDDQELGFKAGDVIEVMDATNREWWWGRVADGE
  GWFPASFVRLRVNQDEPADDDAPLAGNSGAEDGGAEAQSSKDQMRTNVINEILSTERDYI
  KHLRDICEGYVRQCRKRADMFSEEQLRTIFGNIEDIYRCQKAFVKALEQRFNRERPHLSE
  LGACFLEHQADFQIYSEYCNNHPNACVELSRLTKLSKYVYFFEACRLLQKMIDISLDGFL
  LTPVQKICKYPLQLAELLKYTHPQHRDFKDVEAALHAMKNVAQLINERKRRLENIDKIAQ
  WQSSIEDWEGEDLLVRSSELIYSGELTRVTQPQAKSQQRMFFLFDHQLIYCKKDLLRRDV
  LYYKGRLDMDGLEVVDLEDGKDRDLHVSIKNAFRLHRGATGDSHLLCTRKPEQKQRWLKA
  FAREREQVQLDQETGFSITELQRKQAMLNASKQQVTGKPKAVGRPCYLTRQKHPALPSNR
  PQQQVLVLAEPRRKPSTFWHSISRLAPFRK
• Function: Acts as a guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases. Binding of APC may activate RAC1 GEF activity. The APC-ARHGEF4 complex seems to be involved in cell migration as well as in E-cadherin-mediated cell-cell adhesion. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression.
• Tissue Specificity: Expressed at high levels in the brain, skeletal muscle and testis and at low levels in the kidney, lung, small intestine, ovary and prostate. Expression is aberrantly enhanced in most colorectal tumors.
• KEGG Pathway: Regulation of actin cytoskeleton (hsa04810)
• 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[3]
Familial adenomatous polyposis	DISW53RE	Strong	Altered Expression	[4]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[5]
Pancreatic cancer	DISJC981	moderate	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[15]

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 guanine nucleotide exchange factor 4 (ARHGEF4).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[13]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[19]
Manganese	DMKT129	Investigative	Manganese increases the expression of Rho guanine nucleotide exchange factor 4 (ARHGEF4).	[20]

References

• [1] Wnt signalling and the actin cytoskeleton.Oncogene. 2006 Dec 4;25(57):7538-44. doi: 10.1038/sj.onc.1210063.
• [2] Truncated Adenomatous Polyposis Coli Mutation Induces Asef-Activated Golgi Fragmentation.Mol Cell Biol. 2018 Aug 15;38(17):e00135-18. doi: 10.1128/MCB.00135-18. Print 2018 Sep 1.
• [3] Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study.Epigenetics. 2019 Feb;14(2):146-157. doi: 10.1080/15592294.2019.1580111. Epub 2019 Mar 1.
• [4] Adenomatous polyposis coli-stimulated GEF 1 (Asef1) is a negative regulator of excitatory synaptic function.J Neurochem. 2018 Dec;147(5):595-608. doi: 10.1111/jnc.14570. Epub 2018 Nov 20.
• [5] IGF2BP3-mediated translation in cell protrusions promotes cell invasiveness and metastasis of pancreatic cancer.Oncotarget. 2014 Aug 30;5(16):6832-45. doi: 10.18632/oncotarget.2257.
• [6] ARHGEF4 predicts poor prognosis and promotes cell invasion by influencing ERK1/2 and GSK-3/ signaling in pancreatic cancer.Int J Oncol. 2018 Nov;53(5):2224-2240. doi: 10.3892/ijo.2018.4549. Epub 2018 Aug 31.
• [7] 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.
• [8] 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.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] 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.
• [17] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [18] 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.
• [19] 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.
• [20] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.