Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOXEK8Y)

DOT Name Rho guanine nucleotide exchange factor 18 (ARHGEF18)
Synonyms 114 kDa Rho-specific guanine nucleotide exchange factor; p114-Rho-GEF; p114RhoGEF; Septin-associated RhoGEF; SA-RhoGEF
Gene Name ARHGEF18
Related Disease
Retinitis pigmentosa 78 ( )
Acute myelogenous leukaemia ( )
Neuroblastoma ( )
Retinitis pigmentosa ( )
UniProt ID
ARHGI_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF17838 ; PF00621
Sequence
MGDDQEDDFPRRLSESMEDLSLDLGALQGSEYLQDLGLGAPSHSQPGETPDSRPTGEEPG
RDSLFSSLAGSQDLSRRRSWERSRSCSESWRRLSLDASAVDEEPCLPRTLASLALNLPGG
GLKTWTQGCLSGGGTPAESPGKECDSPKKRGRSRSVPVSFYEIRSPEISPGLEVPTPPVQ
GLEPPVLECMEKDHVEPDHVLIVQQVLQELRQYHGARQRACMSASPGGAHSNLTWFEFLS
ESEDGAGKNEKSDKSTSVKRRLSCLRSRVTRQKEKGKSPAHLKDKGQDARERRECVNGHQ
LLQGTFSGPSSCPLCGKPFLSSASLKEHPRGTLLSDGSPALSRNVGMTVSQKGGPQPTPS
PAGPGTQLGPITGEMDEADSAFLKFKQTADDSLSLTSPNTESIFVEDPYTASLRSEIESD
GHEFEAESWSLAVDAAYAKKQKREVVKRQDVLYELMQTEVHHVRTLKIMLKVYSRALQEE
LQFSSKAIGRLFPCADDLLETHSHFLARLKERRQESLEEGSDRNYVIQKIGDLLVQQFSG
ENGERMKEKYGVFCSGHNEAVSHYKLLLQQNKKFQNLIKKIGNFSIVRRLGVQECILLVT
QRITKYPVLVERIIQNTEAGTEDYEDLTQALNLIKDIISQVDAKVSECEKGQRLREIAGK
MDLKSSSKLKNGLTFRKEDMLQRQLHLEGMLCWKTTSGRLKDILAILLTDVLLLLQEKDQ
KYVFASVDSKPPVISLQKLIVREVANEEKAMFLISASLQGPEMYEIYTSSKEDRNAWMAH
IQRAVESCPDEEEGPFSLPEEERKVVEARATRLRDFQERLSMKDQLIAQSLLEKQQIYLE
MAEMGGLEDLPQPRGLFRGGDPSETLQGELILKSAMSEIEGIQSLICRQLGSANGQAEDG
GSSTGPPRRAETFAGYDCTNSPTKNGSFKKKVSSTDPRPRDWRGPPNSPDLKLSDSDIPG
SSEESPQVVEAPGTESDPRLPTVLESELVQRIQTLSQLLLNLQAVIAHQDSYVETQRAAI
QEREKQFRLQSTRGNLLLEQERQRNFEKQREERAALEKLQSQLRHEQQRWERERQWQHQE
LERAGARLQEREGEARQLRERLEQERAELERQRQAYQHDLERLREAQRAVERERERLELL
RRLKKQNTAPGALPPDTLAEAQPPSHPPSFNGEGLEGPRVSMLPSGVGPEYAERPEVARR
DSAPTENRLAKSDVPIQLLSATNQFQRQAAVQQQIPTKLAASTKGGKDKGGKSRGSQRWE
SSASFDLKQQLLLNKLMGKDESTSRNRRSLSPILPGRHSPAPPPDPGFPAPSPPPADSPS
EGFSLKAGGTALLPGPPAPSPLPATPLSAKEDASKEDVIFF
Function
Acts as a guanine nucleotide exchange factor (GEF) for RhoA GTPases. Its activation induces formation of actin stress fibers. Also acts as a GEF for RAC1, inducing production of reactive oxygen species (ROS). Does not act as a GEF for CDC42. The G protein beta-gamma (Gbetagamma) subunits of heterotrimeric G proteins act as activators, explaining the integrated effects of LPA and other G-protein coupled receptor agonists on actin stress fiber formation, cell shape change and ROS production. Required for EPB41L4B-mediated regulation of the circumferential actomyosin belt in epithelial cells.
Tissue Specificity
Expressed in all tissues tested with highest expression in kidney and pancreas. Weakly or not expressed in liver, skeletal muscle and testis. Isoform 1: Expressed in eosinophils . Isoform 2: Expressed in eosinophils . Isoform 3: Expressed in eosinophils . Isoform 4: Not detected in eosinophils .
KEGG Pathway
Tight junction (hsa04530 )
Reactome Pathway
TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) (R-HSA-2173791 )
G alpha (12/13) signalling events (R-HSA-416482 )
RHOA GTPase cycle (R-HSA-8980692 )
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
Retinitis pigmentosa 78 DISRKC0Q Strong Autosomal recessive [1]
Acute myelogenous leukaemia DISCSPTN moderate Genetic Variation [2]
Neuroblastoma DISVZBI4 moderate Biomarker [3]
Retinitis pigmentosa DISCGPY8 Supportive Autosomal dominant [1]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
12 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 guanine nucleotide exchange factor 18 (ARHGEF18). [4]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [5]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [6]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [7]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [8]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [9]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [11]
Testosterone DM7HUNW Approved Testosterone increases the expression of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [11]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [12]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [13]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [14]
Milchsaure DM462BT Investigative Milchsaure decreases the expression of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [16]
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⏷ Show the Full List of 12 Drug(s)
3 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 guanine nucleotide exchange factor 18 (ARHGEF18). [10]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [15]
Coumarin DM0N8ZM Investigative Coumarin increases the phosphorylation of Rho guanine nucleotide exchange factor 18 (ARHGEF18). [15]
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References

1 Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration. Am J Hum Genet. 2017 Feb 2;100(2):334-342. doi: 10.1016/j.ajhg.2016.12.014. Epub 2017 Jan 26.
2 Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
3 Involvement of p114-RhoGEF and Lfc in Wnt-3a- and dishevelled-induced RhoA activation and neurite retraction in N1E-115 mouse neuroblastoma cells.Mol Biol Cell. 2010 Oct 15;21(20):3590-600. doi: 10.1091/mbc.E10-02-0095. Epub 2010 Sep 1.
4 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
5 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
6 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
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 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
9 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
10 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.
11 Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
12 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
13 New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
14 Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
15 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
16 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.