Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9QUXJ3)

• DOT Name: Ephexin-1 (NGEF)
• Synonyms: Eph-interacting exchange protein; Neuronal guanine nucleotide exchange factor
• Gene Name: NGEF
• Related Disease:
  Depression
  Schizophrenia
  Subarachnoid hemorrhage
• UniProt ID: NGEF_HUMAN
• Pfam ID: PF00169 ; PF00621 ; PF00018
• Sequence:
  METRESEDLEKTRRKSASDQWNTDNEPAKVKPELLPEKEETSQADQDIQDKEPHCHIPIK
  RNSIFNRSIRRKSKAKARDNPERNASCLADSQDNGKSVNEPLTLNIPWSRMPPCRTAMQT
  DPGAQEMSESSSTPGNGATPEEWPALADSPTTLTEALRMIHPIPADSWRNLIEQIGLLYQ
  EYRDKSTLQEIETRRQQDAEIEDNTNGSPASEDTPEEEEEEEEEEEPASPPERKTLPQIC
  LLSNPHSRFNLWQDLPEIRSSGVLEILQPEEIKLQEAMFELVTSEASYYKSLNLLVSHFM
  ENERIRKILHPSEAHILFSNVLDVLAVSERFLLELEHRMEENIVISDVCDIVYRYAADHF
  SVYITYVSNQTYQERTYKQLLQEKAAFRELIAQLELDPKCRGLPFSSFLILPFQRITRLK
  LLVQNILKRVEERSERECTALDAHKELEMVVKACNEGVRKMSRTEQMISIQKKMEFKIKS
  VPIISHSRWLLKQGELQQMSGPKTSRTLRTKKLFHEIYLFLFNDLLVICRQIPGDKYQVF
  DSAPRGLLRVEELEDQGQTLANVFILRLLENADDREATYMLKASSQSEMKRWMTSLAPNR
  RTKFVSFTSRLLDCPQVQCVHPYVAQQPDELTLELADILNILDKTDDGWIFGERLHDQER
  GWFPSSMTEEILNPKIRSQNLKECFRVHKMDDPQRSQNKDRRKLGSRNRQ
• Function: Acts as a guanine nucleotide exchange factor (GEF) which differentially activates the GTPases RHOA, RAC1 and CDC42. Plays a role in axon guidance regulating ephrin-induced growth cone collapse and dendritic spine morphogenesis. Upon activation by ephrin through EPHA4, the GEF activity switches toward RHOA resulting in its activation. Activated RHOA promotes cone retraction at the expense of RAC1- and CDC42-stimulated growth cone extension.
• Tissue Specificity: Highly expressed in brain specifically in caudate nucleus and to a lower extent in amygdala and hippocampus. Also detected in lung.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  EPHA-mediated growth cone collapse (R-HSA-3928663)
  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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Depression	DIS3XJ69	Strong	Biomarker	[1]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[2]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Altered Expression	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Daunorubicin	DMQUSBT	Approved	Ephexin-1 (NGEF) affects the response to substance of Daunorubicin.	[18]

4 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 Ephexin-1 (NGEF).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ephexin-1 (NGEF).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ephexin-1 (NGEF).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ephexin-1 (NGEF).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ephexin-1 (NGEF).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ephexin-1 (NGEF).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ephexin-1 (NGEF).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ephexin-1 (NGEF).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ephexin-1 (NGEF).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ephexin-1 (NGEF).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Ephexin-1 (NGEF).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Ephexin-1 (NGEF).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ephexin-1 (NGEF).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ephexin-1 (NGEF).	[12]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ephexin-1 (NGEF).	[17]

References

• [1] Increased EphA4-ephexin1 signaling in the medial prefrontal cortex plays a role in depression-like phenotype.Sci Rep. 2017 Aug 2;7(1):7133. doi: 10.1038/s41598-017-07325-2.
• [2] Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
• [3] Critical role of EphA4 in early brain injury after subarachnoid hemorrhage in rat.Exp Neurol. 2017 Oct;296:41-48. doi: 10.1016/j.expneurol.2017.07.003. Epub 2017 Jul 8.
• [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] 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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] 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.
• [12] 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.
• [13] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [17] 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.
• [18] Mapping genes that contribute to daunorubicin-induced cytotoxicity. Cancer Res. 2007 Jun 1;67(11):5425-33. doi: 10.1158/0008-5472.CAN-06-4431.