Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIGXT2L)

• DOT Name: Rho guanine nucleotide exchange factor 16 (ARHGEF16)
• Synonyms: Ephexin-4
• Gene Name: ARHGEF16
• UniProt ID: ARHGG_HUMAN
• PDB ID: 1X6B
• Pfam ID: PF00169 ; PF00621 ; PF00018
• Sequence:
  MAQRHSDSSLEEKLLGHRFHSELRLDAGGNPASGLPMVRGSPRVRDDAAFQPQVPAPPQP
  RPPGHEEPWPIVLSTESPAALKLGTQQLIPKSLAVASKAKTPARHQSFGAAVLSREAARR
  DPKLLPAPSFSLDDMDVDKDPGGMLRRNLRNQSYRAAMKGLGKPGGQGDAIQLSPKLQAL
  AEEPSQPHTRSPAKNKKTLGRKRGHKGSFKDDPQLYQEIQERGLNTSQESDDDILDESSS
  PEGTQKVDATIVVKSYRPAQVTWSQLPEVVELGILDQLSTEERKRQEAMFEILTSEFSYQ
  HSLSILVEEFLQSKELRATVTQMEHHHLFSNILDVLGASQRFFEDLEQRHKAQVLVEDIS
  DILEEHAEKHFHPYIAYCSNEVYQQRTLQKLISSNAAFREALREIERRPACGGLPMLSFL
  ILPMQRVTRLPLLMDTLCLKTQGHSERYKAASRALKAISKLVRQCNEGAHRMERMEQMYT
  LHTQLDFSKVKSLPLISASRWLLKRGELFLVEETGLFRKIASRPTCYLFLFNDVLVVTKK
  KSEESYMVQDYAQMNHIQVEKIEPSELPLPGGGNRSSSVPHPFQVTLLRNSEGRQEQLLL
  SSDSASDRARWIVALTHSERQWQGLSSKGDLPQVEITKAFFAKQADEVTLQQADVVLVLQ
  QEDGWLYGERLRDGETGWFPEDFARFITSRVAVEGNVRRMERLRVETDV
• Function: Guanyl-nucleotide exchange factor of the RHOG GTPase stimulating the exchange of RHOG-associated GDP for GTP. May play a role in chemotactic cell migration by mediating the activation of RAC1 by EPHA2. May also activate CDC42 and mediate activation of CDC42 by the viral protein HPV16 E6.
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  CDC42 GTPase cycle (R-HSA-9013148)
  RHOG GTPase cycle (R-HSA-9013408)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

6 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 16 (ARHGEF16).	[1]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[6]

8 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 16 (ARHGEF16).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[8]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[9]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Rho guanine nucleotide exchange factor 16 (ARHGEF16).	[12]

References

• [1] 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.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] 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.
• [7] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [10] 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.
• [11] 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.
• [12] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.