Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK9JXIJ)

• DOT Name: Arfaptin-2 (ARFIP2)
• Synonyms: ADP-ribosylation factor-interacting protein 2; Partner of RAC1; POR1
• Gene Name: ARFIP2
• Related Disease:
  Adenocarcinoma
  Hepatocellular carcinoma
  Huntington disease
  Hypoglycemia
• UniProt ID: ARFP2_HUMAN
• PDB ID: 1I49; 1I4D; 1I4L; 1I4T; 4DCN
• Pfam ID: PF06456
• Sequence:
  MTDGILGKAATMEIPIHGNGEARQLPEDDGLEQDLQQVMVSGPNLNETSIVSGGYGGSGD
  GLIPTGSGRHPSHSTTPSGPGDEVARGIAGEKFDIVKKWGINTYKCTKQLLSERFGRGSR
  TVDLELELQIELLRETKRKYESVLQLGRALTAHLYSLLQTQHALGDAFADLSQKSPELQE
  EFGYNAETQKLLCKNGETLLGAVNFFVSSINTLVTKTMEDTLMTVKQYEAARLEYDAYRT
  DLEELSLGPRDAGTRGRLESAQATFQAHRDKYEKLRGDVAIKLKFLEENKIKVMHKQLLL
  FHNAVSAYFAGNQKQLEQTLQQFNIKLRPPGAEKPSWLEEQ
• Function: Plays a role in constitutive metalloproteinase (MMP) secretion from the trans Golgi network. May have important functions during vesicle biogenesis at certain cargo subdomains, which could be predominantly utilized by secreted MMPs, such as MMP7 and MMP2. Also involved in autophagy by regulating the starvation-dependent trafficking of ATG9A vesicles which deliver the phosphatidylinositol 4-kinase beta (PI4KB) to the autophagosome initiation site. Involved in phagophore growth during mitophagy by regulating ATG9A trafficking to mitochondria. In addition, plays a role in NF-kappa-B inhibition by interacting with IKBKB and IKBKG.
• Reactome Pathway: Retrograde transport at the Trans-Golgi-Network (R-HSA-6811440)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Huntington disease	DISQPLA4	Strong	Altered Expression	[3]
Hypoglycemia	DISRCKR7	Strong	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Arfaptin-2 (ARFIP2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Arfaptin-2 (ARFIP2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Arfaptin-2 (ARFIP2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Arfaptin-2 (ARFIP2).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Arfaptin-2 (ARFIP2).	[9]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Arfaptin-2 (ARFIP2).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Arfaptin-2 (ARFIP2).	[11]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Arfaptin-2 (ARFIP2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Arfaptin-2 (ARFIP2).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Arfaptin-2 (ARFIP2).	[13]

References

• [1] Differences between gastric signet-ring cell carcinoma and poorly differentiated adenocarcinoma: A comparison of histopathologic features determined by mucin core protein and trefoil factor family peptide immunohistochemistry.Pathol Int. 2017 Aug;67(8):398-403. doi: 10.1111/pin.12559. Epub 2017 Jul 9.
• [2] Proteome Differences between Hepatitis B Virus Genotype-B- and Genotype-C-Induced Hepatocellular Carcinoma Revealed by iTRAQ-Based Quantitative Proteomics.J Proteome Res. 2016 Feb 5;15(2):487-98. doi: 10.1021/acs.jproteome.5b00838. Epub 2016 Jan 14.
• [3] Arfaptin 2 regulates the aggregation of mutant huntingtin protein.Nat Cell Biol. 2002 Mar;4(3):240-5. doi: 10.1038/ncb761.
• [4] Interaction between variants in the CYP2C9 and POR genes and the risk of sulfonylurea-induced hypoglycaemia: A GoDARTS Study.Diabetes Obes Metab. 2018 Jan;20(1):211-214. doi: 10.1111/dom.13046. Epub 2017 Aug 25.
• [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] 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.
• [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] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [11] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [12] 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.
• [13] 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.
• [14] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.