Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHVMXE3)

• DOT Name: Integral membrane protein 2C (ITM2C)
• Synonyms: Cerebral protein 14; Transmembrane protein BRI3
• Gene Name: ITM2C
• Related Disease: Subarachnoid hemorrhage
• UniProt ID: ITM2C_HUMAN
• Pfam ID: PF04089
• Sequence:
  MVKISFQPAVAGIKGDKADKASASAPAPASATEILLTPAREEQPPQHRSKRGGSVGGVCY
  LSMGMVVLLMGLVFASVYIYRYFFLAQLARDNFFRCGVLYEDSLSSQVRTQMELEEDVKI
  YLDENYERINVPVPQFGGGDPADIIHDFQRGLTAYHDISLDKCYVIELNTTIVLPPRNFW
  ELLMNVKRGTYLPQTYIIQEEMVVTEHVSDKEALGSFIYHLCNGKDTYRLRRRATRRRIN
  KRGAKNCNAIRHFENTFVVETLICGVV
• Function: Negative regulator of amyloid-beta peptide production. May inhibit the processing of APP by blocking its access to alpha- and beta-secretase. Binding to the beta-secretase-cleaved APP C-terminal fragment is negligible, suggesting that ITM2C is a poor gamma-secretase cleavage inhibitor. May play a role in TNF-induced cell death and neuronal differentiation.
• Tissue Specificity: High levels in the brain, specifically in the cerebral cortex, medulla, amygdala, hippocampus, thalamus, caudate nucleus, cerebellum, olfactory lobe and spinal cord. Very low levels in other organs.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Subarachnoid hemorrhage	DISI7I8Y	Limited	Biomarker	[1]

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 Integral membrane protein 2C (ITM2C).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Integral membrane protein 2C (ITM2C).	[8]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Integral membrane protein 2C (ITM2C).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Integral membrane protein 2C (ITM2C).	[15]

12 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 Integral membrane protein 2C (ITM2C).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Integral membrane protein 2C (ITM2C).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Integral membrane protein 2C (ITM2C).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Integral membrane protein 2C (ITM2C).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Integral membrane protein 2C (ITM2C).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Integral membrane protein 2C (ITM2C).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Integral membrane protein 2C (ITM2C).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Integral membrane protein 2C (ITM2C).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Integral membrane protein 2C (ITM2C).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Integral membrane protein 2C (ITM2C).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Integral membrane protein 2C (ITM2C).	[13]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Integral membrane protein 2C (ITM2C).	[16]

References

• [1] Association of genetic variants with hemorrhagic stroke in Japanese individuals.Int J Mol Med. 2010 Apr;25(4):649-56. doi: 10.3892/ijmm_00000388.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] 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.
• [7] 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.
• [8] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [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] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [13] 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.
• [14] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [15] 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.
• [16] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.