Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM9VMN3)

• DOT Name: EF-hand domain-containing protein D2 (EFHD2)
• Synonyms: Swiprosin-1
• Gene Name: EFHD2
• Related Disease:
  Asthma
  Diabetic kidney disease
  Hyperglycemia
  Nephropathy
  Advanced cancer
  Alzheimer disease
  Atopic dermatitis
  Brain disease
  Drug dependence
  Mental disorder
  Motion sickness
  Schizophrenia
  Tauopathy
  Alcohol dependence
• UniProt ID: EFHD2_HUMAN
• PDB ID: 5H0P; 5I2L; 5I2O; 5I2Q; 7YGY
• Pfam ID: PF21008
• Sequence:
  MATDELATKLSRRLQMEGEGGGETPEQPGLNGAAAAAAGAPDEAAEALGSADCELSAKLL
  RRADLNQGIGEPQSPSRRVFNPYTEFKEFSRKQIKDMEKMFKQYDAGRDGFIDLMELKLM
  MEKLGAPQTHLGLKNMIKEVDEDFDSKLSFREFLLIFRKAAAGELQEDSGLCVLARLSEI
  DVSSEGVKGAKSFFEAKVQAINVSSRFEEEIKAEQEERKKQAEEMKQRKAAFKELQSTFK
• Function: May regulate B-cell receptor (BCR)-induced immature and primary B-cell apoptosis. Plays a role as negative regulator of the canonical NF-kappa-B-activating branch. Controls spontaneous apoptosis through the regulation of BCL2L1 abundance.
• Tissue Specificity: Found in lymphocytes; preferentially expressed in CD8+ cells.
• Reactome Pathway: RHOD GTPase cycle (R-HSA-9013405)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Definitive	Biomarker	[1]
Diabetic kidney disease	DISJMWEY	Definitive	Biomarker	[2]
Hyperglycemia	DIS0BZB5	Definitive	Biomarker	[2]
Nephropathy	DISXWP4P	Definitive	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[6]
Brain disease	DIS6ZC3X	Strong	Biomarker	[7]
Drug dependence	DIS9IXRC	Strong	Biomarker	[7]
Mental disorder	DIS3J5R8	Strong	Biomarker	[7]
Motion sickness	DISZ2WZW	Strong	Biomarker	[8]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[9]
Tauopathy	DISY2IPA	Strong	Biomarker	[5]
Alcohol dependence	DIS4ZSCO	moderate	Biomarker	[10]

10 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 EF-hand domain-containing protein D2 (EFHD2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of EF-hand domain-containing protein D2 (EFHD2).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of EF-hand domain-containing protein D2 (EFHD2).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of EF-hand domain-containing protein D2 (EFHD2).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of EF-hand domain-containing protein D2 (EFHD2).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of EF-hand domain-containing protein D2 (EFHD2).	[17]
Selenium	DM25CGV	Approved	Selenium increases the expression of EF-hand domain-containing protein D2 (EFHD2).	[18]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of EF-hand domain-containing protein D2 (EFHD2).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of EF-hand domain-containing protein D2 (EFHD2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of EF-hand domain-containing protein D2 (EFHD2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the phosphorylation of EF-hand domain-containing protein D2 (EFHD2).	[15]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of EF-hand domain-containing protein D2 (EFHD2).	[20]
G1	DMTV42K	Phase 1/2	G1 decreases the phosphorylation of EF-hand domain-containing protein D2 (EFHD2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of EF-hand domain-containing protein D2 (EFHD2).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of EF-hand domain-containing protein D2 (EFHD2).	[23]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of EF-hand domain-containing protein D2 (EFHD2).	[24]

References

• [1] Comprehensive analysis of miRNA-mRNA-lncRNA networks in severe asthma.Epigenomics. 2019 Feb;11(2):115-131. doi: 10.2217/epi-2018-0132. Epub 2018 Nov 14.
• [2] Swiprosin-1 Promotes Mitochondria-Dependent Apoptosis of Glomerular Podocytes via P38 MAPK Pathway in Early-Stage Diabetic Nephropathy.Cell Physiol Biochem. 2018;45(3):899-916. doi: 10.1159/000487285. Epub 2018 Feb 2.
• [3] LY333531, a PKC inhibitor, attenuates glomerular endothelial cell apoptosis in the early stage of mouse diabetic nephropathy via down-regulating swiprosin-1.Acta Pharmacol Sin. 2017 Jul;38(7):1009-1023. doi: 10.1038/aps.2016.172. Epub 2017 Apr 17.
• [4] Swiprosin-1: Its Expression and Diverse Biological Functions.J Cell Biochem. 2018 Jan;119(1):150-156. doi: 10.1002/jcb.26199. Epub 2017 Jun 30.
• [5] Impact of Swiprosin-1/Efhd2 on Adult Hippocampal Neurogenesis.Stem Cell Reports. 2018 Feb 13;10(2):347-355. doi: 10.1016/j.stemcr.2017.12.010. Epub 2018 Jan 11.
• [6] Swiprosin-1 is expressed in mast cells and up-regulated through the protein kinase C beta I/eta pathway.J Cell Biochem. 2009 Oct 15;108(3):705-15. doi: 10.1002/jcb.22307.
• [7] Swiprosin-1/ EFhd2: from Immune Regulator to Personality and Brain Disorders.Neurosignals. 2019;27(S1):1-19. doi: 10.33594/000000179.
• [8] Low level of swiprosin-1/EFhd2 in vestibular nuclei of spontaneously hypersensitive motion sickness mice.Sci Rep. 2017 Jan 27;7:40986. doi: 10.1038/srep40986.
• [9] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [10] EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction.Mol Psychiatry. 2018 May;23(5):1303-1319. doi: 10.1038/mp.2017.63. Epub 2017 Apr 11.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [16] 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.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.
• [19] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [20] 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.
• [21] 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.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] 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.
• [24] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.