Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2K30P7)

• DOT Name: Band 4.1-like protein 4B (EPB41L4B)
• Synonyms: Erythrocyte membrane protein band 4.1-like 4B; FERM-containing protein CG1; Protein EHM2
• Gene Name: EPB41L4B
• Related Disease:
  Advanced cancer
  Autosomal dominant nonsyndromic hearing loss 5
  Breast cancer
  Breast carcinoma
  Lung adenocarcinoma
  Lung cancer
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Stroke
  Type-1/2 diabetes
  Peroxisome biogenesis disorder
  Chronic renal failure
  End-stage renal disease
• UniProt ID: E41LB_HUMAN
• Pfam ID: PF08736 ; PF09380 ; PF00373 ; PF09379
• Sequence:
  MLRFLRRTFGRRSMQRYARGAAGRGAAGLGDERDGGPRGGPAAAASSSALPAAPGGSVFP
  AGGGPLLTGGAAVHISAAGAAKATLYCRVFLLDGTEVSVDLPKHAKGQDLFDQIVYHLDL
  VETDYFGLQFLDSAQVAHWLDHAKPIKKQMKIGPAYALHFRVKYYSSEPNNLREEFTRYL
  FVLQLRHDILSGKLKCPYETAVELAALCLQAELGECELPEHTPELVSEFRFIPNQTEAME
  FDIFQRWKECRGKSPAQAELSYLNKAKWLEMYGVDMHVVRGRDGCEYSLGLTPTGILIFE
  GANKIGLFFWPKITKMDFKKSKLTLVVVEDDDQGREQEHTFVFRLDSARTCKHLWKCAVE
  HHAFFRLRTPGNSKSNRSDFIRLGSRFRFSGRTEYQATHGSRLRRTSTFERKPSKRYPSR
  RHSTFKASNPVIAAQLCSKTNPEVHNYQPQYHPNIHPSQPRWHPHSPNVSYPLPSPVLSS
  SDRLPFGIEENGGTPFLTAASGRHHHQHQHQHQHQHHSNYSLSLTLENKEGPLRSPNSSS
  KSLTKLSPGTPALFSEAAAHLKKLELETVKAAGPWPPLHININKAEEKKVSEKTLQTPLL
  PSPVADHVKCNILKAQLENASRVNIQGGKEESPFVNINKKSSLQDASVRSPIPIRVETAQ
  PAVEKPEIKPPRVRKLTRQYSFDEDDLPPDLAEAVGVTTSTTTNTTTAATQVSVPLPSPK
  VQNVSSPHKSEGKGLLSPGAKSPSDRGGAFTLEPGDLLMDFTEATPLAEPASNPHCAHSR
  CSPPLSLPMKEETTGVCMYPPIKTRLIKTFPVDTMNPFPDTFTTGPQFTADFRDSKLQCC
  PGPTSPLIPAATLRPLTETVSTVQTIYTTRKPVSLAASAETLRQELEREKMMKRLLMTEL
• Function: Up-regulates the activity of the Rho guanine nucleotide exchange factor ARHGEF18. Involved in the regulation of the circumferential actomyosin belt in epithelial cells. Promotes cellular adhesion, migration and motility in vitro and may play a role in wound healing. May have a role in mediating cytoskeletal changes associated with steroid-induced cell differentiation.
• Tissue Specificity: Expressed at higher levels in acute wounds than chronic wounds with increased expression in healing wounds, especially at the leading wound edge . Isoform 1 is highly expressed in brain. Isoform 2 is highly expressed in testis with lower levels in prostate and breast .
• KEGG Pathway: Tight junction (hsa04530)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Autosomal dominant nonsyndromic hearing loss 5	DISZ795Z	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]
Stroke	DISX6UHX	moderate	Biomarker	[4]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[4]
Peroxisome biogenesis disorder	DISBQ6QJ	Disputed	Genetic Variation	[5]
Chronic renal failure	DISGG7K6	Limited	Biomarker	[6]
End-stage renal disease	DISXA7GG	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Band 4.1-like protein 4B (EPB41L4B).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Band 4.1-like protein 4B (EPB41L4B).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Band 4.1-like protein 4B (EPB41L4B).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Band 4.1-like protein 4B (EPB41L4B).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Band 4.1-like protein 4B (EPB41L4B).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Band 4.1-like protein 4B (EPB41L4B).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Band 4.1-like protein 4B (EPB41L4B).	[12]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Band 4.1-like protein 4B (EPB41L4B).	[13]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Band 4.1-like protein 4B (EPB41L4B).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Band 4.1-like protein 4B (EPB41L4B).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Band 4.1-like protein 4B (EPB41L4B).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Band 4.1-like protein 4B (EPB41L4B).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Band 4.1-like protein 4B (EPB41L4B).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Band 4.1-like protein 4B (EPB41L4B).	[20]

References

• [1] Clinical implications of the influence of Ehm2 on the aggressiveness of breast cancer cells through regulation of matrix metalloproteinase-9 expression.Mol Cancer Res. 2010 Nov;8(11):1501-12. doi: 10.1158/1541-7786.MCR-10-0186. Epub 2010 Oct 5.
• [2] Refined mapping of a gene for autosomal dominant progressive sensorineural hearing loss (DFNA5) to a 2-cM region, and exclusion of a candidate gene that is expressed in the cochlea.Eur J Hum Genet. 1997 Nov-Dec;5(6):397-405.
• [3] Differential expression and functions of Ehm2 transcript variants in lung adenocarcinoma.Int J Oncol. 2019 May;54(5):1747-1758. doi: 10.3892/ijo.2019.4732. Epub 2019 Feb 27.
• [4] Clinical and molecular epidemiology of community-onset, extended-spectrum beta-lactamase-producing Escherichia coli infections in Thailand: a case-case-control study.Am J Infect Control. 2007 Nov;35(9):606-12. doi: 10.1016/j.ajic.2007.05.008.
• [5] Peroxisome biogenesis and molecular defects in peroxisome assembly disorders.Cell Biochem Biophys. 2000;32 Spring:155-64. doi: 10.1385/cbb:32:1-3:155.
• [6] A grading system that predicts the risk of dialysis induction in IgA nephropathy patients based on the combination of the clinical and histological severity.Clin Exp Nephrol. 2019 Jan;23(1):16-25. doi: 10.1007/s10157-018-1657-0. Epub 2018 Oct 26.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [11] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [12] 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.
• [13] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [14] 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.
• [15] 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.
• [16] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.