Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNWTUA8)

• DOT Name: Erbin (ERBIN)
• Synonyms: Densin-180-like protein; Erbb2-interacting protein; Protein LAP2
• Gene Name: ERBIN
• Related Disease:
  Advanced cancer
  Carcinoma of esophagus
  Cardiac arrest
  Cardiac failure
  Cholangiocarcinoma
  Congestive heart failure
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Dystrophic epidermolysis bullosa
  Epidermolysis bullosa
  Esophageal cancer
  Familial dilated cardiomyopathy
  Herpes simplex infection
  Neoplasm of esophagus
  Non-alcoholic fatty liver disease
  Hepatocellular carcinoma
  Cardiomyopathy
  Cutaneous squamous cell carcinoma
  Large cell carcinoma
  Neoplasm
• UniProt ID: ERBIN_HUMAN
• PDB ID: 1MFG; 1MFL; 1N7T; 2H3L; 2QBW; 3CH8; 6Q0M; 6Q0N; 6Q0U; 6UBH; 7LUL
• Pfam ID: PF13855 ; PF00595
• Sequence:
  MTTKRSLFVRLVPCRCLRGEEETVTTLDYSHCSLEQVPKEIFTFEKTLEELYLDANQIEE
  LPKQLFNCQSLHKLSLPDNDLTTLPASIANLINLRELDVSKNGIQEFPENIKNCKVLTIV
  EASVNPISKLPDGFSQLLNLTQLYLNDAFLEFLPANFGRLTKLQILELRENQLKMLPKTM
  NRLTQLERLDLGSNEFTEVPEVLEQLSGLKEFWMDANRLTFIPGFIGSLKQLTYLDVSKN
  NIEMVEEGISTCENLQDLLLSSNSLQQLPETIGSLKNITTLKIDENQLMYLPDSIGGLIS
  VEELDCSFNEVEALPSSIGQLTNLRTFAADHNYLQQLPPEIGSWKNITVLFLHSNKLETL
  PEEMGDMQKLKVINLSDNRLKNLPFSFTKLQQLTAMWLSDNQSKPLIPLQKETDSETQKM
  VLTNYMFPQQPRTEDVMFISDNESFNPSLWEEQRKQRAQVAFECDEDKDEREAPPREGNL
  KRYPTPYPDELKNMVKTVQTIVHRLKDEETNEDSGRDLKPHEDQQDINKDVGVKTSESTT
  TVKSKVDEREKYMIGNSVQKISEPEAEISPGSLPVTANMKASENLKHIVNHDDVFEESEE
  LSSDEEMKMAEMRPPLIETSINQPKVVALSNNKKDDTKETDSLSDEVTHNSNQNNSNCSS
  PSRMSDSVSLNTDSSQDTSLCSPVKQTHIDINSKIRQEDENFNSLLQNGDILNSSTEEKF
  KAHDKKDFNLPEYDLNVEERLVLIEKSVDSTATADDTHKLDHINMNLNKLITNDTFQPEI
  MERSKTQDIVLGTSFLSINSKEETEHLENGNKYPNLESVNKVNGHSEETSQSPNRTEPHD
  SDCSVDLGISKSTEDLSPQKSGPVGSVVKSHSITNMEIGGLKIYDILSDNGPQQPSTTVK
  ITSAVDGKNIVRSKSATLLYDQPLQVFTGSSSSSDLISGTKAIFKFDSNHNPEEPNIIRG
  PTSGPQSAPQIYGPPQYNIQYSSSAAVKDTLWHSKQNPQIDHASFPPQLLPRSESTENQS
  YAKHSANMNFSNHNNVRANTAYHLHQRLGPARHGEMWAISPNDRLIPAVTRSTIQRQSSV
  SSTASVNLGDPGSTRRAQIPEGDYLSYREFHSAGRTPPMMPGSQRPLSARTYSIDGPNAS
  RPQSARPSINEIPERTMSVSDFNYSRTSPSKRPNARVGSEHSLLDPPGKSKVPRDWREQV
  LRHIEAKKLEKKHPQTSSSGDPCQDGIFISGQQNYSSATLSHKDVPPDSLMKMPLSNGQM
  GQPLRPQANYSQIHHPPQASVARHPSREQLIDYLMLKVAHQPPYTQPHCSPRQGHELAKQ
  EIRVRVEKDPELGFSISGGVGGRGNPFRPDDDGIFVTRVQPEGPASKLLQPGDKIIQANG
  YSFINIEHGQAVSLLKTFQNTVELIIVREVSS
• Function: Acts as an adapter for the receptor ERBB2, in epithelia. By binding the unphosphorylated 'Tyr-1248' of receptor ERBB2, it may contribute to stabilize this unphosphorylated state. Inhibits NOD2-dependent NF-kappa-B signaling and pro-inflammatory cytokine secretion.
• Tissue Specificity: Highly expressed in brain, heart, kidney, muscle and stomach, followed by liver, spleen and intestine.
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)
• Reactome Pathway:
  Downregulation of ERBB2 signaling (R-HSA-8863795)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOG GTPase cycle (R-HSA-9013408)
  RAC3 GTPase cycle (R-HSA-9013423)
  Constitutive Signaling by Overexpressed ERBB2 (R-HSA-9634285)
  Drug-mediated inhibition of ERBB2 signaling (R-HSA-9652282)
  Signaling by ERBB2 KD Mutants (R-HSA-9664565)
  Resistance of ERBB2 KD mutants to trastuzumab (R-HSA-9665233)
  Resistance of ERBB2 KD mutants to sapitinib (R-HSA-9665244)
  Resistance of ERBB2 KD mutants to tesevatinib (R-HSA-9665245)
  Resistance of ERBB2 KD mutants to neratinib (R-HSA-9665246)
  Resistance of ERBB2 KD mutants to osimertinib (R-HSA-9665247)
  Resistance of ERBB2 KD mutants to afatinib (R-HSA-9665249)
  Resistance of ERBB2 KD mutants to AEE788 (R-HSA-9665250)
  Resistance of ERBB2 KD mutants to lapatinib (R-HSA-9665251)
  Signaling by ERBB2 ECD mutants (R-HSA-9665348)
  Signaling by ERBB2 TMD/JMD mutants (R-HSA-9665686)
  Drug resistance in ERBB2 TMD/JMD mutants (R-HSA-9665737)
  Signaling by ERBB2 (R-HSA-1227986)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[2]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[1]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Dilated cardiomyopathy	DISX608J	Strong	Biomarker	[5]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[5]
Dystrophic epidermolysis bullosa	DISALMGH	Strong	Altered Expression	[6]
Epidermolysis bullosa	DISVOTZQ	Strong	Biomarker	[6]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[2]
Familial dilated cardiomyopathy	DISBHDU9	Strong	Genetic Variation	[5]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[7]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[2]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[9]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[10]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Genetic Variation	[11]
Large cell carcinoma	DISYMCOF	Limited	Genetic Variation	[12]
Neoplasm	DISZKGEW	Limited	Altered Expression	[13]

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 Erbin (ERBIN).	[14]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Erbin (ERBIN).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Erbin (ERBIN).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Erbin (ERBIN).	[28]

14 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 Erbin (ERBIN).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Erbin (ERBIN).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Erbin (ERBIN).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Erbin (ERBIN).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Erbin (ERBIN).	[19]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Erbin (ERBIN).	[20]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Erbin (ERBIN).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Erbin (ERBIN).	[22]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol affects the expression of Erbin (ERBIN).	[24]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Erbin (ERBIN).	[25]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Erbin (ERBIN).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Erbin (ERBIN).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Erbin (ERBIN).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Erbin (ERBIN).	[30]

References

• [1] Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer.Science. 2014 May 9;344(6184):641-5. doi: 10.1126/science.1251102.
• [2] Transcriptional regulation of miR-146b by C/EBP LAP2 in esophageal cancer cells.Biochem Biophys Res Commun. 2014 Mar 28;446(1):267-71. doi: 10.1016/j.bbrc.2014.02.096. Epub 2014 Feb 28.
• [3] Tapping CD4 T cells for cancer immunotherapy: the choice of personalized genomics.J Immunol. 2015 Mar 1;194(5):2049-56. doi: 10.4049/jimmunol.1402669.
• [4] FHL2 switches MITF from activator to repressor of Erbin expression during cardiac hypertrophy.Int J Cardiol. 2015 Sep 15;195:85-94. doi: 10.1016/j.ijcard.2015.05.108. Epub 2015 May 20.
• [5] Thymopoietin (lamina-associated polypeptide 2) gene mutation associated with dilated cardiomyopathy. Hum Mutat. 2005 Dec;26(6):566-74. doi: 10.1002/humu.20250.
• [6] Disruption of ERBB2IP is not associated with dystrophic epidermolysis bullosa in both father and son carrying a balanced 5;13 translocation.J Invest Dermatol. 2005 Oct;125(4):700-4. doi: 10.1111/j.0022-202X.2005.23875.x.
• [7] Long-term neuroprotection achieved with latency-associated promoter-driven herpes simplex virus gene transfer to the peripheral nervous system.Mol Ther. 2005 Aug;12(2):307-13. doi: 10.1016/j.ymthe.2005.04.009.
• [8] Nuclear lamina genetic variants, including a truncated LAP2, in twins and siblings with nonalcoholic fatty liver disease.Hepatology. 2018 May;67(5):1710-1725. doi: 10.1002/hep.29522. Epub 2018 Mar 24.
• [9] LncRNA KTN1-AS1 promotes tumor growth of hepatocellular carcinoma by targeting miR-23c/ERBB2IP axis.Biomed Pharmacother. 2019 Jan;109:1140-1147. doi: 10.1016/j.biopha.2018.10.105. Epub 2018 Nov 6.
• [10] Analysis of RNA-Seq datasets reveals enrichment of tissue-specific splice variants for nuclear envelope proteins.Nucleus. 2018;9(1):410-430. doi: 10.1080/19491034.2018.1469351.
• [11] A Genome-Wide Association Study of Cutaneous Squamous Cell Carcinoma among European Descendants.Cancer Epidemiol Biomarkers Prev. 2016 Apr;25(4):714-20. doi: 10.1158/1055-9965.EPI-15-1070. Epub 2016 Feb 12.
• [12] Constitutional abnormality of nuclear membrane proteins in small cell lung carcinoma.Virchows Arch. 2019 Oct;475(4):407-414. doi: 10.1007/s00428-019-02597-7. Epub 2019 Jun 15.
• [13] Expression of the CCAAT/enhancer-binding proteins C/EBPalpha, C/EBPbeta and C/EBPdelta in breast cancer: correlations with clinicopathologic parameters and cell-cycle regulatory proteins.Breast Cancer Res Treat. 2003 May;79(2):175-85. doi: 10.1023/a:1023929504884.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] 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.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [20] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [21] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [22] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [23] 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.
• [24] 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.
• [25] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] 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.
• [29] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [30] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.