Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOYK5A8)

• DOT Name: EMILIN-2 (EMILIN2)
• Synonyms: Elastin microfibril interface-located protein 2; Elastin microfibril interfacer 2; Protein FOAP-10
• Gene Name: EMILIN2
• Related Disease:
  Porokeratosis of Mibelli
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiac disease
  Lung adenocarcinoma
  Neoplasm
• UniProt ID: EMIL2_HUMAN
• Pfam ID: PF00386 ; PF07546
• Sequence:
  MWQPRRPWPRVPWRWALALLALVGAGLCHAGPQPGYPARPSARNKNWCAYIVNKNVSCSV
  LEGSESFIQAQYNCAWNQMPCPSALVYRVNFRPRYVTRYKTVTQLEWRCCPGFRGGDCQE
  GPKDPVKTLRPTPARPRNSLKKATDNEPSQFSEPRKTLSPTGTAQPSWGVDPKEGPQELQ
  EKKIQVLEEKVLRLTRTVLDLQSSLAGVSENLKHATQDDASRTRAPGLSSQHPKPDTTVS
  GDTETGQSPGVFNTKESGMKDIKSELAEVKDTLKNKSDKLEELDGKVKGYEGQLRQLQEA
  AQGPTVTMTTNELYQAYVDSKIDALREELMEGMDRKLADLKNSCEYKLTGLQQQCDDYGS
  SYLGVIELIGEKETSLRKEINNLRARLQEPSAQANCCDSEKNGDIGQQIKTLDQKIERVA
  EATRMLNGRLDNEFDRLIVPEPDVDFDAKWNELDARINVTEKNAEEHCFYIEETLRGAIN
  GEVGDLKQLVDQKIQSLEDRLGSVLLQMTNNTGAELSPPGAAALPGVSGSGDERVMMELN
  HLKDKVQVVEDICLLNIQGKPHGMEGALPNREDRAVRDSLHLLKSLNDTMHRKFQETEQT
  IQKLQQDFSFLYSQLNHTENDVTHLQKEMSNCRAGENAGMGRFTKVGEQERTVDTLPSPQ
  HPVAHCCSQLEERWQRLQSQVISELDACKECTQGVQREVSMVEGRVSHMEKTCSKLDSIS
  GNLQRIKEGLNKHVSSLWNCVRQMNGTLRSHSRDISGLKNSVQQFYSHVFQISTDLQDLV
  KFQPSAKAPSPPPPAEAPKEPLQPEPAPPRPSGPATAEDPGRRPVLPQRPPEERPPQPPG
  STGVIAETGQAGPPAGAGVSGRGLPRGVDGQTGSGTVPGAEGFAGAPGYPKSPPVASPGA
  PVPSLVSFSAGLTQKPFPSDGGVVLFNKVLVNDGDVYNPSTGVFTAPYDGRYLITATLTP
  ERDAYVEAVLSVSNASVAQLHTAGYRREFLEYHRPPGALHTCGGPGAFHLIVHLKAGDAV
  NVVVTGGKLAHTDFDEMYSTFSGVFLYPFLSHL
• Function: May be responsible for anchoring smooth muscle cells to elastic fibers, and may be involved not only in the formation of the elastic fiber, but also in the processes that regulate vessel assembly. Has cell adhesive capacity.
• Tissue Specificity: Highest levels are present in fetal heart and adult lung. Intermediate levels in peripheral leukocytes, placenta, and spinal cord and low expression in fetal brain, spleen, thymus, and lung and in adult heart, aorta, testis, bone marrow, small intestine, thymus, lymph node, and appendix.
• Reactome Pathway: Molecules associated with elastic fibres (R-HSA-2129379)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Porokeratosis of Mibelli	DISF48DQ	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Cardiac disease	DISVO1I5	Strong	Altered Expression	[4]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]

3 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 EMILIN-2 (EMILIN2).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of EMILIN-2 (EMILIN2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of EMILIN-2 (EMILIN2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of EMILIN-2 (EMILIN2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of EMILIN-2 (EMILIN2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of EMILIN-2 (EMILIN2).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of EMILIN-2 (EMILIN2).	[12]
Marinol	DM70IK5	Approved	Marinol decreases the expression of EMILIN-2 (EMILIN2).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of EMILIN-2 (EMILIN2).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of EMILIN-2 (EMILIN2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of EMILIN-2 (EMILIN2).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of EMILIN-2 (EMILIN2).	[18]

References

• [1] Identification of an interstitial 18p11.32-p11.31 duplication including the EMILIN2 gene in a family with porokeratosis of Mibelli.PLoS One. 2013 Apr 10;8(4):e61311. doi: 10.1371/journal.pone.0061311. Print 2013.
• [2] EMILIN2 down-modulates the Wnt signalling pathway and suppresses breast cancer cell growth and migration.J Pathol. 2014 Mar;232(4):391-404. doi: 10.1002/path.4316.
• [3] Identification of 5 novel genes methylated in breast and other epithelial cancers.Mol Cancer. 2010 Mar 5;9:51. doi: 10.1186/1476-4598-9-51.
• [4] EMILIN2 regulates platelet activation, thrombus formation, and clot retraction.PLoS One. 2015 Feb 6;10(2):e0115284. doi: 10.1371/journal.pone.0115284. eCollection 2015.
• [5] Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers.Carcinogenesis. 2014 Jun;35(6):1248-57. doi: 10.1093/carcin/bgt494. Epub 2014 Jan 7.
• [6] The ablation of the matricellular protein EMILIN2 causes defective vascularization due to impaired EGFR-dependent IL-8 production affecting tumor growth.Oncogene. 2018 Jun;37(25):3399-3414. doi: 10.1038/s41388-017-0107-x. Epub 2018 Feb 27.
• [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] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [16] 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.
• [17] 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.
• [18] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.