Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT04OQQJ)

• DOT Name: monooxygenase MICAL2 (MICAL2)
• Synonyms: EC 1.14.13.225; MICAL C-terminal-like protein; Mical-cL; Molecule interacting with CasL protein 2; MICAL-2
• Gene Name: MICAL2
• Related Disease:
  Neoplasm
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Colorectal carcinoma
  Gastric cancer
  Narcolepsy
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Stroke
• UniProt ID: MICA2_HUMAN
• PDB ID: 2E9K; 5SZH; 5SZI; 5SZJ; 5SZK
• EC Number: 1.14.13.225
• Pfam ID: PF12130 ; PF00307 ; PF01494 ; PF00412
• Sequence:
  MGENEDEKQAQAGQVFENFVQASTCKGTLQAFNILTRHLDLDPLDHRNFYSKLKSKVTTW
  KAKALWYKLDKRGSHKEYKRGKSCTNTKCLIVGGGPCGLRTAIELAYLGAKVVVVEKRDS
  FSRNNVLHLWPFTIHDLRGLGAKKFYGKFCAGSIDHISIRQLQLILFKVALMLGVEIHVN
  VEFVKVLEPPEDQENQKIGWRAEFLPTDHSLSEFEFDVIIGADGRRNTLEGFRRKEFRGK
  LAIAITANFINRNSTAEAKVEEISGVAFIFNQKFFQDLKEETGIDLENIVYYKDCTHYFV
  MTAKKQSLLDKGVIINDYIDTEMLLCAENVNQDNLLSYAREAADFATNYQLPSLDFAMNH
  YGQPDVAMFDFTCMYASENAALVRERQAHQLLVALVGDSLLEPFWPMGTGCARGFLAAFD
  TAWMVKSWNQGTPPLELLAERESLYRLLPQTTPENINKNFEQYTLDPGTRYPNLNSHCVR
  PHQVKHLYITKELEHYPLERLGSVRRSVNLSRKESDIRPSKLLTWCQQQTEGYQHVNVTD
  LTTSWRSGLALCAIIHRFRPELINFDSLNEDDAVENNQLAFDVAEREFGIPPVTTGKEMA
  SAQEPDKLSMVMYLSKFYELFRGTPLRPVDSWRKNYGENADLSLAKSSISNNYLNLTFPR
  KRTPRVDGQTGENDMNKRRRKGFTNLDEPSNFSSRSLGSNQECGSSKEGGNQNKVKSMAN
  QLLAKFEESTRNPSLMKQERRVSGIGKPVLCSSSGPPVHSCCPKPEEATPSPSPPLKRQF
  PSVVVTGHVLRELKQVSAGSECLSRPWRARAKSDLQLGGTENFATLPSTRPRAQALSGVL
  WRLQQVEEKILQKRAQNLANREFHTKNIKEKAAHLASMFGHGDFPQNKLLSKGLSHTHPP
  SPPSRLPSPDPAASSSPSTVDSASPARKEKKSPSGFHFHPSHLRTVHPQLTVGKVSSGIG
  AAAEVLVNLYMNDHRPKAQATSPDLESMRKSFPLNLGGSDTCYFCKKRVYVMERLSAEGH
  FFHRECFRCSICATTLRLAAYTFDCDEGKFYCKPHFIHCKTNSKQRKRRAELKQQREEEA
  TWQEQEAPRRDTPTESSCAVAAIGTLEGSPPDEPTSPKRPKSISEPQHSDAEGDAASPLP
  SEWTSVRISPGEEAAGQDVLAVRVLVTSEDSSSDTESDYGGSEGSHTEPCEEKPWRPGSP
  HLPHTSLGEALSRAVSPQCPEEPRAVHAALQRANSFQSPTPSKYQNWRREFWWSLTPVNK
  RTMSPPKDPSPSLPLPSSSSHSSSPPSSSSTSVSGNAPDGSSPPQMTASEPLSQVSRGHP
  SPPTPNFRRRAVAQGAPREIPLYLPHHPKPEWAEYCLVSPGEDGLSDPAEMTSDECQPAE
  APLGDIGSNHRDPHPIWGKDRSWTGQELSPLAGEDREKGSTGARKEEEGGPVLVKEKLGL
  KKLVLTQEQKTMLLDWNDSIPESVHLKAGERISQKSAENGRGGRVLKPVRPLLLPRAAGE
  PLPTQRGAQEKMGTPAEQAQGERNVPPPKSPLRLIANAIRRSLEPLLSNSEGGKKAWAKQ
  ESKTLPAQACTRSFSLRKTNSNKDGDQHSPGRNQSSAFSPPDPALRTHSLPNRPSKVFPA
  LRSPPCSKIEDVPTLLEKVSLQENFPDASKPPKKRISLFSSLRLKDKSFESFLQESRQRK
  DIRDLFGSPKRKVLPEDSAQALEKLLQPFKSTSLRQAAPPPPPPPPPPPPPPTAGGADSK
  NFPLRAQVTEASSSASSTSSSSADEEFDPQLSLQLKEKKTLRRRKKLEKAMKQLVKQEEL
  KRLYKAQAIQRQLEEVEERQRASEIQGVRLEKALRGEADSGTQDEAQLLQEWFKLVLEKN
  KLMRYESELLIMAQELELEDHQSRLEQKLREKMLKEESQKDEKDLNEEQEVFTELMQVIE
  QRDKLVDSLEEQRIREKAEDQHFESFVFSRGCQLSRT
• Function: Methionine monooxygenase that promotes depolymerization of F-actin by mediating oxidation of residues 'Met-44' and 'Met-47' on actin to form methionine-sulfoxide, resulting in actin filament disassembly and preventing repolymerization. Regulates the disassembly of branched actin networks also by oxidizing ARP3B-containing ARP2/3 complexes leading to ARP3B dissociation from the network. Acts as a key regulator of the SRF signaling pathway elicited by nerve growth factor and serum: mediates oxidation and subsequent depolymerization of nuclear actin, leading to increase MKL1/MRTF-A presence in the nucleus and promote SRF:MKL1/MRTF-A-dependent gene transcription. Does not activate SRF:MKL1/MRTF-A through RhoA.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[8]
Stroke	DISX6UHX	moderate	Genetic Variation	[9]

27 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 monooxygenase MICAL2 (MICAL2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of monooxygenase MICAL2 (MICAL2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of monooxygenase MICAL2 (MICAL2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of monooxygenase MICAL2 (MICAL2).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of monooxygenase MICAL2 (MICAL2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of monooxygenase MICAL2 (MICAL2).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of monooxygenase MICAL2 (MICAL2).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of monooxygenase MICAL2 (MICAL2).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of monooxygenase MICAL2 (MICAL2).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of monooxygenase MICAL2 (MICAL2).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of monooxygenase MICAL2 (MICAL2).	[20]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of monooxygenase MICAL2 (MICAL2).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of monooxygenase MICAL2 (MICAL2).	[18]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of monooxygenase MICAL2 (MICAL2).	[22]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of monooxygenase MICAL2 (MICAL2).	[23]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of monooxygenase MICAL2 (MICAL2).	[22]
Estrone	DM5T6US	Approved	Estrone increases the expression of monooxygenase MICAL2 (MICAL2).	[22]
Mestranol	DMG3F94	Approved	Mestranol increases the expression of monooxygenase MICAL2 (MICAL2).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of monooxygenase MICAL2 (MICAL2).	[24]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of monooxygenase MICAL2 (MICAL2).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of monooxygenase MICAL2 (MICAL2).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of monooxygenase MICAL2 (MICAL2).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of monooxygenase MICAL2 (MICAL2).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of monooxygenase MICAL2 (MICAL2).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of monooxygenase MICAL2 (MICAL2).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of monooxygenase MICAL2 (MICAL2).	[31]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of monooxygenase MICAL2 (MICAL2).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of monooxygenase MICAL2 (MICAL2).	[28]

References

• [1] Overexpression of MICAL2, a novel tumor-promoting factor, accelerates tumor progression through regulating cell proliferation and EMT.J Cancer. 2018 Jan 1;9(3):521-527. doi: 10.7150/jca.22355. eCollection 2018.
• [2] MICAL2 is expressed in cancer associated neo-angiogenic capillary endothelia and it is required for endothelial cell viability, motility and VEGF response.Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2111-2124. doi: 10.1016/j.bbadis.2019.04.008. Epub 2019 Apr 18.
• [3] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [4] MICAL2 promotes breast cancer cell migration by maintaining epidermal growth factor receptor (EGFR) stability and EGFR/P38 signalling activation.Acta Physiol (Oxf). 2018 Feb;222(2). doi: 10.1111/apha.12920. Epub 2017 Aug 19.
• [5] MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance.Theranostics. 2018 Oct 22;8(19):5289-5306. doi: 10.7150/thno.28228. eCollection 2018.
• [6] MICAL2 is a novel human cancer gene controlling mesenchymal to epithelial transition involved in cancer growth and invasion.Oncotarget. 2016 Jan 12;7(2):1808-25. doi: 10.18632/oncotarget.6577.
• [7] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [8] Expression of novel molecules, MICAL2-PV (MICAL2 prostate cancer variants), increases with high Gleason score and prostate cancer progression.Clin Cancer Res. 2006 May 1;12(9):2767-73. doi: 10.1158/1078-0432.CCR-05-1995.
• [9] Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans.Stroke. 2015 Aug;46(8):2063-8. doi: 10.1161/STROKEAHA.115.009044. Epub 2015 Jun 18.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [17] 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.
• [18] 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.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [21] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [22] Moving toward integrating gene expression profiling into high-throughput testing: a gene expression biomarker accurately predicts estrogen receptor alpha modulation in a microarray compendium. Toxicol Sci. 2016 May;151(1):88-103.
• [23] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [24] 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.
• [25] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [32] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.