Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1IQM3K)

• DOT Name: MICAL-like protein 2 (MICALL2)
• Synonyms: Junctional Rab13-binding protein; Molecule interacting with CasL-like 2; MICAL-L2
• Gene Name: MICALL2
• Related Disease:
  Advanced cancer
  Attention deficit hyperactivity disorder
  Epithelial ovarian cancer
  High blood pressure
  Mental disorder
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: MILK2_HUMAN
• Pfam ID: PF12130 ; PF00307 ; PF00412
• Sequence:
  MAAIRALQQWCRQQCEGYRDVNICNMTTSFRDGLAFCAILHRHRPDLINFSALKKENIYE
  NNKLAFRVAEEHLGIPALLDAEDMVALKVPDRLSILTYVSQYYNYFHGRSPIGGMAGVKR
  ASEDSEEEPSGKKAPVQAAKLPSPAPARKPPLSPAQTNPVVQRRNEGAGGPPPKTDQALA
  GSLVSSTCGVCGKHVHLVQRHLADGRLYHRSCFRCKQCSCTLHSGAYKATGEPGTFVCTS
  HLPAAASASPKLTGLVPRQPGAMGVDSRTSCSPQKAQEANKARPSAWEPAAGNSPARASV
  PAAPNPAATSATSVHVRSPARPSESRLAPTPTEGKVRPRVTNSSPMGWSSAAPCTAAAAS
  HPAVPPSAPDPRPATPQGGGAPRVAAPQTTLSSSSTSAATVDPPAWTPSASRTQQARNKF
  FQTSAVPPGTSLSGRGPTPSLVLSKDSSKEQARNFLKQALSALEEAGAPAPGRPSPATAA
  VPSSQPKTEAPQASPLAKPLQSSSPRVLGLPSRMEPPAPLSTSSTSQASALPPAGRRNLA
  ESSGVGRVGAGSRPKPEAPMAKGKSTTLTQDMSTSLQEGQEDGPAGWRANLKPVDRRSPA
  ERTLKPKEPRALAEPRAGEAPRKVSGSFAGSVHITLTPVRPDRTPRPASPGPSLPARSPS
  PPRRRRLAVPASLDVCDNWLRPEPPGQEARVQSWKEEEKKPHLQGKPGRPLSPANVPALP
  GETVTSPVRLHPDYLSPEEIQRQLQDIERRLDALELRGVELEKRLRAAEGDDAEDSLMVD
  WFWLIHEKQLLLRQESELMYKSKAQRLEEQQLDIEGELRRLMAKPEALKSLQERRREQEL
  LEQYVSTVNDRSDIVDSLDEDRLREQEEDQMLRDMIEKLGLQRKKSKFRLSKIWSPKSKS
  SPSQ
• Function: Effector of small Rab GTPases which is involved in junctional complexes assembly through the regulation of cell adhesion molecules transport to the plasma membrane and actin cytoskeleton reorganization. Regulates the endocytic recycling of occludins, claudins and E-cadherin to the plasma membrane and may thereby regulate the establishment of tight junctions and adherens junctions. In parallel, may regulate actin cytoskeleton reorganization directly through interaction with F-actin or indirectly through actinins and filamins. Most probably involved in the processes of epithelial cell differentiation, cell spreading and neurite outgrowth.
• KEGG Pathway: Tight junction (hsa04530)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[1]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[3]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[2]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[1]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of MICAL-like protein 2 (MICALL2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of MICAL-like protein 2 (MICALL2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of MICAL-like protein 2 (MICALL2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of MICAL-like protein 2 (MICALL2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of MICAL-like protein 2 (MICALL2).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of MICAL-like protein 2 (MICALL2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of MICAL-like protein 2 (MICALL2).	[10]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of MICAL-like protein 2 (MICALL2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of MICAL-like protein 2 (MICALL2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of MICAL-like protein 2 (MICALL2).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of MICAL-like protein 2 (MICALL2).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of MICAL-like protein 2 (MICALL2).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of MICAL-like protein 2 (MICALL2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of MICAL-like protein 2 (MICALL2).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of MICAL-like protein 2 (MICALL2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of MICAL-like protein 2 (MICALL2).	[15]

References

• [1] Silencing of MICAL-L2 suppresses malignancy of ovarian cancer by inducing mesenchymal-epithelial transition.Cancer Lett. 2015 Jul 10;363(1):71-82. doi: 10.1016/j.canlet.2015.04.002. Epub 2015 Apr 9.
• [2] A new locus regulating MICALL2 expression was identified for association with executive inhibition in children with attention deficit hyperactivity disorder.Mol Psychiatry. 2018 Apr;23(4):1014-1020. doi: 10.1038/mp.2017.74. Epub 2017 Apr 18.
• [3] Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.Am J Hypertens. 2019 Nov 15;32(12):1146-1153. doi: 10.1093/ajh/hpz150.
• [4] 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.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [12] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.