Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHCYR6Y)

• DOT Name: Ankyrin repeat and LEM domain-containing protein 2 (ANKLE2)
• Synonyms: LEM domain-containing protein 4
• Gene Name: ANKLE2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Estrogen-receptor positive breast cancer
  Microcephaly 16, primary, autosomal recessive
  Neoplasm
  Autosomal recessive primary microcephaly
  Isolated congenital microcephaly
• UniProt ID: ANKL2_HUMAN
• Pfam ID: PF00023 ; PF01693 ; PF03020
• Sequence:
  MLWPRLAAAEWAALAWELLGASVLLIAVRWLVRRLGPRPGGLGRSGTPVPPPSAAAAPAS
  GEMTMDALLARLKLLNPDDLREEIVKAGLKCGPITSTTRFIFEKKLAQALLEQGGRLSSF
  YHHEAGVTALSQDPQRILKPAEGNPTDQAGFSEDRDFGYSVGLNPPEEEAVTSKTCSVPP
  SDTDTYRAGATASKEPPLYYGVCPVYEDVPARNERIYVYENKKEALQAVKMIKGSRFKAF
  STREDAEKFARGICDYFPSPSKTSLPLSPVKTAPLFSNDRLKDGLCLSESETVNKERANS
  YKNPRTQDLTAKLRKAVEKGEEDTFSDLIWSNPRYLIGSGDNPTIVQEGCRYNVMHVAAK
  ENQASICQLTLDVLENPDFMRLMYPDDDEAMLQKRIRYVVDLYLNTPDKMGYDTPLHFAC
  KFGNADVVNVLSSHHLIVKNSRNKYDKTPEDVICERSKNKSVELKERIREYLKGHYYVPL
  LRAEETSSPVIGELWSPDQTAEASHVSRYGGSPRDPVLTLRAFAGPLSPAKAEDFRKLWK
  TPPREKAGFLHHVKKSDPERGFERVGRELAHELGYPWVEYWEFLGCFVDLSSQEGLQRLE
  EYLTQQEIGKKAQQETGEREASCRDKATTSGSNSISVRAFLDEDDMSLEEIKNRQNAARN
  NSPPTVGAFGHTRCSAFPLEQEADLIEAAEPGGPHSSRNGLCHPLNHSRTLAGKRPKAPR
  GEEAHLPPVSDLTVEFDKLNLQNIGRSVSKTPDESTKTKDQILTSRINAVERDLLEPSPA
  DQLGNGHRRTESEMSARIAKMSLSPSSPRHEDQLEVTREPARRLFLFGEEPSKLDQDVLA
  ALECADVDPHQFPAVHRWKSAVLCYSPSDRQSWPSPAVKGRFKSQLPDLSGPHSYSPGRN
  SVAGSNPAKPGLGSPGRYSPVHGSQLRRMARLAELAAL
• Function: Involved in mitotic nuclear envelope reassembly by promoting dephosphorylation of BAF/BANF1 during mitotic exit. Coordinates the control of BAF/BANF1 dephosphorylation by inhibiting VRK1 kinase and promoting dephosphorylation of BAF/BANF1 by protein phosphatase 2A (PP2A), thereby facilitating nuclear envelope assembly. May regulate nuclear localization of VRK1 in non-dividing cells. It is unclear whether it acts as a real PP2A regulatory subunit or whether it is involved in recruitment of the PP2A complex. Involved in brain development.
• Reactome Pathway:
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOG GTPase cycle (R-HSA-9013408)
  Initiation of Nuclear Envelope (NE) Reformation (R-HSA-2995383)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[1]
Microcephaly 16, primary, autosomal recessive	DIS10DE3	Strong	Autosomal recessive	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[2]
Isolated congenital microcephaly	DISUXHZ6	Limited	Biomarker	[3]

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 Ankyrin repeat and LEM domain-containing protein 2 (ANKLE2).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ankyrin repeat and LEM domain-containing protein 2 (ANKLE2).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Ankyrin repeat and LEM domain-containing protein 2 (ANKLE2).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ankyrin repeat and LEM domain-containing protein 2 (ANKLE2).	[13]

6 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 Ankyrin repeat and LEM domain-containing protein 2 (ANKLE2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ankyrin repeat and LEM domain-containing protein 2 (ANKLE2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ankyrin repeat and LEM domain-containing protein 2 (ANKLE2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ankyrin repeat and LEM domain-containing protein 2 (ANKLE2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ankyrin repeat and LEM domain-containing protein 2 (ANKLE2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ankyrin repeat and LEM domain-containing protein 2 (ANKLE2).	[12]

References

• [1] LEM4 confers tamoxifen resistance to breast cancer cells by activating cyclin D-CDK4/6-Rb and ER pathway.Nat Commun. 2018 Oct 9;9(1):4180. doi: 10.1038/s41467-018-06309-8.
• [2] A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell. 2014 Sep 25;159(1):200-214. doi: 10.1016/j.cell.2014.09.002.
• [3] Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly.Dev Cell. 2019 Dec 16;51(6):713-729.e6. doi: 10.1016/j.devcel.2019.10.009. Epub 2019 Nov 14.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] 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.
• [11] 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.
• [12] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [13] 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.