Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ8G92T)

• DOT Name: Catenin alpha-2 (CTNNA2)
• Synonyms: Alpha N-catenin; Alpha-catenin-related protein
• Gene Name: CTNNA2
• Related Disease:
  Alzheimer disease
  Bladder cancer
  Breast carcinoma
  Carcinoma
  Carcinoma of esophagus
  Cortical dysplasia, complex, with other brain malformations 9
  Esophageal cancer
  Gastric cancer
  Gastric neoplasm
  Head-neck squamous cell carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Intellectual disability
  Lissencephaly spectrum disorders
  Mantle cell lymphoma
  Narcolepsy
  Neoplasm
  Neoplasm of esophagus
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Acute myelogenous leukaemia
  Alcohol dependence
  Alcohol-induced disorders
  Alcohol-related disorders
  Heroin dependence
  Neuroblastoma
• UniProt ID: CTNA2_HUMAN
• PDB ID: 6DUW
• Pfam ID: PF01044
• Sequence:
  MTSATSPIILKWDPKSLEIRTLTVERLLEPLVTQVTTLVNTSNKGPSGKKKGRSKKAHVL
  AASVEQATQNFLEKGEQIAKESQDLKEELVAAVEDVRKQGETMRIASSEFADDPCSSVKR
  GTMVRAARALLSAVTRLLILADMADVMRLLSHLKIVEEALEAVKNATNEQDLANRFKEFG
  KEMVKLNYVAARRQQELKDPHCRDEMAAARGALKKNATMLYTASQAFLRHPDVAATRANR
  DYVFKQVQEAIAGISNAAQATSPTDEAKGHTGIGELAAALNEFDNKIILDPMTFSEARFR
  PSLEERLESIISGAALMADSSCTRDDRRERIVAECNAVRQALQDLLSEYMNNTGRKEKGD
  PLNIAIDKMTKKTRDLRRQLRKAVMDHISDSFLETNVPLLVLIEAAKSGNEKEVKEYAQV
  FREHANKLVEVANLACSISNNEEGVKLVRMAATQIDSLCPQVINAALTLAARPQSKVAQD
  NMDVFKDQWEKQVRVLTEAVDDITSVDDFLSVSENHILEDVNKCVIALQEGDVDTLDRTA
  GAIRGRAARVIHIINAEMENYEAGVYTEKVLEATKLLSETVMPRFAEQVEVAIEALSANV
  PQPFEENEFIDASRLVYDGVRDIRKAVLMIRTPEELEDDSDFEQEDYDVRSRTSVQTEDD
  QLIAGQSARAIMAQLPQEEKAKIAEQVEIFHQEKSKLDAEVAKWDDSGNDIIVLAKQMCM
  IMMEMTDFTRGKGPLKNTSDVINAAKKIAEAGSRMDKLARAVADQCPDSACKQDLLAYLQ
  RIALYCHQLNICSKVKAEVQNLGGELIVSGTGVQSTFTTFYEVDCDVIDGGRASQLSTHL
  PTCAEGAPIGSGSSDSSMLDSATSLIQAAKNLMNAVVLTVKASYVASTKYQKVYGTAAVN
  SPVVSWKMKAPEKKPLVKREKPEEFQTRVRRGSQKKHISPVQALSEFKAMDSF
• Function: May function as a linker between cadherin adhesion receptors and the cytoskeleton to regulate cell-cell adhesion and differentiation in the nervous system. Required for proper regulation of cortical neuronal migration and neurite growth. It acts as a negative regulator of Arp2/3 complex activity and Arp2/3-mediated actin polymerization. It thereby suppresses excessive actin branching which would impair neurite growth and stability. Regulates morphological plasticity of synapses and cerebellar and hippocampal lamination during development. Functions in the control of startle modulation.
• Tissue Specificity: Expressed in neural tissues, with strongest expression in fetal and adult brain. Expressed in the developing cortical plate and marginal zone of 20-week-old human fetal brain.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Adherens junction (hsa04520)
  Leukocyte transendothelial migration (hsa04670)
  Bacterial invasion of epithelial cells (hsa05100)
  Pathways in cancer (hsa05200)
  Endometrial cancer (hsa05213)
  Gastric cancer (hsa05226)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
• Reactome Pathway: Myogenesis (R-HSA-525793)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[5]
Cortical dysplasia, complex, with other brain malformations 9	DIS4Y3A1	Strong	Autosomal recessive	[6]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[7]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[4]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[6]
Lissencephaly spectrum disorders	DISBCZL7	Strong	Biomarker	[8]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[9]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[12]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[13]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[14]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[14]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[14]
Heroin dependence	DISQ1H57	moderate	Genetic Variation	[14]
Neuroblastoma	DISVZBI4	Disputed	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Catenin alpha-2 (CTNNA2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Catenin alpha-2 (CTNNA2).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Catenin alpha-2 (CTNNA2).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Catenin alpha-2 (CTNNA2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Catenin alpha-2 (CTNNA2).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Catenin alpha-2 (CTNNA2).	[17]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Catenin alpha-2 (CTNNA2).	[17]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Catenin alpha-2 (CTNNA2).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Catenin alpha-2 (CTNNA2).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Catenin alpha-2 (CTNNA2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Catenin alpha-2 (CTNNA2).	[25]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Catenin alpha-2 (CTNNA2).	[21]

References

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• [3] A pilot genome-wide association study of breast cancer susceptibility loci in Indonesia.Asian Pac J Cancer Prev. 2015;16(6):2231-5. doi: 10.7314/apjcp.2015.16.6.2231.
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• [5] Novel-miR-4885 Promotes Migration and Invasion of Esophageal Cancer Cells Through Targeting CTNNA2.DNA Cell Biol. 2019 Feb;38(2):151-161. doi: 10.1089/dna.2018.4377. Epub 2018 Dec 8.
• [6] Biallelic loss of human CTNNA2, encoding N-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration. Nat Genet. 2018 Aug;50(8):1093-1101. doi: 10.1038/s41588-018-0166-0. Epub 2018 Jul 16.
• [7] Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.Nat Genet. 2014 Jun;46(6):573-82. doi: 10.1038/ng.2983. Epub 2014 May 11.
• [8] Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein 2, Leads to Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay. Am J Hum Genet. 2019 Oct 3;105(4):844-853. doi: 10.1016/j.ajhg.2019.08.013.
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• [10] 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.
• [11] Identification of -N-catenin as a novel tumor suppressor in neuroblastoma.Oncotarget. 2019 Aug 20;10(49):5028-5040. doi: 10.18632/oncotarget.27096. eCollection 2019 Aug 20.
• [12] Identifying the genetic risk factors for treatment response to lurasidone by genome-wide association study: A meta-analysis of samples from three independent clinical trials.Schizophr Res. 2018 Sep;199:203-213. doi: 10.1016/j.schres.2018.04.006. Epub 2018 May 2.
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• [14] Identification of novel risk loci with shared effects on alcoholism, heroin, and methamphetamine dependence.Mol Psychiatry. 2021 Apr;26(4):1152-1161. doi: 10.1038/s41380-019-0497-y. Epub 2019 Aug 28.
• [15] 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.
• [16] 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.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] 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.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [22] 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.
• [23] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [24] 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.
• [25] 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.