Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYKE30Y)

• DOT Name: Catenin delta-2 (CTNND2)
• Synonyms: Delta-catenin; GT24; Neural plakophilin-related ARM-repeat protein; NPRAP; Neurojungin
• Gene Name: CTNND2
• Related Disease:
  Asthma
  Esophageal squamous cell carcinoma
  Alzheimer disease
  Autism
  Autism spectrum disorder
  Benign prostatic hyperplasia
  Breast cancer
  Breast carcinoma
  Carcinoma
  Colorectal carcinoma
  Complex neurodevelopmental disorder
  Epilepsy
  Epilepsy, familial adult myoclonic, 1
  Glioma
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Major depressive disorder
  Marinesco-Sjogren syndrome
  Mental disorder
  Movement disorder
  Myopia
  Narcolepsy
  Neoplasm
  Neuralgia
  Non-small-cell lung cancer
  Pervasive developmental disorder
  Prostate neoplasm
  Schizophrenia
  Advanced cancer
  Encephalitis
  Glioblastoma multiforme
  HIV infectious disease
  Intellectual disability
  Lung carcinoma
  Benign adult familial myoclonic epilepsy
  Adenocarcinoma
  Amyotrophic lateral sclerosis type 1
  Epithelial ovarian cancer
  Lung cancer
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: CTND2_HUMAN
• Pfam ID: PF00514
• Sequence:
  MFARKPPGAAPLGAMPVPDQPSSASEKTSSLSPGLNTSNGDGSETETTSAILASVKEQEL
  QFERLTRELEAERQIVASQLERCKLGSETGSMSSMSSAEEQFQWQSQDGQKDIEDELTTG
  LELVDSCIRSLQESGILDPQDYSTGERPSLLSQSALQLNSKPEGSFQYPASYHSNQTLAL
  GETTPSQLPARGTQARATGQSFSQGTTSRAGHLAGPEPAPPPPPPPREPFAPSLGSAFHL
  PDAPPAAAAAALYYSSSTLPAPPRGGSPLAAPQGGSPTKLQRGGSAPEGATYAAPRGSSP
  KQSPSRLAKSYSTSSPINIVVSSAGLSPIRVTSPPTVQSTISSSPIHQLSSTIGTYATLS
  PTKRLVHASEQYSKHSQELYATATLQRPGSLAAGSRASYSSQHGHLGPELRALQSPEHHI
  DPIYEDRVYQKPPMRSLSQSQGDPLPPAHTGTYRTSTAPSSPGVDSVPLQRTGSQHGPQN
  AAAATFQRASYAAGPASNYADPYRQLQYCPSVESPYSKSGPALPPEGTLARSPSIDSIQK
  DPREFGWRDPELPEVIQMLQHQFPSVQSNAAAYLQHLCFGDNKIKAEIRRQGGIQLLVDL
  LDHRMTEVHRSACGALRNLVYGKANDDNKIALKNCGGIPALVRLLRKTTDLEIRELVTGV
  LWNLSSCDALKMPIIQDALAVLTNAVIIPHSGWENSPLQDDRKIQLHSSQVLRNATGCLR
  NVSSAGEEARRRMRECDGLTDALLYVIQSALGSSEIDSKTVENCVCILRNLSYRLAAETS
  QGQHMGTDELDGLLCGEANGKDAESSGCWGKKKKKKKSQDQWDGVGPLPDCAEPPKGIQM
  LWHPSIVKPYLTLLSECSNPDTLEGAAGALQNLAAGSWKWSVYIRAAVRKEKGLPILVEL
  LRIDNDRVVCAVATALRNMALDVRNKELIGKYAMRDLVHRLPGGNNSNNTASKAMSDDTV
  TAVCCTLHEVITKNMENAKALRDAGGIEKLVGISKSKGDKHSPKVVKAASQVLNSMWQYR
  DLRSLYKKDGWSQYHFVASSSTIERDRQRPYSSSRTPSISPVRVSPNNRSASAPASPREM
  ISLKERKTDYECTGSNATYHGAKGEHTSRKDAMTAQNTGISTLYRNSYGAPAEDIKHNQV
  SAQPVPQEPSRKDYETYQPFQNSTRNYDESFFEDQVHHRPPASEYTMHLGLKSTGNYVDF
  YSAARPYSELNYETSHYPASPDSWV
• Function: Has a critical role in neuronal development, particularly in the formation and/or maintenance of dendritic spines and synapses. Involved in the regulation of Wnt signaling. It probably acts on beta-catenin turnover, facilitating beta-catenin interaction with GSK3B, phosphorylation, ubiquitination and degradation. Functions as a transcriptional activator when bound to ZBTB33. May be involved in neuronal cell adhesion and tissue morphogenesis and integrity by regulating adhesion molecules.
• Tissue Specificity: Expressed in brain; highest expression is observed in fetal brain .
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Definitive	Altered Expression	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Autism	DISV4V1Z	Strong	Biomarker	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[5]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Carcinoma	DISH9F1N	Strong	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[9]
Complex neurodevelopmental disorder	DISB9AFI	Strong	Autosomal dominant	[5]
Epilepsy	DISBB28L	Strong	Genetic Variation	[10]
Epilepsy, familial adult myoclonic, 1	DIS10Z6D	Strong	GermlineCausalMutation	[10]
Glioma	DIS5RPEH	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[13]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[14]
Marinesco-Sjogren syndrome	DISKEU0B	Strong	Biomarker	[15]
Mental disorder	DIS3J5R8	Strong	Biomarker	[14]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[10]
Myopia	DISK5S60	Strong	Genetic Variation	[16]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Neuralgia	DISWO58J	Strong	Biomarker	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[19]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[5]
Prostate neoplasm	DISHDKGQ	Strong	Genetic Variation	[20]
Schizophrenia	DISSRV2N	Strong	Biomarker	[14]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[13]
Encephalitis	DISLD1RL	moderate	Biomarker	[21]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[22]
HIV infectious disease	DISO97HC	moderate	Genetic Variation	[23]
Intellectual disability	DISMBNXP	moderate	Biomarker	[24]
Lung carcinoma	DISTR26C	moderate	Biomarker	[13]
Benign adult familial myoclonic epilepsy	DISIMWOV	Supportive	Autosomal dominant	[10]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[25]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Limited	Genetic Variation	[26]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[27]
Lung cancer	DISCM4YA	Limited	Altered Expression	[19]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[27]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[27]

10 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 Catenin delta-2 (CTNND2).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Catenin delta-2 (CTNND2).	[29]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Catenin delta-2 (CTNND2).	[30]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Catenin delta-2 (CTNND2).	[31]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Catenin delta-2 (CTNND2).	[32]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Catenin delta-2 (CTNND2).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Catenin delta-2 (CTNND2).	[32]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Catenin delta-2 (CTNND2).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Catenin delta-2 (CTNND2).	[37]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Catenin delta-2 (CTNND2).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Catenin delta-2 (CTNND2).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Catenin delta-2 (CTNND2).	[36]

References

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• [2] Oncogenic properties of a novel gene JK-1 located in chromosome 5p and its overexpression in human esophageal squamous cell carcinoma.Int J Mol Med. 2007 Jun;19(6):915-23.
• [3] -Catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes.PLoS One. 2012;7(9):e43728. doi: 10.1371/journal.pone.0043728. Epub 2012 Sep 11.
• [4] Improved memory and reduced anxiety in -catenin transgenic mice.Exp Neurol. 2019 Aug;318:22-31. doi: 10.1016/j.expneurol.2019.04.006. Epub 2019 Apr 11.
• [5] The clinical significance of small copy number variants in neurodevelopmental disorders. J Med Genet. 2014 Oct;51(10):677-88. doi: 10.1136/jmedgenet-2014-102588. Epub 2014 Aug 8.
• [6] Expression analysis of delta-catenin and prostate-specific membrane antigen: their potential as diagnostic markers for prostate cancer.Int J Cancer. 2002 Jul 10;100(2):228-37. doi: 10.1002/ijc.10468.
• [7] -catenin promotes the malignant phenotype in breast cancer.Tumour Biol. 2015 Feb;36(2):569-75. doi: 10.1007/s13277-014-2680-8. Epub 2014 Oct 2.
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• [9] Overexpression of -catenin is associated with a malignant phenotype and poor prognosis in colorectal cancer.Mol Med Rep. 2015 Sep;12(3):4259-4265. doi: 10.3892/mmr.2015.3918. Epub 2015 Jun 11.
• [10] -Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy. Neurology. 2017 Dec 5;89(23):2341-2350. doi: 10.1212/WNL.0000000000004709. Epub 2017 Nov 10.
• [11] -Catenin Promotes Bevacizumab-Induced Glioma Invasion.Mol Cancer Ther. 2019 Apr;18(4):812-822. doi: 10.1158/1535-7163.MCT-18-0138. Epub 2019 Mar 14.
• [12] Hypoxia induced -Catenin to enhance mice hepatocellular carcinoma progression via Wnt signaling.Exp Cell Res. 2019 Jan 1;374(1):94-103. doi: 10.1016/j.yexcr.2018.11.011. Epub 2018 Nov 17.
• [13] -Catenin promotes tumorigenesis and metastasis of lung adenocarcinoma.Oncol Rep. 2018 Feb;39(2):809-817. doi: 10.3892/or.2017.6140. Epub 2017 Dec 8.
• [14] Further confirmation of the association between anxiety and CTNND2: replication in humans.Genes Brain Behav. 2014 Feb;13(2):195-201. doi: 10.1111/gbb.12095. Epub 2013 Nov 21.
• [15] Instability of a dinucleotide repeat in the 3'-untranslated region (UTR) of the microsomal prostaglandin E synthase-1 (mPGES-1) gene in microsatellite instability-high (MSI-H) colorectal carcinoma.Mol Oncol. 2015 Aug;9(7):1252-8. doi: 10.1016/j.molonc.2015.01.009. Epub 2015 Mar 5.
• [16] Polymorphism in the 11q24.1 genomic region is associated with myopia: a comprehensive genetic study in Chinese and Japanese populations.Mol Vis. 2014 Mar 21;20:352-8. eCollection 2014.
• [17] 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.
• [18] Palmitoylation of -catenin promotes kinesin-mediated membrane trafficking of Na(v)1.6 in sensory neurons to promote neuropathic pain.Sci Signal. 2018 Mar 27;11(523):eaar4394. doi: 10.1126/scisignal.aar4394.
• [19] Overexpression of small GTPases directly correlates with expression of -catenin and their coexpression predicts a poor clinical outcome in nonsmall cell lung cancer.Mol Carcinog. 2013 May;52(5):338-47. doi: 10.1002/mc.21854. Epub 2011 Dec 27.
• [20] Increased nucleotide polymorphic changes in the 5'-untranslated region of delta-catenin (CTNND2) gene in prostate cancer.Oncogene. 2009 Jan 29;28(4):555-64. doi: 10.1038/onc.2008.399. Epub 2008 Nov 3.
• [21] Environmental Correlation Analysis for Genes Associated with Protection against Malaria.Mol Biol Evol. 2016 May;33(5):1188-204. doi: 10.1093/molbev/msw004. Epub 2016 Jan 6.
• [22] The integrated landscape of driver genomic alterations in glioblastoma.Nat Genet. 2013 Oct;45(10):1141-9. doi: 10.1038/ng.2734. Epub 2013 Aug 5.
• [23] Genome-wide admixture and association study of subclinical atherosclerosis in the Women's Interagency HIV Study (WIHS).PLoS One. 2017 Dec 4;12(12):e0188725. doi: 10.1371/journal.pone.0188725. eCollection 2017.
• [24] A child with autism, behavioral issues, and dysmorphic features found to have a tandem duplication within CTNND2 by mate-pair sequencing.Am J Med Genet A. 2020 Mar;182(3):543-547. doi: 10.1002/ajmg.a.61442. Epub 2019 Dec 8.
• [25] Human homolog of Drosophila Hairy and enhancer of split 1, Hes1, negatively regulates -catenin (CTNND2) expression in cooperation with E2F1 in prostate cancer.Mol Cancer. 2010 Nov 24;9:304. doi: 10.1186/1476-4598-9-304.
• [26] Genome-wide association study combining pathway analysis for typical sporadic amyotrophic lateral sclerosis in Chinese Han populations.Neurobiol Aging. 2014 Jul;35(7):1778.e9-1778.e23. doi: 10.1016/j.neurobiolaging.2014.01.014. Epub 2014 Jan 17.
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• [28] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [29] 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.
• [30] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [31] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [32] 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.
• [33] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [34] 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.
• [35] 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.
• [36] 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.
• [37] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [38] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.