Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6KLHPA)

• DOT Name: Beta-catenin-like protein 1 (CTNNBL1)
• Synonyms: Nuclear-associated protein; NAP; Testis development protein NYD-SP19
• Gene Name: CTNNBL1
• Related Disease:
  Cerebellar degeneration
  Lung cancer
  Lung carcinoma
  Parkinson disease
  Advanced cancer
  Allergic asthma
  Alzheimer disease
  Amyloidosis
  Atrial fibrillation
  Autism
  Colitis
  Colorectal neoplasm
  Depression
  Disorder of orbital region
  Epithelial ovarian cancer
  Gastric cancer
  Hepatitis C virus infection
  Lung neoplasm
  Neuroblastoma
  Ovarian cancer
  Ovarian neoplasm
  Pheochromocytoma
  Progressive supranuclear palsy
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Tauopathy
  Anxiety
  Anxiety disorder
  Asthma
  Common variable immunodeficiency
  Diabetic retinopathy
  Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias
  Neoplasm
  Neuroendocrine neoplasm
  Schizophrenia
  Tuberculosis
• UniProt ID: CTBL1_HUMAN
• PDB ID: 4CB8; 4CB9; 4CBA; 4HM9; 4HNM; 4MFU; 4MFV; 7ABI
• Pfam ID: PF08216
• Sequence:
  MDVGELLSYQPNRGTKRPRDDEEEEQKMRRKQTGTRERGRYREEEMTVVEEADDDKKRLL
  QIIDRDGEEEEEEEEPLDESSVKKMILTFEKRSYKNQELRIKFPDNPEKFMESELDLNDI
  IQEMHVVATMPDLYHLLVELNAVQSLLGLLGHDNTDVSIAVVDLLQELTDIDTLHESEEG
  AEVLIDALVDGQVVALLVQNLERLDESVKEEADGVHNTLAIVENMAEFRPEMCTEGAQQG
  LLQWLLKRLKAKMPFDANKLYCSEVLAILLQDNDENRELLGELDGIDVLLQQLSVFKRHN
  PSTAEEQEMMENLFDSLCSCLMLSSNRERFLKGEGLQLMNLMLREKKISRSSALKVLDHA
  MIGPEGTDNCHKFVDILGLRTIFPLFMKSPRKIKKVGTTEKEHEEHVCSILASLLRNLRG
  QQRTRLLNKFTENDSEKVDRLMELHFKYLGAMQVADKKIEGEKHDMVRRGEIIDNDTEEE
  FYLRRLDAGLFVLQHICYIMAEICNANVPQIRQRVHQILNMRGSSIKIVRHIIKEYAENI
  GDGRSPEFRENEQKRILGLLENF
• Function: Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. Participates in AID/AICDA-mediated somatic hypermutation (SHM) and class-switch recombination (CSR), 2 processes resulting in the production of high-affinity, mutated isotype-switched antibodies.
• Tissue Specificity: Widely expressed with highest levels in skeletal muscle, placenta, heart, spleen, testis and thyroid.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar degeneration	DISPBCM3	Definitive	Biomarker	[1]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[2]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[2]
Parkinson disease	DISQVHKL	Definitive	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Allergic asthma	DISHF0H3	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Amyloidosis	DISHTAI2	Strong	Biomarker	[7]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[8]
Autism	DISV4V1Z	Strong	Biomarker	[9]
Colitis	DISAF7DD	Strong	Biomarker	[10]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[11]
Depression	DIS3XJ69	Strong	Biomarker	[12]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[13]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[14]
Gastric cancer	DISXGOUK	Strong	Biomarker	[15]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[16]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[17]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[6]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[14]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[14]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[18]
Progressive supranuclear palsy	DISO5KRQ	Strong	Biomarker	[19]
Prostate cancer	DISF190Y	Strong	Biomarker	[20]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[20]
Stomach cancer	DISKIJSX	Strong	Biomarker	[15]
Tauopathy	DISY2IPA	Strong	Biomarker	[19]
Anxiety	DISIJDBA	Limited	Biomarker	[21]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[21]
Asthma	DISW9QNS	Limited	Biomarker	[22]
Common variable immunodeficiency	DISHE7JQ	Limited	Autosomal recessive	[23]
Diabetic retinopathy	DISHGUJM	Limited	Biomarker	[13]
Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias	DISUNBB3	Limited	Unknown	[24]
Neoplasm	DISZKGEW	Limited	Biomarker	[25]
Neuroendocrine neoplasm	DISNPLOO	Limited	Biomarker	[25]
Schizophrenia	DISSRV2N	Limited	Biomarker	[21]
Tuberculosis	DIS2YIMD	Limited	Biomarker	[26]

8 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 Beta-catenin-like protein 1 (CTNNBL1).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Beta-catenin-like protein 1 (CTNNBL1).	[28]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Beta-catenin-like protein 1 (CTNNBL1).	[29]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Beta-catenin-like protein 1 (CTNNBL1).	[30]
Selenium	DM25CGV	Approved	Selenium increases the expression of Beta-catenin-like protein 1 (CTNNBL1).	[31]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Beta-catenin-like protein 1 (CTNNBL1).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Beta-catenin-like protein 1 (CTNNBL1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Beta-catenin-like protein 1 (CTNNBL1).	[35]

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 Beta-catenin-like protein 1 (CTNNBL1).	[32]

1 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 affects the methylation of Beta-catenin-like protein 1 (CTNNBL1).	[33]

References

• [1] ATM binds to beta-adaptin in cytoplasmic vesicles.Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10146-51. doi: 10.1073/pnas.95.17.10146.
• [2] Toll-like receptor agonist rMBP-NAP enhances antitumor cytokines production and CTL activity of peripheral blood mononuclear cells from patients with lung cancer.Oncol Lett. 2018 Oct;16(4):4707-4712. doi: 10.3892/ol.2018.9182. Epub 2018 Jul 20.
• [3] Impairment of mitochondria dynamics by human A53T -synuclein and rescue by NAP (davunetide) in a cell model for Parkinson's disease.Exp Brain Res. 2017 Mar;235(3):731-742. doi: 10.1007/s00221-016-4836-9. Epub 2016 Nov 19.
• [4] Down-regulation of a novel gene, DRLM, in human liver malignancy from 4q22 that encodes a NAP-like protein.Gene. 2002 Aug 21;296(1-2):171-7. doi: 10.1016/s0378-1119(02)00855-7.
• [5] The neutrophil-activating protein of Helicobacter pylori down-modulates Th2 inflammation in ovalbumin-induced allergic asthma.Cell Microbiol. 2008 Nov;10(11):2355-63. doi: 10.1111/j.1462-5822.2008.01217.x. Epub 2008 Aug 15.
• [6] Reduction of aluminum ion neurotoxicity through a small peptide application - NAP treatment of Alzheimer's disease.J Food Drug Anal. 2019 Apr;27(2):551-564. doi: 10.1016/j.jfda.2018.11.009. Epub 2019 Jan 12.
• [7] Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in a transgenic mouse model of Alzheimer's disease at early pathological stage.J Mol Neurosci. 2007;31(2):165-70. doi: 10.1385/jmn/31:02:165.
• [8] Safety and efficacy of mechanical thrombectomy in acute ischemic stroke of anticoagulated patients.J Neurointerv Surg. 2018 Dec;10(12):e29. doi: 10.1136/neurintsurg-2017-013714. Epub 2018 Mar 30.
• [9] The autism/neuroprotection-linked ADNP/NAP regulate the excitatory glutamatergic synapse.Transl Psychiatry. 2019 Jan 15;9(1):2. doi: 10.1038/s41398-018-0357-6.
• [10] The octapetide NAP alleviates intestinal and extra-intestinal anti-inflammatory sequelae of acute experimental colitis.Peptides. 2018 Mar;101:1-9. doi: 10.1016/j.peptides.2017.12.023. Epub 2017 Dec 27.
• [11] Serum response factor enhances liver metastasis of colorectal carcinoma via alteration of the E-cadherin/beta-catenin complex.Oncol Rep. 2009 Jan;21(1):57-63.
• [12] Antidepressant effect of recombinant NT4-NAP/AAV on social isolated mice through intranasal route.Oncotarget. 2017 Feb 7;8(6):10103-10113. doi: 10.18632/oncotarget.14356.
• [13] NAP modulates hyperglycemic-inflammatory event of diabetic retina by counteracting outer blood retinal barrier damage.J Cell Physiol. 2019 Apr;234(4):5230-5240. doi: 10.1002/jcp.27331. Epub 2018 Oct 30.
• [14] Spliceosome-associated factor CTNNBL1 promotes proliferation and invasion in ovarian cancer.Exp Cell Res. 2017 Aug 1;357(1):124-134. doi: 10.1016/j.yexcr.2017.05.008. Epub 2017 May 10.
• [15] Detection and evaluation of antibodies against neutrophil-activating protein of Helicobacter pylori in patients with gastric cancer.World J Gastroenterol. 2009 May 21;15(19):2381-8. doi: 10.3748/wjg.15.2381.
• [16] Standardized hepatitis C virus RNA panels for nucleic acid testing assays.J Clin Virol. 2001 Jan;20(1-2):35-40. doi: 10.1016/s1386-6532(00)00153-0.
• [17] Recombinant protein rMBP-NAP restricts tumor progression by triggering antitumor immunity in mouse metastatic lung cancer.Can J Physiol Pharmacol. 2018 Feb;96(2):113-119. doi: 10.1139/cjpp-2017-0186. Epub 2017 Sep 1.
• [18] NAP Protects against Tau Hyperphosphorylation Through GSK3.Curr Pharm Des. 2018;24(33):3868-3877. doi: 10.2174/1381612824666181112105954.
• [19] NAP (davunetide) preferential interaction with dynamic 3-repeat Tau explains differential protection in selected tauopathies.PLoS One. 2019 Mar 13;14(3):e0213666. doi: 10.1371/journal.pone.0213666. eCollection 2019.
• [20] Differential tissue expression of extracellular vesicle-derived proteins in prostate cancer.Prostate. 2019 Jun;79(9):1032-1042. doi: 10.1002/pros.23813. Epub 2019 Apr 24.
• [21] Risperidone and NAP protect cognition and normalize gene expression in a schizophrenia mouse model.Sci Rep. 2015 Nov 10;5:16300. doi: 10.1038/srep16300.
• [22] The recombinant fusion protein of cholera toxin B and neutrophil-activating protein expressed on Bacillus subtilis spore surface suppresses allergic inflammation in mice.Appl Microbiol Biotechnol. 2017 Jul;101(14):5819-5829. doi: 10.1007/s00253-017-8370-x. Epub 2017 Jun 12.
• [23] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [24] Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID. J Clin Invest. 2020 Aug 3;130(8):4411-4422. doi: 10.1172/JCI131297.
• [25] An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors.Mol Ther. 2013 Nov;21(11):2008-18. doi: 10.1038/mt.2013.153. Epub 2013 Jul 2.
• [26] Early identification of Mycobacterium tuberculosis complex in BACTEC cultures by ligase chain reaction.J Med Microbiol. 2002 Aug;51(8):710-712. doi: 10.1099/0022-1317-51-8-710.
• [27] 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.
• [28] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [29] 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.
• [30] 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.
• [31] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [32] 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.
• [33] 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.
• [34] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [35] 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.