Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ6IB4T)

• DOT Name: Tax1-binding protein 3 (TAX1BP3)
• Synonyms: Glutaminase-interacting protein 3; Tax interaction protein 1; TIP-1; Tax-interacting protein 1
• Gene Name: TAX1BP3
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Glioblastoma multiforme
  Malignant glioma
  Neoplasm
  Rheumatoid arthritis
  Cervical carcinoma
  Cardiomyopathy
  Dilated cardiomyopathy
  Septooptic dysplasia
• UniProt ID: TX1B3_HUMAN
• PDB ID: 2KG2; 2L4S; 2L4T; 2VZ5; 3GJ9; 3SFJ; 4E3B; 4NNL; 4NNM
• Pfam ID: PF00595
• Sequence:
  MSYIPGQPVTAVVQRVEIHKLRQGENLILGFSIGGGIDQDPSQNPFSEDKTDKGIYVTRV
  SEGGPAEIAGLQIGDKIMQVNGWDMTMVTHDQARKRLTKRSEEVVRLLVTRQSLQKAVQQ
  SMLS
• Function: May regulate a number of protein-protein interactions by competing for PDZ domain binding sites. Binds CTNNB1 and may thereby act as an inhibitor of the Wnt signaling pathway. Competes with LIN7A for KCNJ4 binding, and thereby promotes KCNJ4 internalization. May play a role in the Rho signaling pathway. May play a role in activation of CDC42 by the viral protein HPV16 E6.
• Tissue Specificity: Ubiquitous. Detected in brain, heart, kidney, lung, small intestine and skeletal muscle. Detected in various cell lines including HeLa. Weakly expressed in peripheral blood leukocytes.
• Reactome Pathway: RHO GTPases Activate Rhotekin and Rhophilins (R-HSA-5666185)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Malignant glioma	DISFXKOV	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	moderate	Altered Expression	[5]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[6]
Dilated cardiomyopathy	DISX608J	Limited	Genetic Variation	[6]
Septooptic dysplasia	DISXYR1H	Limited	Genetic Variation	[6]

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 Tax1-binding protein 3 (TAX1BP3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tax1-binding protein 3 (TAX1BP3).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tax1-binding protein 3 (TAX1BP3).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Tax1-binding protein 3 (TAX1BP3).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Tax1-binding protein 3 (TAX1BP3).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tax1-binding protein 3 (TAX1BP3).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tax1-binding protein 3 (TAX1BP3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tax1-binding protein 3 (TAX1BP3).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Tax1-binding protein 3 (TAX1BP3).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Tax1-binding protein 3 (TAX1BP3).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Tax1-binding protein 3 (TAX1BP3).	[14]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Tax1-binding protein 3 (TAX1BP3).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Tax1-binding protein 3 (TAX1BP3).	[16]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Tax1-binding protein 3 (TAX1BP3).	[17]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Tax1-binding protein 3 (TAX1BP3).	[17]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Tax1-binding protein 3 (TAX1BP3).	[18]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of Tax1-binding protein 3 (TAX1BP3).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Tax1-binding protein 3 (TAX1BP3).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Tax1-binding protein 3 (TAX1BP3).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Tax1-binding protein 3 (TAX1BP3).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tax1-binding protein 3 (TAX1BP3).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Tax1-binding protein 3 (TAX1BP3).	[24]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Tax1-binding protein 3 (TAX1BP3).	[25]

References

• [1] Tax-interacting protein 1 coordinates the spatiotemporal activation of Rho GTPases and regulates the infiltrative growth of human glioblastoma.Oncogene. 2014 Mar 20;33(12):1558-69. doi: 10.1038/onc.2013.97. Epub 2013 Apr 8.
• [2] PEGylated peptide to TIP1 is a novel targeting agent that binds specifically to various cancers in vivo.J Control Release. 2019 Mar 28;298:194-201. doi: 10.1016/j.jconrel.2019.02.008. Epub 2019 Feb 11.
• [3] The PDZ protein TIP-1 facilitates cell migration and pulmonary metastasis of human invasive breast cancer cells in athymic mice.Biochem Biophys Res Commun. 2012 May 25;422(1):139-45. doi: 10.1016/j.bbrc.2012.04.123. Epub 2012 Apr 30.
• [4] A cell-penetrating peptide blocks Toll-like receptor-mediated downstream signaling and ameliorates autoimmune and inflammatory diseases in mice.Exp Mol Med. 2019 Apr 26;51(4):1-19. doi: 10.1038/s12276-019-0244-0.
• [5] The PDZ protein Tip-1 is a gain of function target of the HPV16 E6 oncoprotein.Int J Oncol. 2004 Nov;25(5):1249-56.
• [6] Mutations in TAX1BP3 cause dilated cardiomyopathy with septo-optic dysplasia.Hum Mutat. 2015 Apr;36(4):439-42. doi: 10.1002/humu.22759. Epub 2015 Mar 16.
• [7] 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.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] 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.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [14] 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.
• [15] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [16] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [17] Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
• [18] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [19] 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.
• [20] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [21] 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.
• [22] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [23] 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.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.