Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1ECMDL)

• DOT Name: TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3)
• Synonyms: Mitogen-activated protein kinase kinase kinase 7-interacting protein 3; NF-kappa-B-activating protein 1; TAK1-binding protein 3; TAB-3; TGF-beta-activated kinase 1-binding protein 3
• Gene Name: TAB3
• Related Disease:
  Neoplasm
  Advanced cancer
  Alzheimer disease
  Cardiac disease
  Colorectal carcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Hypophosphatemia
  Metastatic malignant neoplasm
  Myocardial ischemia
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Psoriasis
  Psoriatic arthritis
  Thiel-Behnke corneal dystrophy
  Common variable immunodeficiency
  Lung cancer
  Lung carcinoma
• UniProt ID: TAB3_HUMAN
• Pfam ID: PF02845
• Sequence:
  MAQSSPQLDIQVLHDLRQRFPEIPEGVVSQCMLQNNNNLEACCRALSQESSKYLYMEYHS
  PDDNRMNRNRLLHINLGIHSPSSYHPGDGAQLNGGRTLVHSSSDGHIDPQHAAGKQLICL
  VQEPHSAPAVVAATPNYNPFFMNEQNRSAATPPSQPPQQPSSMQTGMNPSAMQGPSPPPP
  PPSYMHIPRYSTNPITVTVSQNLPSGQTVPRALQILPQIPSNLYGSPGSIYIRQTSQSSS
  GRQTPQSTPWQSSPQGPVPHYSQRPLPVYPHQQNYQPSQYSPKQQQIPQSAYHSPPPSQC
  PSPFSSPQHQVQPSQLGHIFMPPSPSTTPPHPYQQGPPSYQKQGSHSVAYLPYTASSLSK
  GSMKKIEITVEPSQRPGTAINRSPSPISNQPSPRNQHSLYTATTPPSSSPSRGISSQPKP
  PFSVNPVYITYTQPTGPSCTPSPSPRVIPNPTTVFKITVGRATTENLLNLVDQEERSAAP
  EPIQPISVIPGSGGEKGSHKYQRSSSSGSDDYAYTQALLLHQRARMERLAKQLKLEKEEL
  ERLKSEVNGMEHDLMQRRLRRVSCTTAIPTPEEMTRLRSMNRQLQINVDCTLKEVDLLQS
  RGNFDPKAMNNFYDNIEPGPVVPPKPSKKDSSDPCTIERKARRISVTSKVQADIHDTQAA
  AADEHRTGSTQSPRTQPRDEDYEGAPWNCDSCTFLNHPALNRCEQCEMPRYT
• Function: Adapter required to activate the JNK and NF-kappa-B signaling pathways through the specific recognition of 'Lys-63'-linked polyubiquitin chains by its RanBP2-type zinc finger (NZF). Acts as an adapter linking MAP3K7/TAK1 and TRAF6 to 'Lys-63'-linked polyubiquitin chains. The RanBP2-type zinc finger (NZF) specifically recognizes Lys-63'-linked polyubiquitin chains unanchored or anchored to the substrate proteins such as RIPK1/RIP1 and RIPK2: this acts as a scaffold to organize a large signaling complex to promote autophosphorylation of MAP3K7/TAK1, and subsequent activation of I-kappa-B-kinase (IKK) core complex by MAP3K7/TAK1 ; [Isoform 2]: May be an oncogenic factor.
• Tissue Specificity: Widely expressed. Constitutively overexpressed in certain tumor tissues.; [Isoform 1]: Major transcript.; [Isoform 2]: Minor transcript.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  NOD-like receptor sig.ling pathway (hsa04621)
  IL-17 sig.ling pathway (hsa04657)
  TNF sig.ling pathway (hsa04668)
  Alcoholic liver disease (hsa04936)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  FCERI mediated NF-kB activation (R-HSA-2871837)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)
  activated TAK1 mediates p38 MAPK activation (R-HSA-450302)
  JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 (R-HSA-450321)
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  TICAM1,TRAF6-dependent induction of TAK1 complex (R-HSA-9014325)
  Interleukin-1 signaling (R-HSA-9020702)
  IRAK2 mediated activation of TAK1 complex (R-HSA-937042)
  TRAF6-mediated induction of TAK1 complex within TLR4 complex (R-HSA-937072)
  Alpha-protein kinase 1 signaling pathway (R-HSA-9645460)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation (R-HSA-975163)
  NOD1/2 Signaling Pathway (R-HSA-168638)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Cardiac disease	DISVO1I5	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Hypophosphatemia	DIS9DZYF	Strong	Altered Expression	[8]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[5]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[9]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[6]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[6]
Psoriasis	DIS59VMN	Strong	Altered Expression	[10]
Psoriatic arthritis	DISLWTG2	Strong	Altered Expression	[11]
Thiel-Behnke corneal dystrophy	DIS3GK26	Strong	Biomarker	[12]
Common variable immunodeficiency	DISHE7JQ	Limited	Genetic Variation	[13]
Lung cancer	DISCM4YA	Limited	Biomarker	[14]
Lung carcinoma	DISTR26C	Limited	Biomarker	[14]

2 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 TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[24]

11 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 TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[19]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[21]
Marinol	DM70IK5	Approved	Marinol increases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3).	[27]

References

• [1] A novel triarylboron based ratiometric fluorescent probe for in vivo targeting and specific imaging of cancer cells expressing abnormal concentration of GGT.Biosens Bioelectron. 2019 Oct 1;142:111497. doi: 10.1016/j.bios.2019.111497. Epub 2019 Jul 10.
• [2] Evaluation of the Cepheid Xpert Clostridium difficile Epi assay for diagnosis of Clostridium difficile infection and typing of the NAP1 strain at a cancer hospital.J Clin Microbiol. 2010 Dec;48(12):4519-24. doi: 10.1128/JCM.01648-10. Epub 2010 Oct 13.
• [3] Isolation of hNap1BP which interacts with human Nap1 (NCKAP1) whose expression is down-regulated in Alzheimer's disease.Gene. 2001 Jun 27;271(2):159-69. doi: 10.1016/s0378-1119(01)00521-2.
• [4] TAB3 defect induces augmented cardioprotection loss from ischemic injury.Cell Biol Int. 2017 Jul;41(7):787-797. doi: 10.1002/cbin.10781. Epub 2017 May 11.
• [5] TAB3 upregulates Survivin expression to promote colorectal cancer invasion and metastasis by binding to the TAK1-TRAF6 complex.Oncotarget. 2017 Nov 18;8(63):106565-106576. doi: 10.18632/oncotarget.22497. eCollection 2017 Dec 5.
• [6] Loss of TAB3 expression by shRNA exhibits suppressive bioactivity and increased chemical sensitivity of ovarian cancer cell lines via the NF-B pathway.Cell Prolif. 2016 Dec;49(6):657-668. doi: 10.1111/cpr.12293. Epub 2016 Sep 21.
• [7] TAB3 promotes human esophageal squamous cell carcinoma proliferation and invasion via the NFB pathway.Oncol Rep. 2018 Nov;40(5):2876-2885. doi: 10.3892/or.2018.6686. Epub 2018 Sep 6.
• [8] Phosphatonin washout in Hyp mice proximal tubules: evidence for posttranscriptional regulation.Am J Physiol Renal Physiol. 2005 Feb;288(2):F363-70. doi: 10.1152/ajprenal.00217.2004. Epub 2004 Sep 28.
• [9] Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer.J Exp Clin Cancer Res. 2019 Mar 11;38(1):122. doi: 10.1186/s13046-019-1124-0.
• [10] Upper keratinocytes of psoriatic skin lesions express high levels of NAP-1/IL-8 mRNA in situ.J Invest Dermatol. 1991 Jul;97(1):73-9. doi: 10.1111/1523-1747.ep12478128.
• [11] Evidence for a Role of TGF--Activated Kinase 1 and MAP3K7 Binding Protein 3 in Peanut-Specific T-Cell Responses.Int Arch Allergy Immunol. 2019;179(1):10-16. doi: 10.1159/000496438. Epub 2019 Mar 20.
• [12] Development of a Novel Vaccine Containing Binary Toxin for the Prevention of Clostridium difficile Disease with Enhanced Efficacy against NAP1 Strains.PLoS One. 2017 Jan 26;12(1):e0170640. doi: 10.1371/journal.pone.0170640. eCollection 2017.
• [13] Genome-wide association identifies diverse causes of common variable immunodeficiency.J Allergy Clin Immunol. 2011 Jun;127(6):1360-7.e6. doi: 10.1016/j.jaci.2011.02.039. Epub 2011 Apr 17.
• [14] TAB3 overexpression promotes cell proliferation in non-small cell lung cancer and mediates chemoresistance to CDDP in A549 cells via the NF-B pathway.Tumour Biol. 2016 Mar;37(3):3851-61. doi: 10.1007/s13277-015-3896-y. Epub 2015 Oct 17.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [21] 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.
• [22] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] 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.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [27] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.