Details of Drug Off-Target (DOT)

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

• DOT Name: TNFAIP3-interacting protein 2 (TNIP2)
• Synonyms: A20-binding inhibitor of NF-kappa-B activation 2; ABIN-2; Fetal liver LKB1-interacting protein
• Gene Name: TNIP2
• Related Disease:
  Rabies
  Colitis
  Hepatocellular carcinoma
  Leukemia
  Lupus nephritis
• UniProt ID: TNIP2_HUMAN
• PDB ID: 5H07
• Pfam ID: PF12180
• Sequence:
  MSRDPGSGGWEEAPRAAAALCTLYHEAGQRLRRLQDQLAARDALIARLRARLAALEGDAA
  PSLVDALLEQVARFREQLRRQEGGAAEAQMRQEIERLTERLEEKEREMQQLLSQPQHERE
  KEVVLLRRSMAEGERARAASDVLCRSLANETHQLRRTLTATAHMCQHLAKCLDERQHAQR
  NVGERSPDQSEHTDGHTSVQSVIEKLQEENRLLKQKVTHVEDLNAKWQRYNASRDEYVRG
  LHAQLRGLQIPHEPELMRKEISRLNRQLEEKINDCAEVKQELAASRTARDAALERVQMLE
  QQILAYKDDFMSERADRERAQSRIQELEEKVASLLHQVSWRQDSREPDAGRIHAGSKTAK
  YLAADALELMVPGGWRPGTGSQQPEPPAEGGHPGAAQRGQGDLQCPHCLQCFSDEQGEEL
  LRHVAECCQ
• Function: Inhibits NF-kappa-B activation by blocking the interaction of RIPK1 with its downstream effector NEMO/IKBKG. Forms a ternary complex with NFKB1 and MAP3K8 but appears to function upstream of MAP3K8 in the TLR4 signaling pathway that regulates MAP3K8 activation. Involved in activation of the MEK/ERK signaling pathway during innate immune response; this function seems to be stimulus- and cell type specific. Required for stability of MAP3K8. Involved in regulation of apoptosis in endothelial cells; promotes TEK agonist-stimulated endothelial survival. May act as transcriptional coactivator when translocated to the nucleus. Enhances CHUK-mediated NF-kappa-B activation involving NF-kappa-B p50-p65 and p50-c-Rel complexes.
• Tissue Specificity: Ubiquitously expressed in all tissues examined.
• Reactome Pathway:
  Ovarian tumor domain proteases (R-HSA-5689896)
  MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rabies	DISSC4V5	Definitive	Biomarker	[1]
Colitis	DISAF7DD	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Leukemia	DISNAKFL	Strong	Altered Expression	[4]
Lupus nephritis	DISCVGPZ	moderate	Altered Expression	[5]

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 TNFAIP3-interacting protein 2 (TNIP2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of TNFAIP3-interacting protein 2 (TNIP2).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of TNFAIP3-interacting protein 2 (TNIP2).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of TNFAIP3-interacting protein 2 (TNIP2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TNFAIP3-interacting protein 2 (TNIP2).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of TNFAIP3-interacting protein 2 (TNIP2).	[8]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of TNFAIP3-interacting protein 2 (TNIP2).	[9]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of TNFAIP3-interacting protein 2 (TNIP2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of TNFAIP3-interacting protein 2 (TNIP2).	[11]

References

• [1] Regulation of NF-B by the p105-ABIN2-TPL2 complex and RelAp43 during rabies virus infection.PLoS Pathog. 2017 Oct 30;13(10):e1006697. doi: 10.1371/journal.ppat.1006697. eCollection 2017 Oct.
• [2] ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism.J Immunol. 2018 Dec 1;201(11):3373-3382. doi: 10.4049/jimmunol.1700614. Epub 2018 Oct 24.
• [3] MiR-1180 promoted the proliferation of hepatocellular carcinoma cells by repressing TNIP2 expression.Biomed Pharmacother. 2016 Apr;79:315-20. doi: 10.1016/j.biopha.2016.02.025. Epub 2016 Mar 15.
• [4] The promyelocytic leukemia protein represses A20-mediated transcription.J Biol Chem. 2002 Aug 30;277(35):31734-9. doi: 10.1074/jbc.M201648200. Epub 2002 Jun 21.
• [5] MiR-663a/MiR-423-5p are involved in the pathogenesis of lupus nephritis via modulating the activation of NF-B by targeting TNIP2.Am J Transl Res. 2017 Aug 15;9(8):3796-3803. eCollection 2017.
• [6] 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.
• [7] 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.
• [8] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [9] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [10] 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.
• [11] 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.
• [12] 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.