Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIRCVG7)

• DOT Name: TRAF-interacting protein with FHA domain-containing protein A (TIFA)
• Synonyms: Putative MAPK-activating protein PM14; Putative NF-kappa-B-activating protein 20; TRAF2-binding protein
• Gene Name: TIFA
• Related Disease:
  Advanced cancer
  Acute myelogenous leukaemia
• UniProt ID: TIFA_HUMAN
• PDB ID: 4YM4; 4ZGI; 5ZUJ; 6A33
• Pfam ID: PF00498
• Sequence:
  MTSFEDADTEETVTCLQMTVYHPGQLQCGIFQSISFNREKLPSSEVVKFGRNSNICHYTF
  QDKQVSRVQFSLQLFKKFNSSVLSFEIKNMSKKTNLIVDSRELGYLNKMDLPYRCMVRFG
  EYQFLMEKEDGESLEFFETQFILSPRSLLQENNWPPHRPIPEYGTYSLCSSQSSSPTEMD
  ENES
• Function: Adapter molecule that plays a key role in the activation of pro-inflammatory NF-kappa-B signaling following detection of bacterial pathogen-associated molecular pattern metabolites (PAMPs). Promotes activation of an innate immune response by inducing the oligomerization and polyubiquitination of TRAF6, which leads to the activation of TAK1 and IKK through a proteasome-independent mechanism. TIFA-dependent innate immune response is triggered by ADP-D-glycero-beta-D-manno-heptose (ADP-Heptose), a potent PAMP present in all Gram-negative and some Gram-positive bacteria: ADP-Heptose is recognized by ALPK1, which phosphorylates TIFA at Thr-9, leading to TIFA homooligomerization and subsequent activation of pro-inflammatory NF-kappa-B signaling.
• KEGG Pathway: Shigellosis (hsa05131)
• Reactome Pathway:
  Alpha-protein kinase 1 signaling pathway (R-HSA-9645460)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]

11 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 TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of TRAF-interacting protein with FHA domain-containing protein A (TIFA).	[6]

References

• [1] TIFA Signaling in Gastric Epithelial Cells Initiates the cag Type 4 Secretion System-Dependent Innate Immune Response to Helicobacter pylori Infection.mBio. 2017 Aug 15;8(4):e01168-17. doi: 10.1128/mBio.01168-17.
• [2] Aurora A and NF-B Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA.Cancer Res. 2017 Jan 15;77(2):494-508. doi: 10.1158/0008-5472.CAN-16-1004. Epub 2016 Nov 10.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] 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.
• [8] 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.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [13] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.