Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNG0L8X)

• DOT Name: TRAF3-interacting JNK-activating modulator (TRAF3IP3)
• Synonyms: TRAF3-interacting protein 3
• Gene Name: TRAF3IP3
• Related Disease:
  Advanced cancer
  Melanoma
  Neoplasm
  Isolated cleft lip
  Lung adenocarcinoma
• UniProt ID: T3JAM_HUMAN
• Sequence:
  MISPDPRPSPGLARWAESYEAKCERRQEIRESRRCRPNVTTCRQVGKTLRIQQREQLQRA
  RLQQFFRRRNLELEEKGKAQHPQAREQGPSRRPGQVTVLKEPLSCARRISSPREQVTGTS
  SEVFPAQHPPPSGICRDLSDHLSSQAGGLPPQDTPIKKPPKHHRGTQTKAEGPTIKNDAS
  QQTNYGVAVLDKEIIQLSDYLKEALQRELVLKQKMVILQDLLSTLIQASDSSWKGQLNED
  KLKGKLRSLENQLYTCTQKYSPWGMKKVLLEMEDQKNSYEQKAKESLQKVLEEKMNAEQQ
  LQSTQRSLALAEQKCEEWRSQYEALKEDWRTLGTQHRELESQLHVLQSKLQGADSRDLQM
  NQALRFLENEHQQLQAKIECLQGDRDLCSLDTQDLQDQLKRSEAEKLTLVTRVQQLQGLL
  QNQSLQLQEQEKLLTKKDQALPVWSPKSFPNEVEPEGTGKEKDWDLRDQLQKKTLQLQAK
  EKECRELHSELDNLSDEYLSCLRKLQHCREELNQSQQLPPRRQCGRWLPVLMVVIAAALA
  VFLANKDNLMI
• Function: Adapter protein that plays essential roles in both innate and adaptive immunity. Plays a crucial role in the regulation of thymocyte development. Mechanistically, mediates TCR-stimulated activation through recruiting MAP2K1/MEK1 to the Golgi and, thereby, facilitating the interaction of MAP2K1/MEK1 with its activator BRAF. Also plays an essential role in regulatory T-cell stability and function by recruiting the serine-threonine phosphatase catalytic subunit (PPP2CA) to the lysosome, thereby facilitating the interaction of PP2Ac with the mTORC1 component RPTOR and restricting glycolytic metabolism. Positively regulates TLR4 signaling activity in macrophage-mediated inflammation by acting as a molecular clamp to facilitate LPS-induced translocation of TLR4 to lipid rafts. In response to viral infection, facilitates the recruitment of TRAF3 to MAVS within mitochondria leading to IRF3 activation and interferon production. However, participates in the maintenance of immune homeostasis and the prevention of overzealous innate immunity by promoting 'Lys-48'-dependent ubiquitination of TBK1.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Melanoma	DIS1RRCY	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[2]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of TRAF3-interacting JNK-activating modulator (TRAF3IP3).	[4]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of TRAF3-interacting JNK-activating modulator (TRAF3IP3).	[6]

2 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 TRAF3-interacting JNK-activating modulator (TRAF3IP3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of TRAF3-interacting JNK-activating modulator (TRAF3IP3).	[7]

References

• [1] TRAF3-interacting protein 3, a new oncotarget, promotes tumor growth in melanoma.Melanoma Res. 2018 Jun;28(3):185-194. doi: 10.1097/CMR.0000000000000440.
• [2] Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci.Nat Genet. 2012 Sep;44(9):968-71. doi: 10.1038/ng.2360. Epub 2012 Aug 5.
• [3] Integrated analysis of dysregulated long non-coding RNAs/microRNAs/mRNAs in metastasis of lung adenocarcinoma.J Transl Med. 2018 Dec 27;16(1):372. doi: 10.1186/s12967-018-1732-z.
• [4] 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.
• [5] 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.
• [6] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [7] 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.