Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNYAKP6)

• DOT Name: E3 ubiquitin-protein ligase TRIM15 (TRIM15)
• Synonyms: EC 2.3.2.27; RING finger protein 93; Zinc finger protein 178; Zinc finger protein B7
• Gene Name: TRIM15
• Related Disease:
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Gastric adenocarcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Rheumatoid arthritis
  Vitiligo
  Lupus nephritis
  Ulcerative colitis
• UniProt ID: TRI15_HUMAN
• PDB ID: 7QS2
• EC Number: 2.3.2.27
• Pfam ID: PF13765 ; PF00622 ; PF00643 ; PF00097
• Sequence:
  MPATPSLKVVHELPACTLCAGPLEDAVTIPCGHTFCRLCLPALSQMGAQSSGKILLCPLC
  QEEEQAETPMAPVPLGPLGETYCEEHGEKIYFFCENDAEFLCVFCREGPTHQAHTVGFLD
  EAIQPYRDRLRSRLEALSTERDEIEDVKCQEDQKLQVLLTQIESKKHQVETAFERLQQEL
  EQQRCLLLARLRELEQQIWKERDEYITKVSEEVTRLGAQVKELEEKCQQPASELLQDVRV
  NQSRCEMKTFVSPEAISPDLVKKIRDFHRKILTLPEMMRMFSENLAHHLEIDSGVITLDP
  QTASRSLVLSEDRKSVRYTRQKKSLPDSPLRFDGLPAVLGFPGFSSGRHRWQVDLQLGDG
  GGCTVGVAGEGVRRKGEMGLSAEDGVWAVIISHQQCWASTSPGTDLPLSEIPRGVRVALD
  YEAGQVTLHNAQTQEPIFTFTASFSGKVFPFFAVWKKGSCLTLKG
• Function: E3 ubiquitin ligase that plays a role in several processes including innate antiviral immnity, cell migration and chemotaxis. Acts as a 'Lys-63'-specific ubiquitin ligase for MAPK1/ERK2 and MAPK3/ERK1, promoting their activation by facilitating their interaction with MAP2K1 and MAP2K2. Plays also a role in cell migration and chemotaxis by acting as a stable focal adhesion component upon recruitment by multi-adapter protein paxillin/PXN. Functions in the RIGI-mediated interferon induction pathway upstream or at the level of MAVS. Inhibits NF-kappa-B activation by turnover of 'Lys-63'-linked ubiquitination of MAP3K7/TAK1. Mechanistically, prevents TRIM8 cytoplasmic translocation and thus inhibits TRIM8-mediated 'Lys-63'-linked polyubiquitination of MAP3K7/TAK1 in the cytoplasm. Plays also an important regulatory effect on the activation of hepatic stellate cells (HSCs).

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Gastric adenocarcinoma	DISWWLTC	Strong	Altered Expression	[1]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[3]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[4]
Vitiligo	DISR05SL	Strong	Genetic Variation	[5]
Lupus nephritis	DISCVGPZ	moderate	Biomarker	[6]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[7]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	E3 ubiquitin-protein ligase TRIM15 (TRIM15) decreases the response to substance of Arsenic trioxide.	[14]
Capecitabine	DMTS85L	Approved	E3 ubiquitin-protein ligase TRIM15 (TRIM15) increases the response to substance of Capecitabine.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase TRIM15 (TRIM15).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase TRIM15 (TRIM15).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase TRIM15 (TRIM15).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of E3 ubiquitin-protein ligase TRIM15 (TRIM15).	[12]

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 E3 ubiquitin-protein ligase TRIM15 (TRIM15).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase TRIM15 (TRIM15).	[13]

References

• [1] TRIM15 Exerts Anti-Tumor Effects Through Suppressing Cancer Cell Invasion in Gastric Adenocarcinoma.Med Sci Monit. 2018 Nov 9;24:8033-8041. doi: 10.12659/MSM.911142.
• [2] Role of the focal adhesion protein TRIM15 in colon cancer development.Biochim Biophys Acta. 2015 Feb;1853(2):409-21. doi: 10.1016/j.bbamcr.2014.11.007. Epub 2014 Nov 15.
• [3] Tripartite motif-containing 15 overexpression in non-small cell lung cancer is associated with poor patient prognoses.J Cancer. 2019 Jan 29;10(4):843-852. doi: 10.7150/jca.27856. eCollection 2019.
• [4] REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.Nat Genet. 2009 Jul;41(7):820-3. doi: 10.1038/ng.395. Epub 2009 Jun 7.
• [5] Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC.Nat Genet. 2010 Jul;42(7):614-8. doi: 10.1038/ng.603. Epub 2010 Jun 6.
• [6] Genetic contributions to lupus nephritis in a multi-ethnic cohort of systemic lupus erythematous patients.PLoS One. 2018 Jun 28;13(6):e0199003. doi: 10.1371/journal.pone.0199003. eCollection 2018.
• [7] Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis.Inflamm Bowel Dis. 2018 Mar 19;24(4):829-838. doi: 10.1093/ibd/izx084.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] 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.
• [14] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [15] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.