Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA5GO5K)

• DOT Name: TNF receptor-associated factor 6 (TRAF6)
• Synonyms: EC 2.3.2.27; E3 ubiquitin-protein ligase TRAF6; Interleukin-1 signal transducer; RING finger protein 85; RING-type E3 ubiquitin transferase TRAF6
• Gene Name: TRAF6
• Related Disease: Autosomal dominant hypohidrotic ectodermal dysplasia
• UniProt ID: TRAF6_HUMAN
• PDB ID: 1LB4; 1LB5; 1LB6; 2ECI; 2JMD; 3HCS; 3HCT; 3HCU; 4Z8M; 5ZUJ; 6A33; 7L3L; 8HZ2
• EC Number: 2.3.2.27
• Pfam ID: PF21355 ; PF18048 ; PF13923 ; PF02176
• Sequence:
  MSLLNCENSCGSSQSESDCCVAMASSCSAVTKDDSVGGTASTGNLSSSFMEEIQGYDVEF
  DPPLESKYECPICLMALREAVQTPCGHRFCKACIIKSIRDAGHKCPVDNEILLENQLFPD
  NFAKREILSLMVKCPNEGCLHKMELRHLEDHQAHCEFALMDCPQCQRPFQKFHINIHILK
  DCPRRQVSCDNCAASMAFEDKEIHDQNCPLANVICEYCNTILIREQMPNHYDLDCPTAPI
  PCTFSTFGCHEKMQRNHLARHLQENTQSHMRMLAQAVHSLSVIPDSGYISEVRNFQETIH
  QLEGRLVRQDHQIRELTAKMETQSMYVSELKRTIRTLEDKVAEIEAQQCNGIYIWKIGNF
  GMHLKCQEEEKPVVIHSPGFYTGKPGYKLCMRLHLQLPTAQRCANYISLFVHTMQGEYDS
  HLPWPFQGTIRLTILDQSEAPVRQNHEEIMDAKPELLAFQRPTIPRNPKGFGYVTFMHLE
  ALRQRTFIKDDTLLVRCEVSTRFDMGSLRREGFQPRSTDAGV
• Function: E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as ECSIT, IKBKG, IRAK1, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and JUN. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. Participates also in the TCR signaling by ubiquitinating LAT.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  NF-kappa B sig.ling pathway (hsa04064)
  Ubiquitin mediated proteolysis (hsa04120)
  Autophagy - animal (hsa04140)
  Endocytosis (hsa04144)
  Osteoclast differentiation (hsa04380)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  IL-17 sig.ling pathway (hsa04657)
  Neurotrophin sig.ling pathway (hsa04722)
  Alcoholic liver disease (hsa04936)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Yersinia infection (hsa05135)
  Leishmaniasis (hsa05140)
  Chagas disease (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  MyD88 (R-HSA-166058)
  NOD1/2 Signaling Pathway (R-HSA-168638)
  TICAM1, RIP1-mediated IKK complex recruitment (R-HSA-168927)
  Regulated proteolysis of p75NTR (R-HSA-193692)
  Downstream TCR signaling (R-HSA-202424)
  NRIF signals cell death from the nucleus (R-HSA-205043)
  p75NTR recruits signalling complexes (R-HSA-209543)
  NF-kB is activated and signals survival (R-HSA-209560)
  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)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Ub-specific processing proteases (R-HSA-5689880)
  Ovarian tumor domain proteases (R-HSA-5689896)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  TICAM1,TRAF6-dependent induction of TAK1 complex (R-HSA-9014325)
  Interleukin-1 signaling (R-HSA-9020702)
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  IRAK1 recruits IKK complex (R-HSA-937039)
  IKK complex recruitment mediated by RIP1 (R-HSA-937041)
  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-1 activates/modulates innate immune responses (R-HSA-9692916)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling (R-HSA-975110)
  TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (R-HSA-975138)
  IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation (R-HSA-975144)
  MyD88 dependent cascade initiated on endosome (R-HSA-975155)
  IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation (R-HSA-975163)
  Regulation of NF-kappa B signaling (R-HSA-9758274)
  MyD88 cascade initiated on plasma membrane (R-HSA-975871)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant hypohidrotic ectodermal dysplasia	DISGWW7F	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	TNF receptor-associated factor 6 (TRAF6) decreases the response to substance of Camptothecin.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of TNF receptor-associated factor 6 (TRAF6).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of TNF receptor-associated factor 6 (TRAF6).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TNF receptor-associated factor 6 (TRAF6).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of TNF receptor-associated factor 6 (TRAF6).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of TNF receptor-associated factor 6 (TRAF6).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of TNF receptor-associated factor 6 (TRAF6).	[8]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of TNF receptor-associated factor 6 (TRAF6).	[9]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of TNF receptor-associated factor 6 (TRAF6).	[10]
Aspirin	DM672AH	Approved	Aspirin increases the expression of TNF receptor-associated factor 6 (TRAF6).	[11]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of TNF receptor-associated factor 6 (TRAF6).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of TNF receptor-associated factor 6 (TRAF6).	[13]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of TNF receptor-associated factor 6 (TRAF6).	[14]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of TNF receptor-associated factor 6 (TRAF6).	[10]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 increases the expression of TNF receptor-associated factor 6 (TRAF6).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of TNF receptor-associated factor 6 (TRAF6).	[18]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of TNF receptor-associated factor 6 (TRAF6).	[19]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of TNF receptor-associated factor 6 (TRAF6).	[20]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of TNF receptor-associated factor 6 (TRAF6).	[21]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of TNF receptor-associated factor 6 (TRAF6).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of TNF receptor-associated factor 6 (TRAF6).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of TNF receptor-associated factor 6 (TRAF6).	[16]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the localization of TNF receptor-associated factor 6 (TRAF6).	[15]

References

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• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
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• [5] Analysis of estrogen agonism and antagonism of tamoxifen, raloxifene, and ICI182780 in endometrial cancer cells: a putative role for the epidermal growth factor receptor ligand amphiregulin. J Soc Gynecol Investig. 2005 Oct;12(7):e55-67.
• [6] Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation. J Biochem Mol Toxicol. 2013 Feb;27(2):106-15. doi: 10.1002/jbt.21462. Epub 2013 Jan 11.
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• [8] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [9] Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis. 2006 May;27(5):916-24. doi: 10.1093/carcin/bgi312. Epub 2005 Dec 16.
• [10] MiR-146a affects the alteration in myeloid differentiation induced by hydroquinone in human CD34(+) hematopoietic progenitor cells and HL-60 cells. Toxicol Res (Camb). 2016 Feb 16;5(3):848-858. doi: 10.1039/c5tx00419e. eCollection 2016 May 1.
• [11] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [12] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines. Anticancer Res. 2005 Sep-Oct;25(5):3293-302.
• [15] ON 01910.Na inhibits growth of diffuse large B-cell lymphoma by cytoplasmic sequestration of sumoylated C-MYB/TRAF6 complex. Transl Res. 2016 Sep;175:129-143.e13. doi: 10.1016/j.trsl.2016.04.001. Epub 2016 Apr 13.
• [16] 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.
• [17] Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [19] Probiotic Bacillus subtilis CW14 reduces disruption of the epithelial barrier and toxicity of ochratoxin A to Caco-2?cells. Food Chem Toxicol. 2019 Apr;126:25-33. doi: 10.1016/j.fct.2019.02.009. Epub 2019 Feb 11.
• [20] Epigallocatechin-3-gallate alleviates paraquat-induced acute lung injury and inhibits upregulation of toll-like receptors. Life Sci. 2017 Feb 1;170:25-32. doi: 10.1016/j.lfs.2016.11.021. Epub 2016 Nov 24.
• [21] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [22] Nickel promotes the invasive potential of human lung cancer cells via TLR4/MyD88 signaling. Toxicology. 2011 Jul 11;285(1-2):25-30. doi: 10.1016/j.tox.2011.03.016. Epub 2011 Apr 5.
• [23] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.