Details of Drug Off-Target (DOT)

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

• DOT Name: TNF receptor-associated factor 4 (TRAF4)
• Synonyms: EC 2.3.2.27; Cysteine-rich domain associated with RING and Traf domains protein 1; Metastatic lymph node gene 62 protein; MLN 62; RING finger protein 83
• Gene Name: TRAF4
• Related Disease:
  Advanced cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Cervical carcinoma
  Chondrosarcoma
  Crohn disease
  Endometrial cancer
  Endometrial carcinoma
  Esophageal squamous cell carcinoma
  Gastric adenocarcinoma
  Graves disease
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Intrahepatic cholangiocarcinoma
  Laryngeal disorder
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Malignant glioma
  Metabolic bone disease
  Metastatic malignant neoplasm
  Metastatic prostate carcinoma
  Neoplasm
  Neural tube defect
  Non-small-cell lung cancer
  Osteoporosis
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Ankylosing spondylitis
  Arteriosclerosis
  Atherosclerosis
  Inflammation
• UniProt ID: TRAF4_HUMAN
• PDB ID: 2EOD; 2YUC; 3ZJB; 4K8U; 4M4E; 5YC1
• EC Number: 2.3.2.27
• Pfam ID: PF21355 ; PF00097 ; PF02176
• Sequence:
  MPGFDYKFLEKPKRRLLCPLCGKPMREPVQVSTCGHRFCDTCLQEFLSEGVFKCPEDQLP
  LDYAKIYPDPELEVQVLGLPIRCIHSEEGCRWSGPLRHLQGHLNTCSFNVIPCPNRCPMK
  LSRRDLPAHLQHDCPKRRLKCEFCGCDFSGEAYESHEGMCPQESVYCENKCGARMMRRLL
  AQHATSECPKRTQPCTYCTKEFVFDTIQSHQYQCPRLPVACPNQCGVGTVAREDLPGHLK
  DSCNTALVLCPFKDSGCKHRCPKLAMARHVEESVKPHLAMMCALVSRQRQELQELRRELE
  ELSVGSDGVLIWKIGSYGRRLQEAKAKPNLECFSPAFYTHKYGYKLQVSAFLNGNGSGEG
  THLSLYIRVLPGAFDNLLEWPFARRVTFSLLDQSDPGLAKPQHVTETFHPDPNWKNFQKP
  GTWRGSLDESSLGFGYPKFISHQDIRKRNYVRDDAVFIRAAVELPRKILS
• Function: Adapter protein with E3 ligase activity that is involved in many diverse biological processes including cell proliferation, migration, differentiation, DNA repair, platelet activation or apoptosis. Promotes EGFR-mediated signaling by facilitating the dimerization of EGFR and downstream AKT activation thereby promoting cell proliferation. Ubiquitinates SMURF2 through 'Lys-48'-linked ubiquitin chain leading to SMURF2 degradation through the proteasome and subsequently osteogenic differentiation. Promotes 'Lys-63'-mediated ubiquitination of CHK1 which in turn activates cell cycle arrest and activation of DNA repair. In addition, promotes an atypical 'Lys-29'-linked ubiquitination at the C-terminal end of IRS1 which is crucial for insulin-like growth factor (IGF) signal transduction. Regulates activation of NF-kappa-B in response to signaling through Toll-like receptors. Required for normal skeleton development, and for normal development of the respiratory tract. Required for activation of RPS6KB1 in response to TNF signaling. Modulates TRAF6 functions. Inhibits adipogenic differentiation by activating pyruvate kinase PKM activity and subsequently the beta-catenin signaling pathway.
• Tissue Specificity: Expressed in epithelial cells of thymus, dendritic cells of lymph node, and in the basal cell layer of epithelia such as epidermis, nasopharynx, respiratory tract, salivary gland, and esophagus.
• KEGG Pathway:
  IL-17 sig.ling pathway (hsa04657)
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[6]
Chondrosarcoma	DIS4I7JB	Strong	Biomarker	[6]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[7]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[8]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[1]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[9]
Graves disease	DISU4KOQ	Strong	Biomarker	[10]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[13]
Laryngeal disorder	DISDKUQO	Strong	Biomarker	[14]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[15]
Lung carcinoma	DISTR26C	Strong	Biomarker	[15]
Malignant glioma	DISFXKOV	Strong	Biomarker	[16]
Metabolic bone disease	DISO7RI8	Strong	Biomarker	[17]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[5]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Altered Expression	[18]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neural tube defect	DIS5J95E	Strong	Biomarker	[19]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[20]
Osteoporosis	DISF2JE0	Strong	Biomarker	[17]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[18]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[18]
Ankylosing spondylitis	DISRC6IR	Limited	Altered Expression	[21]
Arteriosclerosis	DISK5QGC	Limited	Biomarker	[22]
Atherosclerosis	DISMN9J3	Limited	Biomarker	[22]
Inflammation	DISJUQ5T	Limited	Biomarker	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of TNF receptor-associated factor 4 (TRAF4).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of TNF receptor-associated factor 4 (TRAF4).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of TNF receptor-associated factor 4 (TRAF4).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of TNF receptor-associated factor 4 (TRAF4).	[26]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of TNF receptor-associated factor 4 (TRAF4).	[27]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of TNF receptor-associated factor 4 (TRAF4).	[28]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of TNF receptor-associated factor 4 (TRAF4).	[29]
Selenium	DM25CGV	Approved	Selenium increases the expression of TNF receptor-associated factor 4 (TRAF4).	[30]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of TNF receptor-associated factor 4 (TRAF4).	[31]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of TNF receptor-associated factor 4 (TRAF4).	[32]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of TNF receptor-associated factor 4 (TRAF4).	[33]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of TNF receptor-associated factor 4 (TRAF4).	[34]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of TNF receptor-associated factor 4 (TRAF4).	[35]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of TNF receptor-associated factor 4 (TRAF4).	[36]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of TNF receptor-associated factor 4 (TRAF4).	[37]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of TNF receptor-associated factor 4 (TRAF4).	[39]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of TNF receptor-associated factor 4 (TRAF4).	[40]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of TNF receptor-associated factor 4 (TRAF4).	[41]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of TNF receptor-associated factor 4 (TRAF4).	[42]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of TNF receptor-associated factor 4 (TRAF4).	[43]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of TNF receptor-associated factor 4 (TRAF4).	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of TNF receptor-associated factor 4 (TRAF4).	[38]

References

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