Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF0CVMC)

• DOT Name: Trafficking protein particle complex subunit 9 (TRAPPC9)
• Synonyms: NIK- and IKBKB-binding protein; Tularik gene 1 protein
• Gene Name: TRAPPC9
• Related Disease:
  Intellectual disability, autosomal recessive 13
  Intellectual disability-obesity-brain malformations-facial dysmorphism syndrome
  Acute gouty arthritis
  Adenoma
  Advanced cancer
  Colorectal carcinoma
  Gastric cancer
  Intellectual disability
  Multiple sclerosis
  Myocardial infarction
  Non-alcoholic fatty liver disease
  Spondyloepiphyseal dysplasia tarda, X-linked
  Stomach cancer
  Colon cancer
  Colon carcinoma
  Isolated congenital microcephaly
  Autosomal recessive non-syndromic intellectual disability
  Cognitive impairment
  Breast cancer
  Breast carcinoma
  Metastatic malignant neoplasm
  Subarachnoid hemorrhage
• UniProt ID: TPPC9_HUMAN
• Pfam ID: PF08626
• Sequence:
  MSVPDYMQCAEDHQTLLVVVQPVGIVSEENFFRIYKRICSVSQISVRDSQRVLYIRYRHH
  YPPENNEWGDFQTHRKVVGLITITDCFSAKDWPQTFEKFHVQKEIYGSTLYDSRLFVFGL
  QGEIVEQPRTDVAFYPNYEDCQTVEKRIEDFIESLFIVLESKRLDRATDKSGDKIPLLCV
  PFEKKDFVGLDTDSRHYKKRCQGRMRKHVGDLCLQAGMLQDSLVHYHMSVELLRSVNDFL
  WLGAALEGLCSASVIYHYPGGTGGKSGARRFQGSTLPAEAANRHRPGAQEVLIDPGALTT
  NGINPDTSTEIGRAKNCLSPEDIIDKYKEAISYYSKYKNAGVIELEACIKAVRVLAIQKR
  SMEASEFLQNAVYINLRQLSEEEKIQRYSILSELYELIGFHRKSAFFKRVAAMQCVAPSI
  AEPGWRACYKLLLETLPGYSLSLDPKDFSRGTHRGWAAVQMRLLHELVYASRRMGNPALS
  VRHLSFLLQTMLDFLSDQEKKDVAQSLENYTSKCPGTMEPIALPGGLTLPPVPFTKLPIV
  RHVKLLNLPASLRPHKMKSLLGQNVSTKSPFIYSPIIAHNRGEERNKKIDFQWVQGDVCE
  VQLMVYNPMPFELRVENMGLLTSGVEFESLPAALSLPAESGLYPVTLVGVPQTTGTITVN
  GYHTTVFGVFSDCLLDNLPGIKTSGSTVEVIPALPRLQISTSLPRSAHSLQPSSGDEIST
  NVSVQLYNGESQQLIIKLENIGMEPLEKLEVTSKVLTTKEKLYGDFLSWKLEETLAQFPL
  QPGKVATFTINIKVKLDFSCQENLLQDLSDDGISVSGFPLSSPFRQVVRPRVEGKPVNPP
  ESNKAGDYSHVKTLEAVLNFKYSGGPGHTEGYYRNLSLGLHVEVEPSVFFTRVSTLPATS
  TRQCHLLLDVFNSTEHELTVSTRSSEALILHAGECQRMAIQVDKFNFESFPESPGEKGQF
  ANPKQLEEERREARGLEIHSKLGICWRIPSLKRSGEASVEGLLNQLVLEHLQLAPLQWDV
  LVDGQPCDREAVAACQVGDPVRLEVRLTNRSPRSVGPFALTVVPFQDHQNGVHNYDLHDT
  VSFVGSSTFYLDAVQPSGQSACLGALLFLYTGDFFLHIRFHEDSTSKELPPSWFCLPSVH
  VCALEAQA
• Function: Functions as an activator of NF-kappa-B through increased phosphorylation of the IKK complex. May function in neuronal cells differentiation. May play a role in vesicular transport from endoplasmic reticulum to Golgi.
• Tissue Specificity: Expressed at high levels in muscle and kidney and to a lower extent in brain, heart and placenta.
• Reactome Pathway:
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal recessive 13	DIS83XC2	Definitive	Autosomal recessive	[1]
Intellectual disability-obesity-brain malformations-facial dysmorphism syndrome	DISK17VG	Definitive	Autosomal recessive	[2]
Acute gouty arthritis	DISY5UJH	Strong	Biomarker	[3]
Adenoma	DIS78ZEV	Strong	Posttranslational Modification	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Intellectual disability	DISMBNXP	Strong	Biomarker	[6]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[7]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[8]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[9]
Spondyloepiphyseal dysplasia tarda, X-linked	DIS9EL3M	Strong	Genetic Variation	[10]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Colon cancer	DISVC52G	moderate	Biomarker	[11]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[11]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[12]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[13]
Cognitive impairment	DISH2ERD	Disputed	Genetic Variation	[14]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[15]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[15]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[15]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Trafficking protein particle complex subunit 9 (TRAPPC9).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Trafficking protein particle complex subunit 9 (TRAPPC9).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Trafficking protein particle complex subunit 9 (TRAPPC9).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Trafficking protein particle complex subunit 9 (TRAPPC9).	[27]

10 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 Trafficking protein particle complex subunit 9 (TRAPPC9).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Trafficking protein particle complex subunit 9 (TRAPPC9).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Trafficking protein particle complex subunit 9 (TRAPPC9).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Trafficking protein particle complex subunit 9 (TRAPPC9).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Trafficking protein particle complex subunit 9 (TRAPPC9).	[22]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Trafficking protein particle complex subunit 9 (TRAPPC9).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Trafficking protein particle complex subunit 9 (TRAPPC9).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Trafficking protein particle complex subunit 9 (TRAPPC9).	[28]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Trafficking protein particle complex subunit 9 (TRAPPC9).	[29]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Trafficking protein particle complex subunit 9 (TRAPPC9).	[30]

References

• [1] Combination of linkage mapping and microarray-expression analysis identifies NF-kappaB signaling defect as a cause of autosomal-recessive mental retardation. Am J Hum Genet. 2009 Dec;85(6):903-8. doi: 10.1016/j.ajhg.2009.11.007.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Factors associated with the decision of the rheumatologist to order sacroiliac joints magnetic resonance imaging (SI-MRI) or HLA-B27 testing in the diagnostic work-up of patients with spondyloarthritis in clinical practice.Clin Exp Rheumatol. 2017 Jan-Feb;35(1):122-128. Epub 2016 Oct 26.
• [4] Knockdown of NIK and IKK-Binding Protein (NIBP) Reduces Colorectal Cancer Metastasis through Down-Regulation of the Canonical NF- Signaling Pathway and Suppression of MAPK Signaling Mediated through ERK and JNK.PLoS One. 2017 Jan 26;12(1):e0170595. doi: 10.1371/journal.pone.0170595. eCollection 2017.
• [5] NIK?and IKKbinding protein contributes to gastric cancer chemoresistance by promoting epithelialmesenchymal transition through the NFB signaling pathway.Oncol Rep. 2018 Jun;39(6):2721-2730. doi: 10.3892/or.2018.6348. Epub 2018 Mar 30.
• [6] The role of CNVs in the etiology of rare autosomal recessive disorders: the example of TRAPPC9-associated intellectual disability.Eur J Hum Genet. 2018 Jan;26(1):143-148. doi: 10.1038/s41431-017-0018-x. Epub 2017 Nov 29.
• [7] A genome-wide association study of brain lesion distribution in multiple sclerosis.Brain. 2013 Apr;136(Pt 4):1012-24. doi: 10.1093/brain/aws363. Epub 2013 Feb 13.
• [8] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [9] Genome-Wide Associations Related to Hepatic Histology in Nonalcoholic Fatty Liver Disease in Hispanic Boys.J Pediatr. 2017 Nov;190:100-107.e2. doi: 10.1016/j.jpeds.2017.08.004. Epub 2017 Sep 14.
• [10] The adaptor function of TRAPPC2 in mammalian TRAPPs explains TRAPPC2-associated SEDT and TRAPPC9-associated congenital intellectual disability.PLoS One. 2011;6(8):e23350. doi: 10.1371/journal.pone.0023350. Epub 2011 Aug 15.
• [11] TRAPPC9: Novel insights into its trafficking and signaling pathways in health and disease (Review).Int J Mol Med. 2018 Dec;42(6):2991-2997. doi: 10.3892/ijmm.2018.3889. Epub 2018 Sep 21.
• [12] Phenotypes in siblings with homozygous mutations of TRAPPC9 and/or MCPH1 support a bifunctional model of MCPH1.Mol Genet Genomic Med. 2018 Apr 24;6(4):660-5. doi: 10.1002/mgg3.400. Online ahead of print.
• [13] Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation. Am J Hum Genet. 2009 Dec;85(6):909-15. doi: 10.1016/j.ajhg.2009.11.009.
• [14] A homozygous splice site mutation in TRAPPC9 causes intellectual disability and microcephaly.Eur J Med Genet. 2012 Dec;55(12):727-31. doi: 10.1016/j.ejmg.2012.08.010. Epub 2012 Aug 30.
• [15] IBP regulates epithelial-to-mesenchymal transition and the motility of breast cancer cells via Rac1, RhoA and Cdc42 signaling pathways.Oncogene. 2014 Jun 26;33(26):3374-82. doi: 10.1038/onc.2013.337. Epub 2013 Aug 26.
• [16] Association of genetic variants with hemorrhagic stroke in Japanese individuals.Int J Mol Med. 2010 Apr;25(4):649-56. doi: 10.3892/ijmm_00000388.
• [17] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [18] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [19] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [23] 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.
• [24] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
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• [26] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
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• [28] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [29] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [30] Identification of early target genes of aflatoxin B1 in human hepatocytes, inter-individual variability and comparison with other genotoxic compounds. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):176-87.