Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3THRCA)

• DOT Name: Trafficking protein particle complex subunit 4 (TRAPPC4)
• Synonyms: Hematopoietic stem/progenitor cell protein 172; Synbindin; TRS23 homolog
• Gene Name: TRAPPC4
• Related Disease:
  Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy
  Adenoma
  Colorectal carcinoma
  Deafness
  Disorder of glycogen metabolism
  Glycogen storage disease Ib
  Intellectual disability
  Neoplasm
  Nervous system disease
  Syndromic intellectual disability
  Parkinson disease
• UniProt ID: TPPC4_HUMAN
• PDB ID: 2J3T; 2JSN; 2ZMV
• Pfam ID: PF04099
• Sequence:
  MAIFSVYVVNKAGGLIYQLDSYAPRAEAEKTFSYPLDLLLKLHDERVLVAFGQRDGIRVG
  HAVLAINGMDVNGRYTADGKEVLEYLGNPANYPVSIRFGRPRLTSNEKLMLASMFHSLFA
  IGSQLSPEQGSSGIEMLETDTFKLHCYQTLTGIKFVVLADPRQAGIDSLLRKIYEIYSDF
  ALKNPFYSLEMPIRCELFDQNLKLALEVAEKAGTFGPGS
• Function: Core component of the TRAPP complexes which has a function of guanine nucleotide exchange factor activity for Rab1 GTPase (Probable). Plays a role in vesicular transport from endoplasmic reticulum to Golgi and autophagy. May play a role in dendrite postsynaptic membrane trafficking.
• Reactome Pathway:
  Syndecan interactions (R-HSA-3000170)
  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

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	DISNATZ2	Definitive	Autosomal recessive	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Deafness	DISKCLH4	Strong	Biomarker	[4]
Disorder of glycogen metabolism	DISYGNOB	Strong	CausalMutation	[5]
Glycogen storage disease Ib	DIS2SL6J	Strong	CausalMutation	[6]
Intellectual disability	DISMBNXP	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[4]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[7]
Parkinson disease	DISQVHKL	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[16]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[17]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Trafficking protein particle complex subunit 4 (TRAPPC4).	[21]

References

• [1] 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.
• [2] TRAPPC4-ERK2 interaction activates ERK1/2, modulates its nuclear localization and regulates proliferation and apoptosis of colorectal cancer cells.PLoS One. 2011;6(8):e23262. doi: 10.1371/journal.pone.0023262. Epub 2011 Aug 3.
• [3] The role of ERK2 in colorectal carcinogenesis is partly regulated by TRAPPC4.Mol Carcinog. 2014 Feb;53 Suppl 1:E72-84. doi: 10.1002/mc.22031. Epub 2013 Apr 26.
• [4] Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability. Brain. 2020 Jan 1;143(1):112-130. doi: 10.1093/brain/awz374.
• [5] Molecular analysis in glycogen storage disease 1 non-A: DHPLC detection of the highly prevalent exon 8 mutations of the G6PT1 gene in German patients.Hum Mutat. 2000 Aug;16(2):177. doi: 10.1002/1098-1004(200008)16:2<177::AID-HUMU13>3.0.CO;2-8.
• [6] Novel SLC37A4 Mutations in Korean Patients With Glycogen Storage Disease Ib. Ann Lab Med. 2017 May;37(3):261-266. doi: 10.3343/alm.2017.37.3.261.
• [7] Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations. Eur J Med Genet. 2020 Jan;63(1):103624. doi: 10.1016/j.ejmg.2019.01.014. Epub 2019 Jan 25.
• [8] Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene.Ann Neurol. 2009 Dec;66(6):792-8. doi: 10.1002/ana.21780.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [15] Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy. 2010 Aug;6(6):711-24. doi: 10.4161/auto.6.6.12397. Epub 2010 Aug 17.
• [16] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [17] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [18] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.