Details of Drug Off-Target (DOT)

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

• DOT Name: Trafficking kinesin-binding protein 1 (TRAK1)
• Synonyms: 106 kDa O-GlcNAc transferase-interacting protein; Protein Milton
• Gene Name: TRAK1
• Related Disease:
  Advanced cancer
  Colorectal adenoma
  Gastric neoplasm
  Mucinous adenocarcinoma
  Neurodevelopmental disorder
  Schizophrenia
  Acute myelogenous leukaemia
  Movement disorder
  Undetermined early-onset epileptic encephalopathy
  Absence epilepsy
  Absence seizure
  Nervous system disease
• UniProt ID: TRAK1_HUMAN
• Pfam ID: PF04849 ; PF12448
• Sequence:
  MALVFQFGQPVRAQPLPGLCHGKLIRTNACDVCNSTDLPEVEIISLLEEQLPHYKLRADT
  IYGYDHDDWLHTPLISPDANIDLTTEQIEETLKYFLLCAERVGQMTKTYNDIDAVTRLLE
  EKERDLELAARIGQSLLKKNKTLTERNELLEEQVEHIREEVSQLRHELSMKDELLQFYTS
  AAEESEPESVCSTPLKRNESSSSVQNYFHLDSLQKKLKDLEEENVVLRSEASQLKTETIT
  YEEKEQQLVNDCVKELRDANVQIASISEELAKKTEDAARQQEEITHLLSQIVDLQKKAKA
  CAVENEELVQHLGAAKDAQRQLTAELRELEDKYAECMEMLHEAQEELKNLRNKTMPNTTS
  RRYHSLGLFPMDSLAAEIEGTMRKELQLEEAESPDITHQKRVFETVRNINQVVKQRSLTP
  SPMNIPGSNQSSAMNSLLSSCVSTPRSSFYGSDIGNVVLDNKTNSIILETEAADLGNDER
  SKKPGTPGTPGSHDLETALRRLSLRRENYLSERRFFEEEQERKLQELAEKGELRSGSLTP
  TESIMSLGTHSRFSEFTGFSGMSFSSRSYLPEKLQIVKPLEGSATLHHWQQLAQPHLGGI
  LDPRPGVVTKGFRTLDVDLDEVYCLNDFEEDDTGDHISLPRLATSTPVQHPETSAHHPGK
  CMSQTNSTFTFTTCRILHPSDELTRVTPSLNSAPTPACGSTSHLKSTPVATPCTPRRLSL
  AESFTNTRESTTTMSTSLGLVWLLKERGISAAVYDPQSWDRAGRGSLLHSYTPKMAVIPS
  TPPNSPMQTPTSSPPSFEFKCTSPPYDNFLASKPASSILREVREKNVRSSESQTDVSVSN
  LNLVDKVRRFGVAKVVNSGRAHVPTLTEEQGPLLCGPPGPAPALVPRGLVPEGLPLRCPT
  VTSAIGGLQLNSGIRRNRSFPTMVGSSMQMKAPVTLTSGILMGAKLSKQTSLR
• Function: Involved in the regulation of endosome-to-lysosome trafficking, including endocytic trafficking of EGF-EGFR complexes and GABA-A receptors. Involved in mitochondrial motility. When O-glycosylated, abolishes mitochondrial motility. Crucial for recruiting OGT to the mitochondrial surface of neuronal processes. TRAK1 and RHOT form an essential protein complex that links KIF5 to mitochondria for light chain-independent, anterograde transport of mitochondria.
• Tissue Specificity: High expression in spinal cord and moderate expression in all other tissues and specific brain regions examined. Expressed in all cell lines examined.
• Reactome Pathway:
  RHOT2 GTPase cycle (R-HSA-9013419)
  RHOT1 GTPase cycle (R-HSA-9013425)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Colorectal adenoma	DISTSVHM	Strong	Biomarker	[2]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[3]
Mucinous adenocarcinoma	DISKNFE8	Strong	Biomarker	[3]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[5]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[6]
Movement disorder	DISOJJ2D	moderate	Genetic Variation	[7]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[4]
Absence epilepsy	DISJPOUD	Limited	Altered Expression	[1]
Absence seizure	DIS4709R	Limited	Altered Expression	[1]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Trafficking kinesin-binding protein 1 (TRAK1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Trafficking kinesin-binding protein 1 (TRAK1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Trafficking kinesin-binding protein 1 (TRAK1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Trafficking kinesin-binding protein 1 (TRAK1).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Trafficking kinesin-binding protein 1 (TRAK1).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Trafficking kinesin-binding protein 1 (TRAK1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Trafficking kinesin-binding protein 1 (TRAK1).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Trafficking kinesin-binding protein 1 (TRAK1).	[17]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Trafficking kinesin-binding protein 1 (TRAK1).	[18]

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 decreases the methylation of Trafficking kinesin-binding protein 1 (TRAK1).	[14]

References

• [1] Hypertonia-linked protein Trak1 functions with mitofusins to promote mitochondrial tethering and fusion.Protein Cell. 2018 Aug;9(8):693-716. doi: 10.1007/s13238-017-0469-4. Epub 2017 Sep 18.
• [2] Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysis.BMC Genomics. 2011 Oct 14;12:505. doi: 10.1186/1471-2164-12-505.
• [3] Identification of TRAK1 (Trafficking protein, kinesin-binding 1) as MGb2-Ag: a novel cancer biomarker.Cancer Lett. 2009 Feb 18;274(2):250-8. doi: 10.1016/j.canlet.2008.09.031. Epub 2008 Nov 4.
• [4] Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy. Brain. 2017 Mar 1;140(3):568-581. doi: 10.1093/brain/awx002.
• [5] Exome sequencing supports a de novo mutational paradigm for schizophrenia.Nat Genet. 2011 Aug 7;43(9):864-8. doi: 10.1038/ng.902.
• [6] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [7] Developmental changes in trak-mediated mitochondrial transport in neurons.Mol Cell Neurosci. 2017 Apr;80:134-147. doi: 10.1016/j.mcn.2017.03.006. Epub 2017 Mar 11.
• [8] Hypertonia-associated protein Trak1 is a novel regulator of endosome-to-lysosome trafficking.J Mol Biol. 2008 Oct 10;382(3):638-51. doi: 10.1016/j.jmb.2008.07.045. Epub 2008 Jul 25.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] 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.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [14] 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.
• [15] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.
• [18] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.