Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXVA7FN)

• DOT Name: Trafficking kinesin-binding protein 2 (TRAK2)
• Synonyms: Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 3 protein
• Gene Name: TRAK2
• Related Disease:
  Amyotrophic lateral sclerosis type 2, juvenile
  Breast carcinoma
  Juvenile amyotrophic lateral sclerosis
  Thyroid gland papillary carcinoma
• UniProt ID: TRAK2_HUMAN
• Pfam ID: PF04849 ; PF12448
• Sequence:
  MSQSQNAIFTSPTGEENLMNSNHRDSESITDVCSNEDLPEVELVSLLEEQLPQYRLKVDT
  LFLYENQDWTQSPHQRQHASDALSPVLAEETFRYMILGTDRVEQMTKTYNDIDMVTHLLA
  ERDRDLELAARIGQALLKRNHVLSEQNESLEEQLGQAFDQVNQLQHELCKKDELLRIVSI
  ASEESETDSSCSTPLRFNESFSLSQGLLQLEMLQEKLKELEEENMALRSKACHIKTETVT
  YEEKEQQLVSDCVKELRETNAQMSRMTEELSGKSDELIRYQEELSSLLSQIVDLQHKLKE
  HVIEKEELKLHLQASKDAQRQLTMELHELQDRNMECLGMLHESQEEIKELRSRSGPTAHL
  YFSQSYGAFTGESLAAEIEGTMRKKLSLDEESSLFKQKAQQKRVFDTVRIANDTRGRSIS
  FPALLPIPGSNRSSVIMTAKPFESGLQQTEDKSLLNQGSSSEEVAGSSQKMGQPGPSGDS
  DLATALHRLSLRRQNYLSEKQFFAEEWQRKIQVLADQKEGVSGCVTPTESLASLCTTQSE
  ITDLSSASCLRGFMPEKLQIVKPLEGSQTLYHWQQLAQPNLGTILDPRPGVITKGFTQLP
  GDAIYHISDLEEDEEEGITFQVQQPLEVEEKLSTSKPVTGIFLPPITSAGGPVTVATANP
  GKCLSCTNSTFTFTTCRILHPSDITQVTPSSGFPSLSCGSSGSSSSNTAVNSPALSYRLS
  IGESITNRRDSTTTFSSTMSLAKLLQERGISAKVYHSPISENPLQPLPKSLAIPSTPPNS
  PSHSPCPSPLPFEPRVHLSENFLASRPAETFLQEMYGLRPSRNPPDVGQLKMNLVDRLKR
  LGIARVVKNPGAQENGRCQEAEIGPQKPDSAVYLNSGSSLLGGLRRNQSLPVIMGSFAAP
  VCTSSPKMGVLKED
• Function: May regulate endosome-to-lysosome trafficking of membrane cargo, including EGFR.
• Tissue Specificity: Widely expressed, with highest expression in heart.
• KEGG Pathway: GABAergic sy.pse (hsa04727)
• Reactome Pathway:
  RHOT1 GTPase cycle (R-HSA-9013425)
  RHOT2 GTPase cycle (R-HSA-9013419)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis type 2, juvenile	DISYFHD8	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Juvenile amyotrophic lateral sclerosis	DISKDZC9	Strong	Biomarker	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Genetic Variation	[3]

13 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 2 (TRAK2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[11]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[12]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[13]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Trafficking kinesin-binding protein 2 (TRAK2).	[14]

References

• [1] Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical region at chromosome 2q33-q34: candidate genes for ALS2.Genomics. 2001 Jan 15;71(2):200-13. doi: 10.1006/geno.2000.6392.
• [2] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [3] Amplification of thymosin beta 10 and AKAP13 genes in metastatic and aggressive papillary thyroid carcinomas.Pathol Oncol Res. 2012 Apr;18(2):449-58. doi: 10.1007/s12253-011-9467-7. Epub 2011 Dec 11.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [10] 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.
• [11] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [12] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.