Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2XWUPN)

• DOT Name: Docking protein 5 (DOK5)
• Synonyms: Downstream of tyrosine kinase 5; Insulin receptor substrate 6; IRS-6; IRS6
• Gene Name: DOK5
• Related Disease:
  Bipolar disorder
  Non-insulin dependent diabetes
  Obesity
  Systemic sclerosis
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Glaucoma/ocular hypertension
• UniProt ID: DOK5_HUMAN
• PDB ID: 1J0W
• Pfam ID: PF02174
• Sequence:
  MASNFNDIVKQGYVRIRSRRLGIYQRCWLVFKKASSKGPKRLEKFSDERAAYFRCYHKVT
  ELNNVKNVARLPKSTKKHAIGIYFNDDTSKTFACESDLEADEWCKVLQMECVGTRINDIS
  LGEPDLLATGVEREQSERFNVYLMPSPNLDVHGECALQITYEYICLWDVQNPRVKLISWP
  LSALRRYGRDTTWFTFEAGRMCETGEGLFIFQTRDGEAIYQKVHSAALAIAEQHERLLQS
  VKNSMLQMKMSERAASLSTMVPLPRSAYWQHITRQHSTGQLYRLQDVSSPLKLHRTETFP
  AYRSEH
• Function: DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK5 functions in RET-mediated neurite outgrowth and plays a positive role in activation of the MAP kinase pathway. Putative link with downstream effectors of RET in neuronal differentiation.
• Tissue Specificity: Highest expression in skeletal muscle, lower in brain, heart and kidney. Also detected in activated peripheral blood T-lymphocytes.
• Reactome Pathway: RET signaling (R-HSA-8853659)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[2]
Obesity	DIS47Y1K	Strong	Biomarker	[3]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[5]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[6]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Docking protein 5 (DOK5).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Docking protein 5 (DOK5).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Docking protein 5 (DOK5).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Docking protein 5 (DOK5).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Docking protein 5 (DOK5).	[11]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of Docking protein 5 (DOK5).	[12]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Docking protein 5 (DOK5).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Docking protein 5 (DOK5).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Docking protein 5 (DOK5).	[16]

References

• [1] A genome-wide association study of amygdala activation in youths with and without bipolar disorder.J Am Acad Child Adolesc Psychiatry. 2010 Jan;49(1):33-41. doi: 10.1097/00004583-201001000-00007.
• [2] Shared and unique components of human population structure and genome-wide signals of positive selection in South Asia.Am J Hum Genet. 2011 Dec 9;89(6):731-44. doi: 10.1016/j.ajhg.2011.11.010.
• [3] Evaluation of DOK5 as a susceptibility gene for type 2 diabetes and obesity in North Indian population.BMC Med Genet. 2010 Feb 27;11:35. doi: 10.1186/1471-2350-11-35.
• [4] The membrane-associated adaptor protein DOK5 is upregulated in systemic sclerosis and associated with IGFBP-5-induced fibrosis.PLoS One. 2014 Feb 13;9(2):e87754. doi: 10.1371/journal.pone.0087754. eCollection 2014.
• [5] 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.
• [6] Thyronamine regulation of TAAR1 expression in breast cancer cells and investigation of its influence on viability and migration.Breast Cancer (Dove Med Press). 2019 Feb 19;11:87-97. doi: 10.2147/BCTT.S178721. eCollection 2019.
• [7] MicroRNA-141-3p inhibits retinal neovascularization and retinal ganglion cell apoptosis in glaucoma mice through the inactivation of Docking protein 5-dependent mitogen-activated protein kinase signaling pathway.J Cell Physiol. 2019 Jun;234(6):8873-8887. doi: 10.1002/jcp.27549. Epub 2018 Dec 4.
• [8] 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.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [12] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [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] 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.
• [16] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.