Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT842U3C)

• DOT Name: Docking protein 3 (DOK3)
• Synonyms: Downstream of tyrosine kinase 3
• Gene Name: DOK3
• Related Disease:
  Lung neoplasm
  Adult respiratory distress syndrome
  Candidemia
  Colorectal carcinoma
  Lung cancer
  Coronary heart disease
• UniProt ID: DOK3_HUMAN
• Pfam ID: PF02174
• Sequence:
  MTRGARLRSDARAQLNQLSLDGGTGSGQKGKCEEFPSSLSSVSPGLEAAALLLAVTMDPL
  ETPIKDGILYQQHVKFGKKCWRKVWALLYAGGPSGVARLESWEVRDGGLGAAGDRSAGPG
  RRGERRVIRLADCVSVLPADGESCPRDTGAFLLTTTERSHLLAAQHRQAWMGPICQLAFP
  GTGEASSGSTDAQSPKRGLVPMEENSIYSSWQEVGEFPVVVQRTEAATRCQLKGPALLVL
  GPDAIQLREAKGTQALYSWPYHFLRKFGSDKGVFSFEAGRRCHSGEGLFAFSTPCAPDLC
  RAVAGAIARQRERLPELTRPQPCPLPRATSLPSLDTPGELREMPPGPEPPTSRKMHLAEP
  GPQSLPLLLGPEPNDLASGLYASVCKRASGPPGNEHLYENLCVLEASPTLHGGEPEPHEG
  PGSRSPTTSPIYHNGQDLSWPGPANDSTLEAQYRRLLELDQVEGTGRPDPQAGFKAKLVT
  LLSRERRKGPAPCDRP
• Function: DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK3 is a negative regulator of JNK signaling in B-cells through interaction with INPP5D/SHIP1. May modulate ABL1 function.
• Tissue Specificity: Expressed in spleen.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung neoplasm	DISVARNB	Definitive	Biomarker	[1]
Adult respiratory distress syndrome	DISIJV47	Strong	Altered Expression	[2]
Candidemia	DISVKFN7	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[5]

7 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 Docking protein 3 (DOK3).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Docking protein 3 (DOK3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Docking protein 3 (DOK3).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Docking protein 3 (DOK3).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Docking protein 3 (DOK3).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Docking protein 3 (DOK3).	[11]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Docking protein 3 (DOK3).	[12]

References

• [1] Identification of DOK genes as lung tumor suppressors.Nat Genet. 2010 Mar;42(3):216-23. doi: 10.1038/ng.527. Epub 2010 Feb 7.
• [2] DOK3 Degradation is Required for the Development of LPS-induced ARDS in Mice.Curr Gene Ther. 2016;16(4):256-262. doi: 10.2174/1566523216666161103142342.
• [3] Dok3-protein phosphatase 1 interaction attenuates Card9 signaling and neutrophil-dependent antifungal immunity.J Clin Invest. 2019 Jun 10;129(7):2717-2729. doi: 10.1172/JCI126341. eCollection 2019 Jun 10.
• [4] Impact of Genetic Variation in MicroRNA-binding Site on Susceptibility to Colorectal Cancer.Anticancer Res. 2016 Jul;36(7):3353-61.
• [5] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] 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.
• [11] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [12] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.