Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIJ38UF)

• DOT Name: Docking protein 2 (DOK2)
• Synonyms: Downstream of tyrosine kinase 2; p56(dok-2)
• Gene Name: DOK2
• Related Disease:
  Lung cancer
  Lung neoplasm
  Acute myelogenous leukaemia
  Adenocarcinoma
  Anaplastic large cell lymphoma
  Breast cancer
  Breast carcinoma
  Gastric adenocarcinoma
  leukaemia
  Leukemia
  Lung carcinoma
  Matthew-Wood syndrome
  Neoplasm
  Primary cutaneous peripheral T-cell lymphoma not otherwise specified
  Gastric cancer
  Stomach cancer
  Astrocytoma
  Epithelial ovarian cancer
  Lung adenocarcinoma
  Ocular infection
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: DOK2_HUMAN
• PDB ID: 2D9W; 2DLW
• Pfam ID: PF02174
• Sequence:
  MGDGAVKQGFLYLQQQQTFGKKWRRFGASLYGGSDCALARLELQEGPEKPRRCEAARKVI
  RLSDCLRVAEAGGEASSPRDTSAFFLETKERLYLLAAPAAERGDWVQAICLLAFPGQRKE
  LSGPEGKQSRPCMEENELYSSAVTVGPHKEFAVTMRPTEASERCHLRGSYTLRAGESALE
  LWGGPEPGTQLYDWPYRFLRRFGRDKVTFSFEAGRRCVSGEGNFEFETRQGNEIFLALEE
  AISAQKNAAPATPQPQPATIPASLPRPDSPYSRPHDSLPPPSPTTPVPAPRPRGQEGEYA
  VPFDAVARSLGKNFRGILAVPPQLLADPLYDSIEETLPPRPDHIYDEPEGVAALSLYDSP
  QEPRGEAWRRQATADRDPAGLQHVQPAGQDFSASGWQPGTEYDNVVLKKGPK
• Function: DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK2 may modulate the cellular proliferation induced by IL-4, as well as IL-2 and IL-3. May be involved in modulating Bcr-Abl signaling. Attenuates EGF-stimulated MAP kinase activation.
• Tissue Specificity: Highly expressed in peripheral blood leukocytes, lymph nodes and spleen. Lower expression in thymus, bone marrow and fetal liver.
• Reactome Pathway:
  RET signaling (R-HSA-8853659)
  Tie2 Signaling (R-HSA-210993)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung neoplasm	DISVARNB	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[5]
leukaemia	DISS7D1V	Strong	Altered Expression	[6]
Leukemia	DISNAKFL	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[1]
Matthew-Wood syndrome	DISA7HR7	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[8]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[8]
Astrocytoma	DISL3V18	Limited	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[9]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[10]
Ocular infection	DISTTJES	Limited	Biomarker	[11]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Docking protein 2 (DOK2).	[12]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Docking protein 2 (DOK2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Docking protein 2 (DOK2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Docking protein 2 (DOK2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Docking protein 2 (DOK2).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Docking protein 2 (DOK2).	[14]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Docking protein 2 (DOK2).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Docking protein 2 (DOK2).	[17]

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] Methylation-associated DOK1 and DOK2 down-regulation: Potential biomarkers for predicting adverse prognosis in acute myeloid leukemia.J Cell Physiol. 2018 Sep;233(9):6604-6614. doi: 10.1002/jcp.26271. Epub 2018 Mar 14.
• [3] Co-expression and significance of Dok2 and Ras p21 protein activator 1 in breast cancer.Oncol Lett. 2017 Nov;14(5):5386-5392. doi: 10.3892/ol.2017.6844. Epub 2017 Aug 28.
• [4] Intracellular TCR-signaling pathway: novel markers for lymphoma diagnosis and potential therapeutic targets.Am J Surg Pathol. 2014 Oct;38(10):1349-59. doi: 10.1097/PAS.0000000000000309.
• [5] DOK2 as a marker of poor prognosis of patients with gastric adenocarcinoma after curative resection.Ann Surg Oncol. 2012 May;19(5):1560-7. doi: 10.1245/s10434-011-2157-6. Epub 2011 Dec 1.
• [6] All-trans retinoic acid induces p62DOK1 and p56DOK2 expression which enhances induced differentiation and G0 arrest of HL-60 leukemia cells.Am J Hematol. 2006 Aug;81(8):603-15. doi: 10.1002/ajh.20667.
• [7] Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations.Nat Commun. 2018 Sep 11;9(1):3688. doi: 10.1038/s41467-018-06136-x.
• [8] Region-Specific Dok2 Overexpression Associates with Poor Prognosis in Human Astrocytoma.Mol Neurobiol. 2018 Jan;55(1):402-408. doi: 10.1007/s12035-016-0324-2. Epub 2016 Dec 14.
• [9] Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis.Gynecol Oncol. 2013 Aug;130(2):369-76. doi: 10.1016/j.ygyno.2013.05.002. Epub 2013 May 14.
• [10] Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis.J Clin Invest. 2019 Jan 2;129(1):215-222. doi: 10.1172/JCI99699. Epub 2018 Nov 26.
• [11] Dok-1 and Dok-2 Are Required To Maintain Herpes Simplex Virus 1-Specific CD8(+) T Cells in a Murine Model of Ocular Infection.J Virol. 2017 Jul 12;91(15):e02297-16. doi: 10.1128/JVI.02297-16. Print 2017 Aug 1.
• [12] 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.
• [13] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [14] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] 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.
• [17] 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.