Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGVRLW6)

• DOT Name: Docking protein 1 (DOK1)
• Synonyms: Downstream of tyrosine kinase 1; p62(dok); pp62
• Gene Name: DOK1
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Breast cancer
  Burkitt lymphoma
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal carcinoma
  Endometriosis
  Head and neck cancer
  Head and neck carcinoma
  Hepatocellular carcinoma
  Leukemia
  Lung cancer
  Lung neoplasm
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Small lymphocytic lymphoma
  Triple negative breast cancer
  Epithelial ovarian cancer
  leukaemia
  Epstein barr virus infection
  Gastric cancer
  Ocular infection
  Stomach cancer
• UniProt ID: DOK1_HUMAN
• PDB ID: 2V76
• Pfam ID: PF02174 ; PF00169
• Sequence:
  MDGAVMEGPLFLQSQRFGTKRWRKTWAVLYPASPHGVARLEFFDHKGSSSGGGRGSSRRL
  DCKVIRLAECVSVAPVTVETPPEPGATAFRLDTAQRSHLLAADAPSSAAWVQTLCRNAFP
  KGSWTLAPTDNPPKLSALEMLENSLYSPTWEGSQFWVTVQRTEAAERCGLHGSYVLRVEA
  ERLTLLTVGAQSQILEPLLSWPYTLLRRYGRDKVMFSFEAGRRCPSGPGTFTFQTAQGND
  IFQAVETAIHRQKAQGKAGQGHDVLRADSHEGEVAEGKLPSPPGPQELLDSPPALYAEPL
  DSLRIAPCPSQDSLYSDPLDSTSAQAGEGVQRKKPLYWDLYEHAQQQLLKAKLTDPKEDP
  IYDEPEGLAPVPPQGLYDLPREPKDAWWCQARVKEEGYELPYNPATDDYAVPPPRSTKPL
  LAPKPQGPAFPEPGTATGSGIKSHNSALYSQVQKSGASGSWDCGLSRVGTDKTGVKSEGS
  T
• Function: DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK1 appears to be a negative regulator of the insulin signaling pathway. Modulates integrin activation by competing with talin for the same binding site on ITGB3.
• Tissue Specificity: Expressed in pancreas, heart, leukocyte and spleen. Expressed in both resting and activated peripheral blood T-cells. Expressed in breast cancer.
• Reactome Pathway:
  RET signaling (R-HSA-8853659)
  PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 (R-HSA-8849469)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Burkitt lymphoma	DIS9D5XU	Strong	Posttranslational Modification	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Endometriosis	DISX1AG8	Strong	Altered Expression	[7]
Head and neck cancer	DISBPSQZ	Strong	Posttranslational Modification	[4]
Head and neck carcinoma	DISOU1DS	Strong	Posttranslational Modification	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Posttranslational Modification	[8]
Leukemia	DISNAKFL	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung neoplasm	DISVARNB	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Therapeutic	[11]
Ovarian neoplasm	DISEAFTY	Strong	Therapeutic	[11]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[12]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[13]
Epithelial ovarian cancer	DIS56MH2	moderate	Biomarker	[11]
leukaemia	DISS7D1V	moderate	Altered Expression	[1]
Epstein barr virus infection	DISOO0WT	Limited	Altered Expression	[14]
Gastric cancer	DISXGOUK	Limited	Biomarker	[10]
Ocular infection	DISTTJES	Limited	Biomarker	[15]
Stomach cancer	DISKIJSX	Limited	Biomarker	[10]

5 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 1 (DOK1).	[16]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the phosphorylation of Docking protein 1 (DOK1).	[21]
Imatinib	DM7RJXL	Approved	Imatinib decreases the phosphorylation of Docking protein 1 (DOK1).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Docking protein 1 (DOK1).	[25]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Docking protein 1 (DOK1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Docking protein 1 (DOK1).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Docking protein 1 (DOK1).	[18]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Docking protein 1 (DOK1).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Docking protein 1 (DOK1).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Docking protein 1 (DOK1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Docking protein 1 (DOK1).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Docking protein 1 (DOK1).	[24]

References

• [1] 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.
• [2] Prognostic role of DOK family adapters in acute myeloid leukemia.Cancer Gene Ther. 2019 Sep;26(9-10):305-312. doi: 10.1038/s41417-018-0052-z. Epub 2018 Oct 22.
• [3] The unique N-terminal region of SRMS regulates enzymatic activity and phosphorylation of its novel substrate docking protein 1.FEBS J. 2013 Sep;280(18):4539-59. doi: 10.1111/febs.12420. Epub 2013 Aug 19.
• [4] Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers.Int J Cancer. 2012 Jun 1;130(11):2484-94. doi: 10.1002/ijc.26299. Epub 2011 Sep 22.
• [5] Decreased tumorigenicity of a human colon adenocarcinoma cell line by an antisense expression vector specific for c-Src.Cell Growth Differ. 1997 Mar;8(3):269-74.
• [6] Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer.EBioMedicine. 2016 Jun;8:159-172. doi: 10.1016/j.ebiom.2016.05.003. Epub 2016 May 5.
• [7] Expression of Ah receptor and dioxin-related genes in human uterine endometrium in women with or without endometriosis.Endocr J. 1999 Dec;46(6):765-72. doi: 10.1507/endocrj.46.765.
• [8] RASSF1A and DOK1 Promoter Methylation Levels in Hepatocellular Carcinoma, Cirrhotic and Non-Cirrhotic Liver, and Correlation with Liver Cancer in Brazilian Patients.PLoS One. 2016 Apr 14;11(4):e0153796. doi: 10.1371/journal.pone.0153796. eCollection 2016.
• [9] 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.
• [10] Docking protein-1 promotes inflammatory macrophage signaling in gastric cancer.Oncoimmunology. 2019 Aug 21;8(11):e1649961. doi: 10.1080/2162402X.2019.1649961. eCollection 2019.
• [11] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [12] Germline mutations in Dok1 do not predispose to chronic lymphocytic leukemia.Leuk Res. 2005 Jan;29(1):59-61. doi: 10.1016/j.leukres.2004.05.022.
• [13] EgoNet: identification of human disease ego-network modules.BMC Genomics. 2014 Apr 28;15:314. doi: 10.1186/1471-2164-15-314.
• [14] Epstein-Barr virus down-regulates tumor suppressor DOK1 expression.PLoS Pathog. 2014 May 8;10(5):e1004125. doi: 10.1371/journal.ppat.1004125. eCollection 2014 May.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] 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.
• [20] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [21] Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway. Cancer Res. 2009 May 1;69(9):3927-36. doi: 10.1158/0008-5472.CAN-08-2978. Epub 2009 Apr 14.
• [22] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [23] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [24] 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.
• [25] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.