Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUEWLG8)

DOT Name Docking protein 4 (DOK4)
Synonyms Downstream of tyrosine kinase 4; Insulin receptor substrate 5; IRS-5; IRS5
Gene Name DOK4
Related Disease
Lung cancer ( )
Lung carcinoma ( )
Lung neoplasm ( )
Non-small-cell lung cancer ( )
Clear cell renal carcinoma ( )
Ductal breast carcinoma in situ ( )
UniProt ID
DOK4_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF02174 ; PF00169
Sequence
MATNFSDIVKQGYVKMKSRKLGIYRRCWLVFRKSSSKGPQRLEKYPDEKSVCLRGCPKVT
EISNVKCVTRLPKETKRQAVAIIFTDDSARTFTCDSELEAEEWYKTLSVECLGSRLNDIS
LGEPDLLAPGVQCEQTDRFNVFLLPCPNLDVYGECKLQITHENIYLWDIHNPRVKLVSWP
LCSLRRYGRDATRFTFEAGRMCDAGEGLYTFQTQEGEQIYQRVHSATLAIAEQHKRVLLE
MEKNVRLLNKGTEHYSYPCTPTTMLPRSAYWHHITGSQNIAEASSYAGEGYGAAQASSET
DLLNRFILLKPKPSQGDSSEAKTPSQ
Function
DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK4 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. May be involved in the regulation of the immune response induced by T-cells.
Tissue Specificity
Widely expressed. High expression in skeletal muscle, heart, kidney and liver. Weaker expression in spleen, lung and small intestine, brain, heart and. Expressed in both resting and activated peripheral blood T-cells.
Reactome Pathway
RET signaling (R-HSA-8853659 )

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 cancer DISCM4YA Definitive Altered Expression [1]
Lung carcinoma DISTR26C Definitive Altered Expression [1]
Lung neoplasm DISVARNB Definitive Posttranslational Modification [1]
Non-small-cell lung cancer DIS5Y6R9 Definitive Biomarker [1]
Clear cell renal carcinoma DISBXRFJ Strong Altered Expression [2]
Ductal breast carcinoma in situ DISLCJY7 Limited Altered Expression [3]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
15 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 4 (DOK4). [4]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Docking protein 4 (DOK4). [5]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Docking protein 4 (DOK4). [6]
Temozolomide DMKECZD Approved Temozolomide increases the expression of Docking protein 4 (DOK4). [7]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of Docking protein 4 (DOK4). [8]
Testosterone DM7HUNW Approved Testosterone increases the expression of Docking protein 4 (DOK4). [8]
Decitabine DMQL8XJ Approved Decitabine increases the expression of Docking protein 4 (DOK4). [9]
Diethylstilbestrol DMN3UXQ Approved Diethylstilbestrol increases the expression of Docking protein 4 (DOK4). [10]
Cytarabine DMZD5QR Approved Cytarabine decreases the expression of Docking protein 4 (DOK4). [11]
Resveratrol DM3RWXL Phase 3 Resveratrol increases the expression of Docking protein 4 (DOK4). [10]
Genistein DM0JETC Phase 2/3 Genistein increases the expression of Docking protein 4 (DOK4). [10]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Docking protein 4 (DOK4). [13]
Formaldehyde DM7Q6M0 Investigative Formaldehyde increases the expression of Docking protein 4 (DOK4). [15]
Milchsaure DM462BT Investigative Milchsaure increases the expression of Docking protein 4 (DOK4). [16]
KOJIC ACID DMP84CS Investigative KOJIC ACID decreases the expression of Docking protein 4 (DOK4). [17]
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⏷ Show the Full List of 15 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene affects the methylation of Docking protein 4 (DOK4). [12]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 increases the phosphorylation of Docking protein 4 (DOK4). [14]
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References

1 Transcriptional regulation of IRS5/DOK4 expression in non-small-cell lung cancer cells.Clin Lung Cancer. 2008 Nov;9(6):367-74. doi: 10.3816/CLC.2008.n.053.
2 DOK4/IRS-5 expression is altered in clear cell renal cell carcinoma.Int J Cancer. 2007 Sep 1;121(5):992-8. doi: 10.1002/ijc.22776.
3 Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer.Breast Cancer Res. 2011 Mar 4;13(2):R24. doi: 10.1186/bcr2839.
4 Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
5 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
6 Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
7 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.
8 Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
9 Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
10 Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
11 Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
12 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.
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 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.
15 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
16 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
17 Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.