Details of Drug Off-Target (DOT)

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

• DOT Name: Differentially expressed in FDCP 6 homolog (DEF6)
• Synonyms: DEF-6; IRF4-binding protein
• Gene Name: DEF6
• Related Disease:
  Rheumatoid arthritis
  Acute gouty arthritis
  Autoimmune disease
  Clear cell renal carcinoma
  Immunodeficiency
  Immunodeficiency 87 and autoimmunity
  Renal cell carcinoma
  Systemic lupus erythematosus
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Breast cancer
  Breast carcinoma
  Metastatic malignant neoplasm
• UniProt ID: DEFI6_HUMAN
• Pfam ID: PF00169
• Sequence:
  MALRKELLKSIWYAFTALDVEKSGKVSKSQLKVLSHNLYTVLHIPHDPVALEEHFRDDDD
  GPVSSQGYMPYLNKYILDKVEEGAFVKEHFDELCWTLTAKKNYRADSNGNSMLSNQDAFR
  LWCLFNFLSEDKYPLIMVPDEVEYLLKKVLSSMSLEVSLGELEELLAQEAQVAQTTGGLS
  VWQFLELFNSGRCLRGVGRDTLSMAIHEVYQELIQDVLKQGYLWKRGHLRRNWAERWFQL
  QPSCLCYFGSEECKEKRGIIPLDAHCCVEVLPDRDGKRCMFCVKTANRTYEMSASDTRQR
  QEWTAAIQMAIRLQAEGKTSLHKDLKQKRREQREQRERRRAAKEEELLRLQQLQEEKERK
  LQELELLQEAQRQAERLLQEEEERRRSQHRELQQALEGQLREAEQARASMQAEMELKEEE
  AARQRQRIKELEEMQQRLQEALQLEVKARRDEESVRIAQTRLLEEEEEKLKQLMQLKEEQ
  ERYIERAQQEKEELQQEMAQQSRSLQQAQQQLEEVRQNRQRADEDVEAAQRKLRQASTNV
  KHWNVQMNRLMHPIEPGDKRPVTSSSFSGFQPPLLAHRDSSLKRLTRWGSQGNRTPSPNS
  NEQQKSLNGGDEAPAPASTPQEDKLDPAPEN
• Function: Phosphatidylinositol 3,4,5-trisphosphate-dependent guanine nucleotide exchange factor (GEF) which plays a role in the activation of Rho GTPases RAC1, RhoA and CDC42. Can regulate cell morphology in cooperation with activated RAC1. Involved in immune homeostasis by ensuring proper trafficking and availability of T-cell regulator CTLA-4 at T-cell surface. Plays a role in Th2 (T helper cells) development and/or activation, perhaps by interfering with ZAP70 signaling.
• Tissue Specificity: Broadly expressed in the immune system. Highly expressed in T cells .
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[1]
Acute gouty arthritis	DISY5UJH	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[4]
Immunodeficiency	DIS093I0	Strong	Biomarker	[3]
Immunodeficiency 87 and autoimmunity	DISPKQV6	Strong	Autosomal recessive	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[4]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[6]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[7]
Lung cancer	DISCM4YA	moderate	Genetic Variation	[7]
Lung carcinoma	DISTR26C	moderate	Genetic Variation	[7]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[8]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[8]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Differentially expressed in FDCP 6 homolog (DEF6) affects the response to substance of Temozolomide.	[22]
DTI-015	DMXZRW0	Approved	Differentially expressed in FDCP 6 homolog (DEF6) affects the response to substance of DTI-015.	[22]

9 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 Differentially expressed in FDCP 6 homolog (DEF6).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Differentially expressed in FDCP 6 homolog (DEF6).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Differentially expressed in FDCP 6 homolog (DEF6).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Differentially expressed in FDCP 6 homolog (DEF6).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Differentially expressed in FDCP 6 homolog (DEF6).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Differentially expressed in FDCP 6 homolog (DEF6).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Differentially expressed in FDCP 6 homolog (DEF6).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Differentially expressed in FDCP 6 homolog (DEF6).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Differentially expressed in FDCP 6 homolog (DEF6).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Differentially expressed in FDCP 6 homolog (DEF6).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Differentially expressed in FDCP 6 homolog (DEF6).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Differentially expressed in FDCP 6 homolog (DEF6).	[20]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Puromycin	DMDKLB5	Preclinical	Puromycin affects the localization of Differentially expressed in FDCP 6 homolog (DEF6).	[19]

References

• [1] Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption.J Immunol. 2017 May 1;198(9):3436-3447. doi: 10.4049/jimmunol.1601716. Epub 2017 Mar 17.
• [2] Factors associated with the decision of the rheumatologist to order sacroiliac joints magnetic resonance imaging (SI-MRI) or HLA-B27 testing in the diagnostic work-up of patients with spondyloarthritis in clinical practice.Clin Exp Rheumatol. 2017 Jan-Feb;35(1):122-128. Epub 2016 Oct 26.
• [3] Publisher Correction: Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis.Nat Commun. 2019 Oct 2;10(1):4555. doi: 10.1038/s41467-019-12454-5.
• [4] Identification of novel targets for antiangiogenic therapy by comparing the gene expressions of tumor and normal endothelial cells.Cancer Sci. 2014 May;105(5):560-7. doi: 10.1111/cas.12394. Epub 2014 Apr 19.
• [5] Loss of IRF-4-binding protein leads to the spontaneous development of systemic autoimmunity. J Clin Invest. 2006 Mar;116(3):703-14. doi: 10.1172/JCI24096. Epub 2006 Feb 9.
• [6] Regulation of age-associated B cells by IRF5 in systemic autoimmunity.Nat Immunol. 2018 Apr;19(4):407-419. doi: 10.1038/s41590-018-0056-8. Epub 2018 Feb 26.
• [7] META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies.PLoS One. 2015 Oct 26;10(10):e0140179. doi: 10.1371/journal.pone.0140179. eCollection 2015.
• [8] IBP regulates epithelial-to-mesenchymal transition and the motility of breast cancer cells via Rac1, RhoA and Cdc42 signaling pathways.Oncogene. 2014 Jun 26;33(26):3374-82. doi: 10.1038/onc.2013.337. Epub 2013 Aug 26.
• [9] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [16] 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.
• [17] 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.
• [18] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [19] DEF6, a novel substrate for the Tec kinase ITK, contains a glutamine-rich aggregation-prone region and forms cytoplasmic granules that co-localize with P-bodies. J Biol Chem. 2012 Sep 7;287(37):31073-84. doi: 10.1074/jbc.M112.346767. Epub 2012 Jul 24.
• [20] 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.
• [21] 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.
• [22] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.