Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3VCNPE)

DOT Name DENN domain-containing protein 1B (DENND1B)
Synonyms Connecdenn 2; Protein FAM31B
Gene Name DENND1B
Related Disease
Anxiety ( )
Asthma ( )
Crohn disease ( )
Major depressive disorder ( )
Primary biliary cholangitis ( )
Immune system disorder ( )
Ankylosing spondylitis ( )
Inflammatory bowel disease ( )
Psoriasis ( )
Sclerosing cholangitis ( )
Ulcerative colitis ( )
UniProt ID
DEN1B_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
3TW8
Pfam ID
PF03455 ; PF02141 ; PF03456
Sequence
MDCRTKANPDRTFDLVLKVKCHASENEDPVVLWKFPEDFGDQEILQSVPKFCFPFDVERV
SQNQVGQHFTFVLTDIESKQRFGFCRLTSGGTICLCILSYLPWFEVYYKLLNTLADYLAK
ELENDLNETLRSLYNHPVPKANTPVNLSVNQEIFIACEQVLKDQPALVPHSYFIAPDVTG
LPTIPESRNLTEYFVAVDVNNMLQLYASMLHERRIVIISSKLSTLTACIHGSAALLYPMY
WQHIYIPVLPPHLLDYCCAPMPYLIGIHSSLIERVKNKSLEDVVMLNVDTNTLESPFSDL
NNLPSDVVSALKNKLKKQSTATGDGVARAFLRAQAALFGSYRDALRYKPGEPITFCEESF
VKHRSSVMKQFLETAINLQLFKQFIDGRLAKLNAGRGFSDVFEEEITSGGFCGGNPRSYQ
QWVHTVKKGGALFNTAMTKATPAVRTAYKFAKNHAKLGLKEVKSKLKHKENEEDYGTCSS
SVQYTPVYKLHNEKGGNSEKRKLAQARLKRPLKSLDGALYDDEDDDDIERASKLSSEDGE
EASAYLYESDDSVETRVKTPYSGEMDLLGEILDTLSTHSSDQGKLAAAKSLDFFRSMDDI
DYKPTNKSNAPSENNLAFLCGGSGDQAEWNLGQDDSALHGKHLPPSPRKRVSSSGLTDSL
FILKEENSNKHLGADNVSDPTSGLDFQLTSPEVSQTDKGKTEKRETLSQISDDLLIPGLG
RHSSTFVPWEKEGKEAKETSEDIGLLHEVVSLCHMTSDFQQSLNISDKNTNGNQT
Function
Guanine nucleotide exchange factor (GEF) for RAB35 that acts as a regulator of T-cell receptor (TCR) internalization in TH2 cells. Acts by promoting the exchange of GDP to GTP, converting inactive GDP-bound RAB35 into its active GTP-bound form. Plays a role in clathrin-mediated endocytosis. Controls cytokine production in TH2 lymphocytes by controlling the rate of TCR internalization and routing to endosomes: acts by mediating clathrin-mediated endocytosis of TCR via its interaction with the adapter protein complex 2 (AP-2) and GEF activity. Dysregulation leads to impaired TCR down-modulation and recycling, affecting cytokine production in TH2 cells.
Tissue Specificity
Highly expressed in dendritic and natural killer cells and at lower levels in other myeloid lineage cells and in pituitary. Significantly up-regulated in effector memory T-cells as compared with naive T-cells.
Reactome Pathway
RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198 )

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Anxiety DISIJDBA Strong Genetic Variation [1]
Asthma DISW9QNS Strong Biomarker [2]
Crohn disease DIS2C5Q8 Strong Genetic Variation [3]
Major depressive disorder DIS4CL3X Strong Genetic Variation [4]
Primary biliary cholangitis DIS43E0O Strong Genetic Variation [5]
Immune system disorder DISAEGPH moderate Genetic Variation [6]
Ankylosing spondylitis DISRC6IR Limited Genetic Variation [7]
Inflammatory bowel disease DISGN23E Limited Genetic Variation [3]
Psoriasis DIS59VMN Limited Genetic Variation [7]
Sclerosing cholangitis DIS7GZNB Limited Genetic Variation [7]
Ulcerative colitis DIS8K27O Limited Genetic Variation [7]
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⏷ Show the Full List of 11 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the methylation of DENN domain-containing protein 1B (DENND1B). [8]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the methylation of DENN domain-containing protein 1B (DENND1B). [20]
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15 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of DENN domain-containing protein 1B (DENND1B). [9]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of DENN domain-containing protein 1B (DENND1B). [10]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of DENN domain-containing protein 1B (DENND1B). [11]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of DENN domain-containing protein 1B (DENND1B). [12]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of DENN domain-containing protein 1B (DENND1B). [13]
Triclosan DMZUR4N Approved Triclosan increases the expression of DENN domain-containing protein 1B (DENND1B). [14]
Panobinostat DM58WKG Approved Panobinostat decreases the expression of DENN domain-containing protein 1B (DENND1B). [15]
SNDX-275 DMH7W9X Phase 3 SNDX-275 decreases the expression of DENN domain-containing protein 1B (DENND1B). [15]
Tocopherol DMBIJZ6 Phase 2 Tocopherol decreases the expression of DENN domain-containing protein 1B (DENND1B). [16]
APR-246 DMNFADH Phase 2 APR-246 affects the expression of DENN domain-containing protein 1B (DENND1B). [17]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of DENN domain-containing protein 1B (DENND1B). [18]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of DENN domain-containing protein 1B (DENND1B). [19]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of DENN domain-containing protein 1B (DENND1B). [21]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of DENN domain-containing protein 1B (DENND1B). [22]
Coumestrol DM40TBU Investigative Coumestrol decreases the expression of DENN domain-containing protein 1B (DENND1B). [12]
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⏷ Show the Full List of 15 Drug(s)

References

1 Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
2 Polymorphisms in DENND1B gene are associated with asthma and atopy phenotypes in Brazilian children.Mol Immunol. 2017 Oct;90:33-41. doi: 10.1016/j.molimm.2017.06.030. Epub 2017 Jun 29.
3 Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
4 Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
5 International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.Nat Commun. 2015 Sep 22;6:8019. doi: 10.1038/ncomms9019.
6 Regulation of T Cell Receptor Signaling by DENND1B in TH2 Cells and Allergic Disease.Cell. 2016 Jan 14;164(1-2):141-155. doi: 10.1016/j.cell.2015.11.052. Epub 2016 Jan 7.
7 Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
8 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.
9 Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
10 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.
11 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
12 Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
13 Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
14 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
15 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.
16 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.
17 Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
18 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.
19 Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
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 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.