Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTONDAA0)

DOT Name DENN domain-containing protein 1A (DENND1A)
Synonyms Connecdenn 1; Connecdenn; Protein FAM31A
Gene Name DENND1A
Related Disease
Anxiety ( )
Endometrial carcinoma ( )
Major depressive disorder ( )
Obesity ( )
Rheumatoid arthritis ( )
Gastric cancer ( )
Stomach cancer ( )
UniProt ID
DEN1A_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
6EKK
Pfam ID
PF03455 ; PF02141 ; PF03456
Sequence
MGSRIKQNPETTFEVYVEVAYPRTGGTLSDPEVQRQFPEDYSDQEVLQTLTKFCFPFYVD
SLTVSQVGQNFTFVLTDIDSKQRFGFCRLSSGAKSCFCILSYLPWFEVFYKLLNILADYT
TKRQENQWNELLETLHKLPIPDPGVSVHLSVHSYFTVPDTRELPSIPENRNLTEYFVAVD
VNNMLHLYASMLYERRILIICSKLSTLTACIHGSAAMLYPMYWQHVYIPVLPPHLLDYCC
APMPYLIGIHLSLMEKVRNMALDDVVILNVDTNTLETPFDDLQSLPNDVISSLKNRLKKV
STTTGDGVARAFLKAQAAFFGSYRNALKIEPEEPITFCEEAFVSHYRSGAMRQFLQNATQ
LQLFKQFIDGRLDLLNSGEGFSDVFEEEINMGEYAGSDKLYHQWLSTVRKGSGAILNTVK
TKANPAMKTVYKFAKDHAKMGIKEVKNRLKQKDIAENGCAPTPEEQLPKTAPSPLVEAKD
PKLREDRRPITVHFGQVRPPRPHVVKRPKSNIAVEGRRTSVPSPEQPQPYRTLRESDSAE
GDEAESPEQQVRKSTGPVPAPPDRAASIDLLEDVFSNLDMEAALQPLGQAKSLEDLRAPK
DLREQPGTFDYQRLDLGGSERSRGVTVALKLTHPYNKLWSLGQDDMAIPSKPPAASPEKP
SALLGNSLALPRRPQNRDSILNPSDKEEVPTPTLGSITIPRPQGRKTPELGIVPPPPIPR
PAKLQAAGAALGDVSERLQTDRDRRAALSPGLLPGVVPQGPTELLQPLSPGPGAAGTSSD
ALLALLDPLSTAWSGSTLPSRPATPNVATPFTPQFSFPPAGTPTPFPQPPLNPFVPSMPA
APPTLPLVSTPAGPFGAPPASLGPAFASGLLLSSAGFCAPHRSQPNLSALSMPNLFGQMP
MGTHTSPLQPLGPPAVAPSRIRTLPLARSSARAAETKQGLALRPGDPPLLPPRPPQGLEP
TLQPSAPQQARDPFEDLLQKTKQDVSPSPALAPAPDSVEQLRKQWETFE
Function
Guanine nucleotide exchange factor (GEF) regulating clathrin-mediated endocytosis through RAB35 activation. Promotes the exchange of GDP to GTP, converting inactive GDP-bound RAB35 into its active GTP-bound form. Regulates clathrin-mediated endocytosis of synaptic vesicles and mediates exit from early endosomes. Binds phosphatidylinositol-phosphates (PtdInsPs), with some preference for PtdIns(3)P.
Reactome Pathway
RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198 )

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Anxiety DISIJDBA Strong Genetic Variation [1]
Endometrial carcinoma DISXR5CY Strong Genetic Variation [2]
Major depressive disorder DIS4CL3X Strong Genetic Variation [3]
Obesity DIS47Y1K Strong Genetic Variation [4]
Rheumatoid arthritis DISTSB4J Strong Genetic Variation [5]
Gastric cancer DISXGOUK Limited Altered Expression [6]
Stomach cancer DISKIJSX Limited Altered Expression [6]
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⏷ Show the Full List of 7 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
16 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the expression of DENN domain-containing protein 1A (DENND1A). [7]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of DENN domain-containing protein 1A (DENND1A). [8]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of DENN domain-containing protein 1A (DENND1A). [9]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of DENN domain-containing protein 1A (DENND1A). [10]
Quercetin DM3NC4M Approved Quercetin decreases the expression of DENN domain-containing protein 1A (DENND1A). [12]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of DENN domain-containing protein 1A (DENND1A). [13]
Panobinostat DM58WKG Approved Panobinostat decreases the expression of DENN domain-containing protein 1A (DENND1A). [13]
Cytarabine DMZD5QR Approved Cytarabine increases the expression of DENN domain-containing protein 1A (DENND1A). [14]
SNDX-275 DMH7W9X Phase 3 SNDX-275 decreases the expression of DENN domain-containing protein 1A (DENND1A). [13]
Belinostat DM6OC53 Phase 2 Belinostat decreases the expression of DENN domain-containing protein 1A (DENND1A). [13]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of DENN domain-containing protein 1A (DENND1A). [15]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of DENN domain-containing protein 1A (DENND1A). [16]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of DENN domain-containing protein 1A (DENND1A). [17]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of DENN domain-containing protein 1A (DENND1A). [20]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of DENN domain-containing protein 1A (DENND1A). [21]
Coumestrol DM40TBU Investigative Coumestrol increases the expression of DENN domain-containing protein 1A (DENND1A). [22]
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⏷ Show the Full List of 16 Drug(s)
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 DENN domain-containing protein 1A (DENND1A). [11]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of DENN domain-containing protein 1A (DENND1A). [18]
Bisphenol A DM2ZLD7 Investigative Bisphenol A affects the methylation of DENN domain-containing protein 1A (DENND1A). [19]
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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 Variants in DENND1A and LHCGR are associated with endometrioid adenocarcinoma.Gynecol Oncol. 2012 Nov;127(2):403-5. doi: 10.1016/j.ygyno.2012.08.007. Epub 2012 Aug 14.
3 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.
4 The role of DENND1A and CYP19A1 gene variants in individual susceptibility to obesity in Turkish population-a preliminary study.Mol Biol Rep. 2018 Dec;45(6):2193-2199. doi: 10.1007/s11033-018-4380-8. Epub 2018 Sep 19.
5 Studying the effects of haplotype partitioning methods on the RA-associated genomic results from the North American Rheumatoid Arthritis Consortium (NARAC) dataset.J Adv Res. 2019 Jan 18;18:113-126. doi: 10.1016/j.jare.2019.01.006. eCollection 2019 Jul.
6 EGF Stimulates Rab35 Activation and Gastric Cancer Cell Migration by Regulating DENND1A-Grb2 Complex Formation.Front Pharmacol. 2018 Nov 22;9:1343. doi: 10.3389/fphar.2018.01343. eCollection 2018.
7 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
8 Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
9 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.
10 The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
11 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.
12 Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
13 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.
14 The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
15 Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
16 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
17 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.
18 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.
19 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.
20 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.
21 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
22 Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.