Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7UH61B)

• DOT Name: DENN domain-containing protein 2B (DENND2B)
• Synonyms: HeLa tumor suppression 1; Suppression of tumorigenicity 5 protein
• Gene Name: DENND2B
• Related Disease:
  Hypospadias
  Malaria
  Neoplasm
• UniProt ID: DEN2B_HUMAN
• Pfam ID: PF03455 ; PF02141 ; PF03456
• Sequence:
  MTMTANKNSSITHGAGGTKAPRGTLSRSQSVSPPPVLSPPRSPIYPLSDSETSACRYPSH
  SSSRVLLKDRHPPAPSPQNPQDPSPDTSPPTCPFKTASFGYLDRSPSACKRDAQKESVQG
  AAQDVAGVAACLPLAQSTPFPGPAAGPRGVLLTRTGTRAHSLGIREKISAWEGRREASPR
  MSMCGEKREGSGSEWAASEGCPSLGCPSVVPSPCSSEKTFDFKGLRRMSRTFSECSYPET
  EEEGEALPVRDSFYRLEKRLGRSEPSAFLRGHGSRKESSAVLSRIQKIEQVLKEQPGRGL
  PQLPSSCYSVDRGKRKTGTLGSLEEPAGGASVSAGSRAVGVAGVAGEAGPPPEREGSGST
  KPGTPGNSPSSQRLPSKSSLDPAVNPVPKPKRTFEYEADKNPKSKPSNGLPPSPTPAAPP
  PLPSTPAPPVTRRPKKDMRGHRKSQSRKSFEFEDASSLQSLYPSSPTENGTENQPKFGSK
  STLEENAYEDIVGDLPKENPYEDVDLKSRRAGRKSQQLSENSLDSLHRMWSPQDRKYNSP
  PTQLSLKPNSQSLRSGNWSERKSHRLPRLPKRHSHDDMLLLAQLSLPSSPSSLNEDSLST
  TSELLSSRRARRIPKLVQRINSIYNAKRGKKRLKKLSMSSIETASLRDENSESESDSDDR
  FKAHTQRLVHIQSMLKRAPSYRTLELELLEWQERELFEYFVVVSLKKKPSRNTYLPEVSY
  QFPKLDRPTKQMREAEERLKAIPQFCFPDAKDWLPVSEYSSETFSFMLTGEDGSRRFGYC
  RRLLPSGKGPRLPEVYCVISRLGCFGLFSKVLDEVERRRGISAALVYPFMRSLMESPFPA
  PGKTIKVKTFLPGAGNEVLELRRPMDSRLEHVDFECLFTCLSVRQLIRIFASLLLERRVI
  FVADKLSTLSSCSHAVVALLYPFSWQHTFIPVLPASMIDIVCCPTPFLVGLLSSSLPKLK
  ELPVEEALMVNLGSDRFIRQMDDEDTLLPRKLQAALEQALERKNELISQDSDSDSDDECN
  TLNGLVSEVFIRFFVETVGHYSLFLTQSEKGERAFQREAFRKSVASKSIRRFLEVFMESQ
  MFAGFIQDRELRKCRAKGLFEQRVEQYLEELPDTEQSGMNKFLRGLGNKMKFLHKKN
• Function: [Isoform 1]: May be involved in cytoskeletal organization and tumorogenicity. Seems to be involved in a signaling transduction pathway leading to activation of MAPK1/ERK2. Plays a role in EGFR trafficking from recycling endosomes back to the cell membrane ; [Isoform 2]: Guanine nucleotide exchange factor (GEF) which may activate RAB9A and RAB9B. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form; [Isoform 3]: May block ERK2 activation stimulated by ABL1 (Probable). May alter cell morphology and cell growth (Probable).
• Tissue Specificity: Widely expressed with the exception of peripheral blood lymphocytes. Isoform 1 is expressed in several epithelial and fibroblast (including tumorigenic) but absent in lymphoid cell lines (at protein level). Isoform 3 is expressed in primary cell or weakly tumorigenic but not in tumorigenic cell lines (at protein level).
• Reactome Pathway: RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypospadias	DIS48CCP	Strong	Genetic Variation	[1]
Malaria	DISQ9Y50	Limited	Biomarker	[2]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[3]

11 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 2B (DENND2B).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DENN domain-containing protein 2B (DENND2B).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DENN domain-containing protein 2B (DENND2B).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DENN domain-containing protein 2B (DENND2B).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DENN domain-containing protein 2B (DENND2B).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of DENN domain-containing protein 2B (DENND2B).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of DENN domain-containing protein 2B (DENND2B).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of DENN domain-containing protein 2B (DENND2B).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of DENN domain-containing protein 2B (DENND2B).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DENN domain-containing protein 2B (DENND2B).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of DENN domain-containing protein 2B (DENND2B).	[16]

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 2B (DENND2B).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DENN domain-containing protein 2B (DENND2B).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DENN domain-containing protein 2B (DENND2B).	[15]

References

• [1] Genome-wide association analyses identify variants in developmental genes associated with hypospadias.Nat Genet. 2014 Sep;46(9):957-63. doi: 10.1038/ng.3063. Epub 2014 Aug 10.
• [2] Malaria diagnosis: standardization of a polymerase chain reaction for the detection of Plasmodium falciparum parasites in individuals with low-grade parasitemia.Parasitol Res. 1996;82(7):612-6. doi: 10.1007/s004360050173.
• [3] Identification of a human chromosome 11 gene which is differentially regulated in tumorigenic and nontumorigenic somatic cell hybrids of HeLa cells.Cell Growth Differ. 1992 Aug;3(8):541-8.
• [4] 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.
• [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] 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.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] 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.
• [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] 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.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.