Details of Drug Off-Target (DOT)

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

• DOT Name: DENN domain-containing protein 2D (DENND2D)
• Gene Name: DENND2D
• Related Disease:
  Chronic obstructive pulmonary disease
  Esophageal squamous cell carcinoma
  Gastric cancer
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Melanoma
  Neoplasm
  Non-small-cell lung cancer
  Stomach cancer
  Squamous cell carcinoma
• UniProt ID: DEN2D_HUMAN
• Pfam ID: PF03455 ; PF02141 ; PF03456
• Sequence:
  MEGQVVGRVFRLFQRRLLQLRAGPPQDNSGEALKEPERAQEHSLPNFAGGQHFFEYLLVV
  SLKKKRSEDDYEPIITYQFPKRENLLRGQQEEEERLLKAIPLFCFPDGNEWASLTEYPRE
  TFSFVLTNVDGSRKIGYCRRLLPAGPGPRLPKVYCIISCIGCFGLFSKILDEVEKRHQIS
  MAVIYPFMQGLREAAFPAPGKTVTLKSFIPDSGTEFISLTRPLDSHLEHVDFSSLLHCLS
  FEQILQIFASAVLERKIIFLAEGLSTLSQCIHAAAALLYPFSWAHTYIPVVPESLLATVC
  CPTPFMVGVQMRFQQEVMDSPMEEVLLVNLCEGTFLMSVGDEKDILPPKLQDDILDSLGQ
  GINELKTAEQINEHVSGPFVQFFVKIVGHYASYIKREANGQGHFQERSFCKALTSKTNRR
  FVKKFVKTQLFSLFIQEAEKSKNPPAGYFQQKILEYEEQKKQKKPREKTVK
• Function: 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.
• Tissue Specificity: In bronchial mucosa, mainly expressed in ciliated and basal epithelial cells and weakly in alveolar cells (at protein level). Tends to be down-regulated in lung cancers, immortalized bronchial epithelial cell lines and precancerous lesions.
• 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
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[4]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[3]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[7]

8 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 2D (DENND2D).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DENN domain-containing protein 2D (DENND2D).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DENN domain-containing protein 2D (DENND2D).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of DENN domain-containing protein 2D (DENND2D).	[11]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of DENN domain-containing protein 2D (DENND2D).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of DENN domain-containing protein 2D (DENND2D).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DENN domain-containing protein 2D (DENND2D).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DENN domain-containing protein 2D (DENND2D).	[16]

1 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 decreases the methylation of DENN domain-containing protein 2D (DENND2D).	[14]

References

• [1] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [2] Reduced expression of DENND2D through promoter hypermethylation is an adverse prognostic factor in squamous cell carcinoma of the esophagus.Oncol Rep. 2014 Feb;31(2):693-700. doi: 10.3892/or.2013.2901. Epub 2013 Dec 5.
• [3] Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer.Gastric Cancer. 2015 Apr;18(2):288-96. doi: 10.1007/s10120-014-0372-0. Epub 2014 Apr 3.
• [4] Suppression of non-small cell lung cancer proliferation and tumorigenicity by DENND2D.Lung Cancer. 2013 Feb;79(2):104-10. doi: 10.1016/j.lungcan.2012.10.012. Epub 2012 Nov 20.
• [5] Identification of ARHGEF17, DENND2D, FGFR3, and RB1 mutations in melanoma by inhibition of nonsense-mediated mRNA decay.Genes Chromosomes Cancer. 2008 Dec;47(12):1076-85. doi: 10.1002/gcc.20598.
• [6] Downregulation of miR-522 suppresses proliferation and metastasis of non-small cell lung cancer cells by directly targeting DENN/MADD domain containing 2D.Sci Rep. 2016 Jan 19;6:19346. doi: 10.1038/srep19346.
• [7] Exosomal microRNA miR-1246 induces cell motility and invasion through the regulation of DENND2D in oral squamous cell carcinoma.Sci Rep. 2016 Dec 8;6:38750. doi: 10.1038/srep38750.
• [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] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [13] 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.
• [14] 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.
• [15] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.