Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD67RF1)

• DOT Name: Segment polarity protein dishevelled homolog DVL-1 (DVL1)
• Synonyms: Dishevelled-1; DSH homolog 1
• Gene Name: DVL1
• Related Disease:
  Autosomal dominant Robinow syndrome 2
  Parkinson disease
  Alzheimer disease
  Breast cancer
  Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy
  Cervical cancer
  Cervical carcinoma
  Chordoma
  Colorectal carcinoma
  Duane retraction syndrome
  Gaucher disease
  Gaucher disease type I
  Glioma
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Neoplasm
  Neural tube defect
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Robinow syndrome
  Squamous cell neoplasm
  Stroke
  Triple negative breast cancer
  Hirschsprung disease
  Leukemia
  Neuroblastoma
  Small lymphocytic lymphoma
  Autosomal dominant Robinow syndrome
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Adenocarcinoma
  Breast carcinoma
  Epithelial ovarian cancer
  Joubert syndrome
  Lung neoplasm
  Meckel syndrome, type 1
  Metastatic malignant neoplasm
  Myocardial infarction
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Squamous cell carcinoma
• UniProt ID: DVL1_HUMAN
• PDB ID: 6LCA; 6LCB; 6TTK
• Pfam ID: PF00610 ; PF02377 ; PF00778 ; PF12316 ; PF00595
• Sequence:
  MAETKIIYHMDEEETPYLVKLPVAPERVTLADFKNVLSNRPVHAYKFFFKSMDQDFGVVK
  EEIFDDNAKLPCFNGRVVSWLVLAEGAHSDAGSQGTDSHTDLPPPLERTGGIGDSRPPSF
  HPNVASSRDGMDNETGTESMVSHRRERARRRNREEAARTNGHPRGDRRRDVGLPPDSAST
  ALSSELESSSFVDSDEDGSTSRLSSSTEQSTSSRLIRKHKRRRRKQRLRQADRASSFSSI
  TDSTMSLNIVTVTLNMERHHFLGISIVGQSNDRGDGGIYIGSIMKGGAVAADGRIEPGDM
  LLQVNDVNFENMSNDDAVRVLREIVSQTGPISLTVAKCWDPTPRSYFTVPRADPVRPIDP
  AAWLSHTAALTGALPRYGTSPCSSAVTRTSSSSLTSSVPGAPQLEEAPLTVKSDMSAVVR
  VMQLPDSGLEIRDRMWLKITIANAVIGADVVDWLYTHVEGFKERREARKYASSLLKHGFL
  RHTVNKITFSEQCYYVFGDLCSNLATLNLNSGSSGTSDQDTLAPLPHPAAPWPLGQGYPY
  QYPGPPPCFPPAYQDPGFSYGSGSTGSQQSEGSKSSGSTRSSRRAPGREKERRAAGAGGS
  GSESDHTAPSGVGSSWRERPAGQLSRGSSPRSQASATAPGLPPPHPTTKAYTVVGGPPGG
  PPVRELAAVPPELTGSRQSFQKAMGNPCEFFVDIM
• Function: Participates in Wnt signaling by binding to the cytoplasmic C-terminus of frizzled family members and transducing the Wnt signal to down-stream effectors. Plays a role both in canonical and non-canonical Wnt signaling. Plays a role in the signal transduction pathways mediated by multiple Wnt genes. Required for LEF1 activation upon WNT1 and WNT3A signaling. DVL1 and PAK1 form a ternary complex with MUSK which is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ).
• KEGG Pathway:
  mTOR sig.ling pathway (hsa04150)
  Wnt sig.ling pathway (hsa04310)
  Notch sig.ling pathway (hsa04330)
  Hippo sig.ling pathway (hsa04390)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Melanogenesis (hsa04916)
  Cushing syndrome (hsa04934)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Basal cell carcinoma (hsa05217)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  WNT mediated activation of DVL (R-HSA-201688)
  PCP/CE pathway (R-HSA-4086400)
  Degradation of DVL (R-HSA-4641258)
  Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262)
  Negative regulation of TCF-dependent signaling by DVL-interacting proteins (R-HSA-5368598)
  RHO GTPases Activate Formins (R-HSA-5663220)
  WNT5 (R-HSA-9673324)
  TCF dependent signaling in response to WNT (R-HSA-201681)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant Robinow syndrome 2	DIS9MS2G	Definitive	Autosomal dominant	[1]
Parkinson disease	DISQVHKL	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy	DIS93Z3E	Strong	Biomarker	[5]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[6]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[6]
Chordoma	DISCHJE7	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
Duane retraction syndrome	DISOEBK2	Strong	Genetic Variation	[1]
Gaucher disease	DISTW5JG	Strong	Biomarker	[9]
Gaucher disease type I	DIS87KKY	Strong	Altered Expression	[9]
Glioma	DIS5RPEH	Strong	Altered Expression	[10]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[12]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[13]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[14]
Prostate cancer	DISF190Y	Strong	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[6]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[6]
Robinow syndrome	DISK1CNU	Strong	Genetic Variation	[15]
Squamous cell neoplasm	DISKBRLI	Strong	Altered Expression	[16]
Stroke	DISX6UHX	Strong	Genetic Variation	[5]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[17]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[18]
Leukemia	DISNAKFL	moderate	Biomarker	[19]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[20]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[19]
Autosomal dominant Robinow syndrome	DIS94N80	Supportive	Autosomal dominant	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Disputed	Biomarker	[21]
Liver cancer	DISDE4BI	Disputed	Biomarker	[21]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[22]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Limited	Posttranslational Modification	[23]
Joubert syndrome	DIS7P5CO	Limited	Genetic Variation	[24]
Lung neoplasm	DISVARNB	Limited	Altered Expression	[22]
Meckel syndrome, type 1	DIS4YWZU	Limited	Altered Expression	[24]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[22]
Myocardial infarction	DIS655KI	Limited	Biomarker	[25]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[26]
Ovarian cancer	DISZJHAP	Limited	Posttranslational Modification	[23]
Ovarian neoplasm	DISEAFTY	Limited	Posttranslational Modification	[23]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[40]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[29]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[30]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[31]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[32]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[33]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[34]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[35]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[28]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[36]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[38]
Calphostin C	DM9X2D0	Terminated	Calphostin C decreases the expression of Segment polarity protein dishevelled homolog DVL-1 (DVL1).	[39]

References

• [1] DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome. Am J Hum Genet. 2015 Apr 2;96(4):612-22. doi: 10.1016/j.ajhg.2015.02.015. Epub 2015 Mar 26.
• [2] Assessing the sensitivity and specificity of cognitive screening measures for people with Parkinson's disease.NeuroRehabilitation. 2018;43(4):491-500. doi: 10.3233/NRE-182433.
• [3] Identification of genomic organisation, sequence variants and analysis of the role of the human dishevelled 1 gene in late onset Alzheimer's disease.Mol Psychiatry. 2002;7(1):104-9. doi: 10.1038/sj.mp.4000941.
• [4] Downregulated miR-1247-5p associates with poor prognosis and facilitates tumor cell growth via DVL1/Wnt/-catenin signaling in breast cancer.Biochem Biophys Res Commun. 2018 Oct 20;505(1):302-308. doi: 10.1016/j.bbrc.2018.09.103. Epub 2018 Sep 22.
• [5] Mapping and sequencing rat dishevelled-1: a candidate gene for cerebral ischaemic insult in a rat model of stroke.Neurogenetics. 2001 Mar;3(2):99-106. doi: 10.1007/s100480000099.
• [6] Upregulation and overexpression of DVL1, the human counterpart of the Drosophila dishevelled gene, in prostate cancer.Tumori. 2005 Nov-Dec;91(6):546-51. doi: 10.1177/030089160509100616.
• [7] Mapping of candidate region for chordoma development to 1p36.13 by LOH analysis.Int J Cancer. 2003 Nov 10;107(3):493-7. doi: 10.1002/ijc.11421.
• [8] Significant overexpression of DVL1 in Taiwanese colorectal cancer patients with liver metastasis.Int J Mol Sci. 2013 Oct 14;14(10):20492-507. doi: 10.3390/ijms141020492.
• [9] A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models.Hum Mol Genet. 2020 Jan 15;29(2):274-285. doi: 10.1093/hmg/ddz293.
• [10] Lectin from Dioclea violacea induces autophagy in U87 glioma cells.Int J Biol Macromol. 2019 Aug 1;134:660-672. doi: 10.1016/j.ijbiomac.2019.04.203. Epub 2019 May 1.
• [11] Expression of Wnt pathway components frizzled and disheveled in colon cancer arising in patients with inflammatory bowel disease.Oncol Rep. 2007 Sep;18(3):691-4.
• [12] Brain metastases from lung cancer show increased expression of DVL1, DVL3 and beta-catenin and down-regulation of E-cadherin.Int J Mol Sci. 2014 Jun 13;15(6):10635-51. doi: 10.3390/ijms150610635.
• [13] Different behaviour of DVL1, DVL2, DVL3 in astrocytoma malignancy grades and their association to TCF1 and LEF1 upregulation.J Cell Mol Med. 2019 Jan;23(1):641-655. doi: 10.1111/jcmm.13969. Epub 2018 Nov 23.
• [14] MARK2/Par1b Insufficiency Attenuates DVL Gene Transcription via Histone Deacetylation in Lumbosacral Spina Bifida.Mol Neurobiol. 2017 Oct;54(8):6304-6316. doi: 10.1007/s12035-016-0164-0. Epub 2016 Oct 6.
• [15] WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. Am J Hum Genet. 2018 Jan 4;102(1):27-43. doi: 10.1016/j.ajhg.2017.10.002. Epub 2017 Dec 21.
• [16] Up-regulation and overproduction of DVL-1, the human counterpart of the Drosophila dishevelled gene, in cervical squamous cell carcinoma.Oncol Rep. 2003 Sep-Oct;10(5):1219-23. doi: 10.3892/or.10.5.1219.
• [17] Acetylation of conserved DVL-1 lysines regulates its nuclear translocation and binding to gene promoters in triple-negative breast cancer.Sci Rep. 2019 Nov 7;9(1):16257. doi: 10.1038/s41598-019-52723-3.
• [18] Expression of dishevelled gene in Hirschsprung's disease.Int J Clin Exp Pathol. 2013 Aug 15;6(9):1791-8. eCollection 2013.
• [19] Dishevelled proteins are significantly upregulated in chronic lymphocytic leukaemia.Tumour Biol. 2016 Sep;37(9):11947-11957. doi: 10.1007/s13277-016-5039-5. Epub 2016 Apr 16.
• [20] Deregulated Wnt/beta-catenin program in high-risk neuroblastomas without MYCN amplification.Oncogene. 2008 Feb 28;27(10):1478-88. doi: 10.1038/sj.onc.1210769. Epub 2007 Aug 27.
• [21] Dishevelled 1, a pivotal positive regulator of the Wnt signalling pathway, mediates 5-fluorouracil resistance in HepG2 cells.Artif Cells Nanomed Biotechnol. 2018;46(sup2):192-200. doi: 10.1080/21691401.2018.1453827. Epub 2018 Mar 27.
• [22] Dishevelled family proteins are expressed in non-small cell lung cancer and function differentially on tumor progression.Lung Cancer. 2008 Nov;62(2):181-92. doi: 10.1016/j.lungcan.2008.06.018. Epub 2008 Aug 9.
• [23] Systematic CpG islands methylation profiling of genes in the wnt pathway in epithelial ovarian cancer identifies biomarkers of progression-free survival.Clin Cancer Res. 2011 Jun 15;17(12):4052-62. doi: 10.1158/1078-0432.CCR-10-3021. Epub 2011 Apr 1.
• [24] Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects.Hum Mol Genet. 2013 Apr 1;22(7):1358-72. doi: 10.1093/hmg/dds546. Epub 2013 Jan 2.
• [25] Expression of Dishevelled-1 in wound healing after acute myocardial infarction: possible involvement in myofibroblast proliferation and migration.J Cell Mol Med. 2004 Apr-Jun;8(2):257-64. doi: 10.1111/j.1582-4934.2004.tb00281.x.
• [26] Dishevelled-1 and dishevelled-3 affect cell invasion mainly through canonical and noncanonical Wnt pathway, respectively, and associate with poor prognosis in nonsmall cell lung cancer.Mol Carcinog. 2010 Aug;49(8):760-70. doi: 10.1002/mc.20651.
• [27] 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.
• [28] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [29] 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.
• [30] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [31] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [32] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [33] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [34] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [35] Cancer genes induced by malathion and parathion in the presence of estrogen in breast cells. Int J Mol Med. 2008 Feb;21(2):261-8. doi: 10.3892/ijmm.21.2.261.
• [36] Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/beta-catenin signaling. Chem Biol Interact. 2009 Oct 7;181(2):263-71. doi: 10.1016/j.cbi.2009.06.012. Epub 2009 Jun 30.
• [37] 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.
• [38] 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.
• [39] Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7516-21. doi: 10.1073/pnas.0610299104. Epub 2007 Apr 23.
• [40] 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.