Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPL9MA3)

• DOT Name: Disabled homolog 1 (DAB1)
• Gene Name: DAB1
• Related Disease:
  Neuroblastoma
  Adult glioblastoma
  Alzheimer disease
  Alzheimer disease 3
  Autism
  Autism spectrum disorder
  Autosomal recessive juvenile Parkinson disease 2
  Cardiac arrest
  Cerebellar ataxia
  Cerebellar degeneration
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Glioblastoma multiforme
  Mental disorder
  Neoplasm
  Non-small-cell lung cancer
  Paroxysmal nocturnal haemoglobinuria
  Retinoblastoma
  Acute myelogenous leukaemia
  Advanced cancer
  Coronary heart disease
  Spinocerebellar ataxia type 37
  Corpus callosum, agenesis of
  Type-1/2 diabetes
  Breast cancer
  Breast carcinoma
  Cognitive impairment
  Schizophrenia
  Status epilepticus seizure
• UniProt ID: DAB1_HUMAN
• Pfam ID: PF21792 ; PF00640
• Sequence:
  MSTETELQVAVKTSAKKDSRKKGQDRSEATLIKRFKGEGVRYKAKLIGIDEVSAARGDKL
  CQDSMMKLKGVVAGARSKGEHKQKIFLTISFGGIKIFDEKTGALQHHHAVHEISYIAKDI
  TDHRAFGYVCGKEGNHRFVAIKTAQAAEPVILDLRDLFQLIYELKQREELEKKAQKDKQC
  EQAVYQTILEEDVEDPVYQYIVFEAGHEPIRDPETEENIYQVPTSQKKEGVYDVPKSQPV
  SNGYSFEDFEERFAAATPNRNLPTDFDEIFEATKAVTQLELFGDMSTPPDITSPPTPATP
  GDAFIPSSSQTLPASADVFSSVPFGTAAVPSGYVAMGAVLPSFWGQQPLVQQQMVMGAQP
  PVAQVMPGAQPIAWGQPGLFPATQQPWPTVAGQFPPAAFMPTQTVMPLPAAMFQGPLTPL
  ATVPGTSDSTRSSPQTDKPRQKMGKETFKDFQMAQPPPVPSRKPDQPSLTCTSEAFSSYF
  NKVGVAQDTDDCDDFDISQLNLTPVTSTTPSTNSPPTPAPRQSSPSKSSASHASDPTTDD
  IFEEGFESPSKSEEQEAPDGSQASSNSDPFGEPSGEPSGDNISPQAGS
• Function: Adapter molecule functioning in neural development. May regulate SIAH1 activity.
• Tissue Specificity: Mainly expressed in brain.
• KEGG Pathway: Spinocerebellar ataxia (hsa05017)
• Reactome Pathway: Reelin signalling pathway (R-HSA-8866376)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Posttranslational Modification	[3]
Alzheimer disease 3	DISVT69G	Strong	Altered Expression	[4]
Autism	DISV4V1Z	Strong	Biomarker	[5]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[6]
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	Strong	Altered Expression	[7]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[8]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[9]
Cerebellar degeneration	DISPBCM3	Strong	Genetic Variation	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[7]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[7]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Mental disorder	DIS3J5R8	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[13]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Strong	Genetic Variation	[14]
Retinoblastoma	DISVPNPB	Strong	Posttranslational Modification	[15]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[16]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[2]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[17]
Spinocerebellar ataxia type 37	DIS3KNNO	Supportive	Autosomal dominant	[8]
Corpus callosum, agenesis of	DISO9P40	Disputed	Biomarker	[18]
Type-1/2 diabetes	DISIUHAP	Disputed	Altered Expression	[19]
Breast cancer	DIS7DPX1	Limited	Biomarker	[12]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[12]
Cognitive impairment	DISH2ERD	Limited	Biomarker	[18]
Schizophrenia	DISSRV2N	Limited	Biomarker	[11]
Status epilepticus seizure	DISY3BIC	Limited	Biomarker	[20]

9 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 Disabled homolog 1 (DAB1).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Disabled homolog 1 (DAB1).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Disabled homolog 1 (DAB1).	[23]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Disabled homolog 1 (DAB1).	[24]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Disabled homolog 1 (DAB1).	[25]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Disabled homolog 1 (DAB1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Disabled homolog 1 (DAB1).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Disabled homolog 1 (DAB1).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Disabled homolog 1 (DAB1).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Disabled homolog 1 (DAB1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Disabled homolog 1 (DAB1).	[27]

References

• [1] Reelin signalling in neuroblastoma: migratory switch in metastatic stages.Int J Oncol. 2012 Aug;41(2):681-9. doi: 10.3892/ijo.2012.1488. Epub 2012 May 18.
• [2] RELN signaling modulates glioblastoma growth and substrate-dependent migration.Brain Pathol. 2018 Sep;28(5):695-709. doi: 10.1111/bpa.12584. Epub 2018 Jan 10.
• [3] The -amyloid peptide compromises Reelin signaling in Alzheimer's disease.Sci Rep. 2016 Aug 17;6:31646. doi: 10.1038/srep31646.
• [4] The AICD interacting protein DAB1 is up-regulated in Alzheimer frontal cortex brain samples and causes deregulation of proteins involved in gene expression changes. Curr Alzheimer Res. 2011 Aug;8(5):573-82.
• [5] Association and gene-gene interactions study of reelin signaling pathway related genes with autism in the Han Chinese population.Autism Res. 2016 Apr;9(4):436-42. doi: 10.1002/aur.1540. Epub 2015 Aug 19.
• [6] Rare RELN variants affect Reelin-DAB1 signal transduction in autism spectrum disorder.Hum Mutat. 2018 Oct;39(10):1372-1383. doi: 10.1002/humu.23584. Epub 2018 Jul 26.
• [7] Disabled-1 is a large common fragile site gene, inactivated in multiple cancers.Genes Chromosomes Cancer. 2008 Feb;47(2):165-74. doi: 10.1002/gcc.20519.
• [8] A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia. Am J Hum Genet. 2017 Jul 6;101(1):87-103. doi: 10.1016/j.ajhg.2017.06.007.
• [9] Developmental abnormality contributes to cortex-dependent motor impairments and higher intracortical current requirement in the reeler homozygous mutants.Brain Struct Funct. 2018 Jul;223(6):2575-2587. doi: 10.1007/s00429-018-1647-8. Epub 2018 Mar 13.
• [10] Promotion of colorectal cancer invasion and metastasis through activation of NOTCH-DAB1-ABL-RHOGEF protein TRIO.Cancer Discov. 2015 Feb;5(2):198-211. doi: 10.1158/2159-8290.CD-14-0595. Epub 2014 Nov 28.
• [11] Dorsal Forebrain-Specific Deficiency of Reelin-Dab1 Signal Causes Behavioral Abnormalities Related to Psychiatric Disorders.Cereb Cortex. 2017 Jul 1;27(7):3485-3501. doi: 10.1093/cercor/bhv334.
• [12] Disabled-1 is down-regulated in clinical breast cancer and regulates cell apoptosis through NF-B/Bcl-2/caspase-9.J Cell Mol Med. 2019 Feb;23(2):1622-1627. doi: 10.1111/jcmm.14047. Epub 2018 Nov 28.
• [13] The 18p11.22 locus is associated with never smoker non-small cell lung cancer susceptibility in Korean populations.Hum Genet. 2012 Mar;131(3):365-72. doi: 10.1007/s00439-011-1080-z. Epub 2011 Aug 25.
• [14] Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia. Nat Genet. 2016 Nov;48(11):1349-1358. doi: 10.1038/ng.3676. Epub 2016 Oct 3.
• [15] Disabled-1 alternative splicing in human fetal retina and neural tumors.PLoS One. 2011;6(12):e28579. doi: 10.1371/journal.pone.0028579. Epub 2011 Dec 6.
• [16] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [17] Genome-Wide Association and Functional Studies Identify SCML4 and THSD7A as Novel Susceptibility Genes for Coronary Artery Disease.Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):964-975. doi: 10.1161/ATVBAHA.117.310594. Epub 2018 Feb 22.
• [18] Interstitial 1p32.1p32.3 deletion in a patient with multiple congenital anomalies.Am J Med Genet A. 2015 Oct;167A(10):2406-10. doi: 10.1002/ajmg.a.37178. Epub 2015 Jun 10.
• [19] Genome-Wide DNA Methylation Profiles of Phlegm-Dampness Constitution.Cell Physiol Biochem. 2018;45(5):1999-2008. doi: 10.1159/000487976. Epub 2018 Mar 2.
• [20] Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus.J Neurosci. 2007 Feb 21;27(8):1803-11. doi: 10.1523/JNEUROSCI.3111-06.2007.
• [21] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [22] 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.
• [23] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [24] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [25] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [26] 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.
• [27] 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.
• [28] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [29] 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.
• [30] 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.