Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC1WVZT)

• DOT Name: Disheveled-associated activator of morphogenesis 2 (DAAM2)
• Gene Name: DAAM2
• Related Disease: Nephrotic syndrome, type 24
• UniProt ID: DAAM2_HUMAN
• Pfam ID: PF06367 ; PF06371 ; PF02181
• Sequence:
  MAPRKRSHHGLGFLCCFGGSDIPEINLRDNHPLQFMEFSSPIPNAEELNIRFAELVDELD
  LTDKNREAMFALPPEKKWQIYCSKKKEQEDPNKLATSWPDYYIDRINSMAAMQSLYAFDE
  EETEMRNQVVEDLKTALRTQPMRFVTRFIELEGLTCLLNFLRSMDHATCESRIHTSLIGC
  IKALMNNSQGRAHVLAQPEAISTIAQSLRTENSKTKVAVLEILGAVCLVPGGHKKVLQAM
  LHYQVYAAERTRFQTLLNELDRSLGRYRDEVNLKTAIMSFINAVLNAGAGEDNLEFRLHL
  RYEFLMLGIQPVIDKLRQHENAILDKHLDFFEMVRNEDDLELARRFDMVHIDTKSASQMF
  ELIHKKLKYTEAYPCLLSVLHHCLQMPYKRNGGYFQQWQLLDRILQQIVLQDERGVDPDL
  APLENFNVKNIVNMLINENEVKQWRDQAEKFRKEHMELVSRLERKERECETKTLEKEEMM
  RTLNKMKDKLARESQELRQARGQVAELVAQLSELSTGPVSSPPPPGGPLTLSSSMTTNDL
  PPPPPPLPFACCPPPPPPPLPPGGPPTPPGAPPCLGMGLPLPQDPYPSSDVPLRKKRVPQ
  PSHPLKSFNWVKLNEERVPGTVWNEIDDMQVFRILDLEDFEKMFSAYQRHQKELGSTEDI
  YLASRKVKELSVIDGRRAQNCIILLSKLKLSNEEIRQAILKMDEQEDLAKDMLEQLLKFI
  PEKSDIDLLEEHKHEIERMARADRFLYEMSRIDHYQQRLQALFFKKKFQERLAEAKPKVE
  AILLASRELVRSKRLRQMLEVILAIGNFMNKGQRGGAYGFRVASLNKIADTKSSIDRNIS
  LLHYLIMILEKHFPDILNMPSELQHLPEAAKVNLAELEKEVGNLRRGLRAVEVELEYQRR
  QVREPSDKFVPVMSDFITVSSFSFSELEDQLNEARDKFAKALMHFGEHDSKMQPDEFFGI
  FDTFLQAFSEARQDLEAMRRRKEEEERRARMEAMLKEQRERERWQRQRKVLAAGSSLEEG
  GEFDDLVSALRSGEVFDKDLCKLKRSRKRSGSQALEVTRERAINRLNY
• Function: Key regulator of the Wnt signaling pathway, which is required for various processes during development, such as dorsal patterning, determination of left/right symmetry or myelination in the central nervous system. Acts downstream of Wnt ligands and upstream of beta-catenin (CTNNB1). Required for canonical Wnt signaling pathway during patterning in the dorsal spinal cord by promoting the aggregation of Disheveled (Dvl) complexes, thereby clustering and formation of Wnt receptor signalosomes and potentiating Wnt activity. During dorsal patterning of the spinal cord, inhibits oligodendrocytes differentiation via interaction with PIP5K1A. Also regulates non-canonical Wnt signaling pathway. Acts downstream of PITX2 in the developing gut and is required for left/right asymmetry within dorsal mesentery: affects mesenchymal condensation by lengthening cadherin-based junctions through WNT5A and non-canonical Wnt signaling, inducing polarized condensation in the left dorsal mesentery necessary to initiate gut rotation. Together with DAAM1, required for myocardial maturation and sarcomere assembly. Is a regulator of actin nucleation and elongation, filopodia formation and podocyte migration.
• Tissue Specificity: Expressed in most tissues examined. Expressed in kidney glomeruli .
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephrotic syndrome, type 24	DISBFCR1	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[13]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Disheveled-associated activator of morphogenesis 2 (DAAM2).	[10]

References

• [1] DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation. Am J Hum Genet. 2020 Dec 3;107(6):1113-1128. doi: 10.1016/j.ajhg.2020.11.008. Epub 2020 Nov 23.
• [2] 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.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [7] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [13] 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.
• [14] Integrated analysis of paraquat-induced microRNAs-mRNAs changes in human neural progenitor cells. Toxicol In Vitro. 2017 Oct;44:196-205. doi: 10.1016/j.tiv.2017.06.010. Epub 2017 Jun 12.