Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8C9841)

• DOT Name: Actin-binding protein WASF1
• Synonyms: Protein WAVE-1; Verprolin homology domain-containing protein 1; Wiskott-Aldrich syndrome protein family member 1; WASP family protein member 1
• Gene Name: WASF1
• Related Disease: Neurodevelopmental disorder with absent language and variable seizures
• UniProt ID: WASF1_HUMAN
• PDB ID: 3P8C; 4N78; 7USC; 7USD; 7USE
• Pfam ID: PF02205
• Sequence:
  MPLVKRNIDPRHLCHTALPRGIKNELECVTNISLANIIRQLSSLSKYAEDIFGELFNEAH
  SFSFRVNSLQERVDRLSVSVTQLDPKEEELSLQDITMRKAFRSSTIQDQQLFDRKTLPIP
  LQETYDVCEQPPPLNILTPYRDDGKEGLKFYTNPSYFFDLWKEKMLQDTEDKRKEKRKQK
  QKNLDRPHEPEKVPRAPHDRRREWQKLAQGPELAEDDANLLHKHIEVANGPASHFETRPQ
  TYVDHMDGSYSLSALPFSQMSELLTRAEERVLVRPHEPPPPPPMHGAGDAKPIPTCISSA
  TGLIENRPQSPATGRTPVFVSPTPPPPPPPLPSALSTSSLRASMTSTPPPPVPPPPPPPA
  TALQAPAVPPPPAPLQIAPGVLHPAPPPIAPPLVQPSPPVARAAPVCETVPVHPLPQGEV
  QGLPPPPPPPPLPPPGIRPSSPVTVTALAHPPSGLHPTPSTAPGPHVPLMPPSPPSQVIP
  ASEPKRHPSTLPVISDARSVLLEAIRKGIQLRKVEEQREQEAKHERIENDVATILSRRIA
  VEYSDSEDDSEFDEVDWLE
• Function: Downstream effector molecule involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. Promotes formation of actin filaments. Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes. Also involved in the regulation of mitochondrial dynamics.
• Tissue Specificity: Highly expressed in brain. Lowly expressed in testis, ovary, colon, kidney, pancreas, thymus, small intestine and peripheral blood.
• KEGG Pathway:
  Adherens junction (hsa04520)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Regulation of actin cytoskeleton (hsa04810)
  Bacterial invasion of epithelial cells (hsa05100)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC3 GTPase cycle (R-HSA-9013423)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with absent language and variable seizures	DISPH3WV	Strong	Autosomal dominant	[1]

10 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 Actin-binding protein WASF1.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Actin-binding protein WASF1.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Actin-binding protein WASF1.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Actin-binding protein WASF1.	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Actin-binding protein WASF1.	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Actin-binding protein WASF1.	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Actin-binding protein WASF1.	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Actin-binding protein WASF1.	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Actin-binding protein WASF1.	[10]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Actin-binding protein WASF1.	[11]

References

• [1] De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures. Am J Hum Genet. 2018 Jul 5;103(1):144-153. doi: 10.1016/j.ajhg.2018.06.001. Epub 2018 Jun 28.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [6] 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.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [9] 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.
• [10] 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.
• [11] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.