Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD03E8M)

• DOT Name: Actin nucleation-promoting factor WAS
• Synonyms: Wiskott-Aldrich syndrome protein; WASp
• Gene Name: WAS
• Related Disease:
  Wiskott-Aldrich syndrome
  X-linked severe congenital neutropenia
  Thrombocytopenia 1
• UniProt ID: WASP_HUMAN
• PDB ID: 1CEE; 1EJ5; 1T84; 2A3Z; 2K42; 2OT0
• Pfam ID: PF00786 ; PF00568 ; PF02205
• Sequence:
  MSGGPMGGRPGGRGAPAVQQNIPSTLLQDHENQRLFEMLGRKCLTLATAVVQLYLALPPG
  AEHWTKEHCGAVCFVKDNPQKSYFIRLYGLQAGRLLWEQELYSQLVYSTPTPFFHTFAGD
  DCQAGLNFADEDEAQAFRALVQEKIQKRNQRQSGDRRQLPPPPTPANEERRGGLPPLPLH
  PGGDQGGPPVGPLSLGLATVDIQNPDITSSRYRGLPAPGPSPADKKRSGKKKISKADIGA
  PSGFKHVSHVGWDPQNGFDVNNLDPDLRSLFSRAGISEAQLTDAETSKLIYDFIEDQGGL
  EAVRQEMRRQEPLPPPPPPSRGGNQLPRPPIVGGNKGRSGPLPPVPLGIAPPPPTPRGPP
  PPGRGGPPPPPPPATGRSGPLPPPPPGAGGPPMPPPPPPPPPPPSSGNGPAPPPLPPALV
  PAGGLAPGGGRGALLDQIRQGIQLNKTPGAPESSALQPPPQSSEGLVGALMHVMQKRSRA
  IHSSDEGEDQAGDEDEDDEWDD
• Function: Effector protein for Rho-type GTPases that regulates actin filament reorganization via its interaction with the Arp2/3 complex. Important for efficient actin polymerization. Possible regulator of lymphocyte and platelet function. Mediates actin filament reorganization and the formation of actin pedestals upon infection by pathogenic bacteria. In addition to its role in the cytoplasmic cytoskeleton, also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA. Promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs).
• Tissue Specificity: Expressed predominantly in the thymus. Also found, to a much lesser extent, in the spleen.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Adherens junction (hsa04520)
  Tight junction (hsa04530)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Yersinia infection (hsa05135)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOJ GTPase cycle (R-HSA-9013409)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Generation of second messenger molecules (R-HSA-202433)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Wiskott-Aldrich syndrome	DISATMDB	Definitive	X-linked	[1]
X-linked severe congenital neutropenia	DISPZ2S7	Definitive	X-linked	[1]
Thrombocytopenia 1	DISTC3AW	Supportive	X-linked	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Actin nucleation-promoting factor WAS.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Actin nucleation-promoting factor WAS.	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Actin nucleation-promoting factor WAS.	[5]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Actin nucleation-promoting factor WAS.	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Actin nucleation-promoting factor WAS.	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Actin nucleation-promoting factor WAS.	[5]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Actin nucleation-promoting factor WAS.	[9]

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 Actin nucleation-promoting factor WAS.	[7]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] WAS-Related Disorders. 2004 Sep 30 [updated 2016 Sep 22]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [6] Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells. Fertil Steril. 2009 Aug;92(2):709-21.
• [7] 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.
• [8] 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.
• [9] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.