Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYE3DN2)

• DOT Name: Actin-related protein 2/3 complex subunit 1B (ARPC1B)
• Synonyms: Arp2/3 complex 41 kDa subunit; p41-ARC
• Gene Name: ARPC1B
• Related Disease:
  Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Gastric neoplasm
  Inflammation
  Inherited bleeding disorder, platelet-type
  Melanoma
  Stomach cancer
  Wiskott-Aldrich syndrome
  Neoplasm
  Squamous cell carcinoma
• UniProt ID: ARC1B_HUMAN
• PDB ID: 6UHC; 6YW6
• Pfam ID: PF00400
• Sequence:
  MAYHSFLVEPISCHAWNKDRTQIAICPNNHEVHIYEKSGAKWTKVHELKEHNGQVTGIDW
  APESNRIVTCGTDRNAYVWTLKGRTWKPTLVILRINRAARCVRWAPNENKFAVGSGSRVI
  SICYFEQENDWWVCKHIKKPIRSTVLSLDWHPNNVLLAAGSCDFKCRIFSAYIKEVEERP
  APTPWGSKMPFGELMFESSSSCGWVHGVCFSASGSRVAWVSHDSTVCLADADKKMAVATL
  ASETLPLLALTFITDNSLVAAGHDCFPVLFTYDAAAGMLSFGGRLDVPKQSSQRGLTARE
  RFQNLDKKASSEGGTAAGAGLDSLHKNSVSQISVLSGGKAKCSQFCTTGMDGGMSIWDVK
  SLESALKDLKIK
• Function: Component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility. In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA. The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs).
• KEGG Pathway:
  Endocytosis (hsa04144)
  Tight junction (hsa04530)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Regulation of actin cytoskeleton (hsa04810)
  Bacterial invasion of epithelial cells (hsa05100)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
• Reactome Pathway:
  EPHB-mediated forward signaling (R-HSA-3928662)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease	DISWCUX9	Definitive	Autosomal recessive	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[3]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[3]
Inflammation	DISJUQ5T	Strong	Genetic Variation	[4]
Inherited bleeding disorder, platelet-type	DISIUNXT	Strong	Biomarker	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[6]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[3]
Wiskott-Aldrich syndrome	DISATMDB	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	moderate	Altered Expression	[7]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[7]

3 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 Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[16]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Actin-related protein 2/3 complex subunit 1B (ARPC1B).	[22]

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] Cortical branched actin determines cell cycle progression.Cell Res. 2019 Jun;29(6):432-445. doi: 10.1038/s41422-019-0160-9. Epub 2019 Apr 10.
• [3] Reduced expression of the insulin-induced protein 1 and p41 Arp2/3 complex genes in human gastric cancers.Int J Cancer. 2002 Jul 1;100(1):57-62. doi: 10.1002/ijc.10464.
• [4] Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease.Nat Commun. 2017 Apr 3;8:14816. doi: 10.1038/ncomms14816.
• [5] Combined immunodeficiency with severe inflammation and allergy caused by ARPC1B deficiency. J Allergy Clin Immunol. 2017 Jul;140(1):273-277.e10. doi: 10.1016/j.jaci.2016.09.061. Epub 2016 Dec 10.
• [6] Arpc1b gene is a candidate prediction marker for choroidal malignant melanomas sensitive to radiotherapy.Invest Ophthalmol Vis Sci. 2006 Jun;47(6):2300-4. doi: 10.1167/iovs.05-0810.
• [7] Caveolin 1 (Cav-1) and actin-related protein 2/3 complex, subunit 1B (ARPC1B) expressions as prognostic indicators for oral squamous cell carcinoma (OSCC).Eur Arch Otorhinolaryngol. 2016 Jul;273(7):1885-93. doi: 10.1007/s00405-015-3703-9. Epub 2015 Jul 3.
• [8] 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.
• [9] 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.
• [10] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] 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.
• [16] 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.
• [17] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [18] 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.
• [19] 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.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [22] 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.