Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT05LJSH)

• DOT Name: Actin-related protein 3 (ACTR3)
• Synonyms: Actin-like protein 3
• Gene Name: ACTR3
• Related Disease:
  Focal segmental glomerulosclerosis
  Glioblastoma multiforme
  Lung cancer
  Lung carcinoma
  Neoplasm
  Schizophrenia
  Ulcerative colitis
  Wiskott-Aldrich syndrome
  Gastric cancer
  Stomach cancer
  Adenocarcinoma
  Gallbladder cancer
  Carcinoma of liver and intrahepatic biliary tract
  Hepatocellular carcinoma
  Liver cancer
  Metastatic malignant neoplasm
• UniProt ID: ARP3_HUMAN
• PDB ID: 6UHC; 6YW6; 6YW7
• Pfam ID: PF00022
• Sequence:
  MAGRLPACVVDCGTGYTKLGYAGNTEPQFIIPSCIAIKESAKVGDQAQRRVMKGVDDLDF
  FIGDEAIEKPTYATKWPIRHGIVEDWDLMERFMEQVIFKYLRAEPEDHYFLLTEPPLNTP
  ENREYTAEIMFESFNVPGLYIAVQAVLALAASWTSRQVGERTLTGTVIDSGDGVTHVIPV
  AEGYVIGSCIKHIPIAGRDITYFIQQLLRDREVGIPPEQSLETAKAVKERYSYVCPDLVK
  EFNKYDTDGSKWIKQYTGINAISKKEFSIDVGYERFLGPEIFFHPEFANPDFTQPISEVV
  DEVIQNCPIDVRRPLYKNIVLSGGSTMFRDFGRRLQRDLKRTVDARLKLSEELSGGRLKP
  KPIDVQVITHHMQRYAVWFGGSMLASTPEFYQVCHTKKDYEEIGPSICRHNPVFGVMS
• Function: ATP-binding 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. Seems to contact the pointed end of the daughter actin filament. In podocytes, required for the formation of lamellipodia downstream of AVIL and PLCE1 regulation. 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). Plays a role in ciliogenesis.
• 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)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[5]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[6]
Wiskott-Aldrich syndrome	DISATMDB	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	moderate	Biomarker	[8]
Stomach cancer	DISKIJSX	moderate	Biomarker	[8]
Adenocarcinoma	DIS3IHTY	Disputed	Biomarker	[9]
Gallbladder cancer	DISXJUAF	Disputed	Altered Expression	[9]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[10]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[10]
Liver cancer	DISDE4BI	Limited	Altered Expression	[10]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Actin-related protein 3 (ACTR3).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Actin-related protein 3 (ACTR3).	[23]

16 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 3 (ACTR3).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Actin-related protein 3 (ACTR3).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Actin-related protein 3 (ACTR3).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Actin-related protein 3 (ACTR3).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Actin-related protein 3 (ACTR3).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Actin-related protein 3 (ACTR3).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Actin-related protein 3 (ACTR3).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Actin-related protein 3 (ACTR3).	[19]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Actin-related protein 3 (ACTR3).	[20]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Actin-related protein 3 (ACTR3).	[21]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Actin-related protein 3 (ACTR3).	[20]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Actin-related protein 3 (ACTR3).	[20]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Actin-related protein 3 (ACTR3).	[22]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Actin-related protein 3 (ACTR3).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Actin-related protein 3 (ACTR3).	[25]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Actin-related protein 3 (ACTR3).	[26]

References

• [1] Effect of Heme Oxygenase-1 Deficiency on Glomerular Proteomics.Am J Nephrol. 2016;43(6):441-50. doi: 10.1159/000446859. Epub 2016 Jun 2.
• [2] RasGRP3 regulates the migration of glioma cells via interaction with Arp3.Oncotarget. 2015 Jan 30;6(3):1850-64. doi: 10.18632/oncotarget.2575.
• [3] Discovering novel lung cancer associated antigens and the utilization of their autoantibodies in detection of lung cancer.Immunobiology. 2020 Mar;225(2):151891. doi: 10.1016/j.imbio.2019.11.026. Epub 2019 Nov 27.
• [4] Long Noncoding RNA CRYBG3 Blocks Cytokinesis by Directly Binding G-Actin.Cancer Res. 2018 Aug 15;78(16):4563-4572. doi: 10.1158/0008-5472.CAN-18-0988. Epub 2018 Jun 22.
• [5] A combined metabonomic and proteomic approach identifies frontal cortex changes in a chronic phencyclidine rat model in relation to human schizophrenia brain pathology.Neuropsychopharmacology. 2013 Nov;38(12):2532-44. doi: 10.1038/npp.2013.160. Epub 2013 Jul 3.
• [6] Actin related protein 3 (ARP3) promotes apoptosis of intestinal epithelial cells in ulcerative colitis.Pathol Res Pract. 2019 Feb;215(2):235-242. doi: 10.1016/j.prp.2018.10.011. Epub 2018 Oct 24.
• [7] Motility determinants in WASP family proteins.Mol Biol Cell. 2002 Nov;13(11):4045-59. doi: 10.1091/mbc.e02-05-0294.
• [8] Clinicopathological and prognostic significance of aberrant Arpin expression in gastric cancer.World J Gastroenterol. 2017 Feb 28;23(8):1450-1457. doi: 10.3748/wjg.v23.i8.1450.
• [9] CFL1 and Arp3 are biomarkers for metastasis and poor prognosis of squamous cell/adenosquamous carcinomas and adenocarcinomas of gallbladder.Cancer Invest. 2013 Feb;31(2):132-9. doi: 10.3109/07357907.2012.756113. Epub 2013 Jan 15.
• [10] ARP3 promotes tumor metastasis and predicts a poor prognosis in hepatocellular carcinoma.Pathol Res Pract. 2018 Sep;214(9):1356-1361. doi: 10.1016/j.prp.2018.05.028. Epub 2018 Jun 7.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [19] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [20] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [21] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [22] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [23] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [24] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [25] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [26] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.