Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3C8U5T)

• DOT Name: Actin-related protein 2 (ACTR2)
• Synonyms: Actin-like protein 2
• Gene Name: ACTR2
• Related Disease:
  Bladder transitional cell carcinoma
  Glioma
  Acquired immune deficiency syndrome
  Bacillary dysentery
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Hirschsprung disease
  Inflammation
  Lung adenocarcinoma
  Neoplasm
  Oral cancer
  Pancreatic cancer
  Schizophrenia
  Severe combined immunodeficiency
  Wiskott-Aldrich syndrome
  Bone osteosarcoma
  Osteosarcoma
  Stomach cancer
  Advanced cancer
  Cardiomyopathy
  Colorectal carcinoma
  Colorectal neoplasm
  GNE myopathy
  Helicoid peripapillary chorioretinal degeneration
  Prostate cancer
  Prostate carcinoma
• UniProt ID: ARP2_HUMAN
• PDB ID: 6UHC; 6YW6; 6YW7
• Pfam ID: PF00022
• Sequence:
  MDSQGRKVVVCDNGTGFVKCGYAGSNFPEHIFPALVGRPIIRSTTKVGNIEIKDLMVGDE
  ASELRSMLEVNYPMENGIVRNWDDMKHLWDYTFGPEKLNIDTRNCKILLTEPPMNPTKNR
  EKIVEVMFETYQFSGVYVAIQAVLTLYAQGLLTGVVVDSGDGVTHICPVYEGFSLPHLTR
  RLDIAGRDITRYLIKLLLLRGYAFNHSADFETVRMIKEKLCYVGYNIEQEQKLALETTVL
  VESYTLPDGRIIKVGGERFEAPEALFQPHLINVEGVGVAELLFNTIQAADIDTRSEFYKH
  IVLSGGSTMYPGLPSRLERELKQLYLERVLKGDVEKLSKFKIRIEDPPRRKHMVFLGGAV
  LADIMKDKDNFWMTRQEYQEKGVRVLEKLGVTVR
• 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).
• 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)
  Neutrophil degranulation (R-HSA-6798695)
  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

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Definitive	Altered Expression	[1]
Glioma	DIS5RPEH	Definitive	Biomarker	[2]
Acquired immune deficiency syndrome	DISL5UOX	Strong	Biomarker	[3]
Bacillary dysentery	DISFZHKN	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Hirschsprung disease	DISUUSM1	Strong	Biomarker	[7]
Inflammation	DISJUQ5T	Strong	Genetic Variation	[8]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Oral cancer	DISLD42D	Strong	Biomarker	[10]
Pancreatic cancer	DISJC981	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[12]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Biomarker	[13]
Wiskott-Aldrich syndrome	DISATMDB	Strong	Biomarker	[14]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[15]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[15]
Stomach cancer	DISKIJSX	moderate	Biomarker	[6]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[16]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[17]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[18]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[18]
GNE myopathy	DIS73X4W	Limited	Altered Expression	[19]
Helicoid peripapillary chorioretinal degeneration	DISFSS5N	Limited	Altered Expression	[20]
Prostate cancer	DISF190Y	Limited	Altered Expression	[21]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[21]

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 2 (ACTR2).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Actin-related protein 2 (ACTR2).	[26]

8 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-related protein 2 (ACTR2).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Actin-related protein 2 (ACTR2).	[24]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Actin-related protein 2 (ACTR2).	[25]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Actin-related protein 2 (ACTR2).	[27]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Actin-related protein 2 (ACTR2).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Actin-related protein 2 (ACTR2).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Actin-related protein 2 (ACTR2).	[30]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Actin-related protein 2 (ACTR2).	[31]

References

• [1] Upregulation of Arp2 expression is associated with the prognosis and prediction of lymph node metastasis in bladder urothelial carcinoma.Cancer Manag Res. 2018 Mar 19;10:503-511. doi: 10.2147/CMAR.S155453. eCollection 2018.
• [2] Actin cytoskeleton regulator Arp2/3 complex is required for DLL1 activating Notch1 signaling to maintain the stem cell phenotype of glioma initiating cells.Oncotarget. 2017 May 16;8(20):33353-33364. doi: 10.18632/oncotarget.16495.
• [3] Inhibiting the Arp2/3 complex limits infection of both intracellular mature vaccinia virus and primate lentiviruses.Mol Biol Cell. 2004 Dec;15(12):5197-207. doi: 10.1091/mbc.e04-04-0279. Epub 2004 Sep 22.
• [4] A complex of N-WASP and WIP integrates signalling cascades that lead to actin polymerization.Nat Cell Biol. 2000 Jul;2(7):441-8. doi: 10.1038/35017080.
• [5] Breast cancer induced nociceptor aberrant growth and collateral sensory axonal branching.Oncotarget. 2017 Sep 1;8(44):76606-76621. doi: 10.18632/oncotarget.20609. eCollection 2017 Sep 29.
• [6] 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.
• [7] MPGES-1 derived PGE2 inhibits cell migration by regulating ARP2/3 in the pathogenesis of Hirschsprung disease.J Pediatr Surg. 2019 Oct;54(10):2032-2037. doi: 10.1016/j.jpedsurg.2019.01.001. Epub 2019 Feb 24.
• [8] 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.
• [9] Identification of risk loci and a polygenic risk score for lung cancer: a large-scale prospective cohort study in Chinese populations.Lancet Respir Med. 2019 Oct;7(10):881-891. doi: 10.1016/S2213-2600(19)30144-4. Epub 2019 Jul 17.
• [10] An update of knowledge on cortactin as a metastatic driver and potential therapeutic target in oral squamous cell carcinoma.Oral Dis. 2019 May;25(4):949-971. doi: 10.1111/odi.12913. Epub 2018 Jul 6.
• [11] Silencing of the ARP2/3 complex disturbs pancreatic cancer cell migration.Anticancer Res. 2013 Jan;33(1):45-52.
• [12] Altered Expression of ARP2/3 Complex Signaling Pathway Genes in Prefrontal Layer 3 Pyramidal Cells in Schizophrenia.Am J Psychiatry. 2017 Feb 1;174(2):163-171. doi: 10.1176/appi.ajp.2016.16020204. Epub 2016 Aug 13.
• [13] The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nat Immunol. 2008 Nov;9(11):1307-15. doi: 10.1038/ni.1662. Epub 2008 Oct 5.
• [14] Single-Turnover Activation of Arp2/3 Complex by Dip1 May Balance Nucleation of Linear versus Branched Actin Filaments.Curr Biol. 2019 Oct 7;29(19):3331-3338.e7. doi: 10.1016/j.cub.2019.08.023. Epub 2019 Sep 26.
• [15] CD99 suppresses osteosarcoma cell migration through inhibition of ROCK2 activity.Oncogene. 2014 Apr 10;33(15):1912-21. doi: 10.1038/onc.2013.152. Epub 2013 May 6.
• [16] Benproperine, an ARPC2 inhibitor, suppresses cancer cell migration and tumor metastasis.Biochem Pharmacol. 2019 May;163:46-59. doi: 10.1016/j.bcp.2019.01.017. Epub 2019 Jan 30.
• [17] Clinical and molecular cytogenetic characterization of four unrelated patients carrying 2p14 microdeletions.Am J Med Genet A. 2017 Aug;173(8):2268-2274. doi: 10.1002/ajmg.a.38307. Epub 2017 Jun 9.
• [18] Correlation between liver metastasis of the colocalization of actin-related protein 2 and 3 complex and WAVE2 in colorectal carcinoma.Cancer Sci. 2007 Jul;98(7):992-9. doi: 10.1111/j.1349-7006.2007.00488.x. Epub 2007 Apr 23.
• [19] 1,25(OH)2D3 Induces Actin Depolymerization in Endometrial Carcinoma Cells by Targeting RAC1 and PAK1.Cell Physiol Biochem. 2016;40(6):1455-1464. doi: 10.1159/000453197. Epub 2016 Dec 20.
• [20] The Red Alga Gracilariopsis chorda and Its Active Constituent Arachidonic Acid Promote Spine Dynamics via Dendritic Filopodia and Potentiate Functional Synaptic Plasticity in Hippocampal Neurons.J Med Food. 2018 May;21(5):481-488. doi: 10.1089/jmf.2017.4026. Epub 2018 Mar 2.
• [21] ARP2, a novel pro-apoptotic protein expressed in epithelial prostate cancer LNCaP cells and epithelial ovary CHO transformed cells.PLoS One. 2014 Jan 22;9(1):e86089. doi: 10.1371/journal.pone.0086089. eCollection 2014.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Distinct genetic profile in peripheral blood mononuclear cells of psoriatic arthritis patients treated with methotrexate and TNF-inhibitors. Clin Rheumatol. 2014 Dec;33(12):1815-21. doi: 10.1007/s10067-014-2807-8. Epub 2014 Oct 24.
• [26] 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.
• [27] 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.
• [28] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [29] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [30] 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.
• [31] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.