Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAXA66U)

• DOT Name: F-actin-capping protein subunit alpha-1 (CAPZA1)
• Synonyms: CapZ alpha-1
• Gene Name: CAPZA1
• Related Disease:
  Esophageal squamous cell carcinoma
  High blood pressure
  Advanced cancer
  Gastric cancer
  Hepatocellular carcinoma
  Neoplasm
  Stomach cancer
• UniProt ID: CAZA1_HUMAN
• PDB ID: 1MQ1; 1MWN; 7T5Q; 8F8Q
• Pfam ID: PF01267
• Sequence:
  MADFDDRVSDEEKVRIAAKFITHAPPGEFNEVFNDVRLLLNNDNLLREGAAHAFAQYNMD
  QFTPVKIEGYEDQVLITEHGDLGNSRFLDPRNKISFKFDHLRKEASDPQPEEADGGLKSW
  RESCDSALRAYVKDHYSNGFCTVYAKTIDGQQTIIACIESHQFQPKNFWNGRWRSEWKFT
  ITPPTAQVVGVLKIQVHYYEDGNVQLVSHKDVQDSLTVSNEAQTAKEFIKIIENAENEYQ
  TAISENYQTMSDTTFKALRRQLPVTRTKIDWNKILSYKIGKEMQNA
• Function: F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike other capping proteins (such as gelsolin and severin), these proteins do not sever actin filaments. May play a role in the formation of epithelial cell junctions. Forms, with CAPZB, the barbed end of the fast growing ends of actin filaments in the dynactin complex and stabilizes dynactin structure. The dynactin multiprotein complex activates the molecular motor dynein for ultra-processive transport along microtubules.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Motor proteins (hsa04814)
  Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway:
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  Advanced glycosylation endproduct receptor signaling (R-HSA-879415)
  Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation (R-HSA-8950505)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  MHC class II antigen presentation (R-HSA-2132295)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[1]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[3]
Gastric cancer	DISXGOUK	Limited	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[4]
Neoplasm	DISZKGEW	Limited	Altered Expression	[3]
Stomach cancer	DISKIJSX	Limited	Biomarker	[3]

2 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 F-actin-capping protein subunit alpha-1 (CAPZA1).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of F-actin-capping protein subunit alpha-1 (CAPZA1).	[10]

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 F-actin-capping protein subunit alpha-1 (CAPZA1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of F-actin-capping protein subunit alpha-1 (CAPZA1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of F-actin-capping protein subunit alpha-1 (CAPZA1).	[8]
Aspirin	DM672AH	Approved	Aspirin increases the expression of F-actin-capping protein subunit alpha-1 (CAPZA1).	[9]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of F-actin-capping protein subunit alpha-1 (CAPZA1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of F-actin-capping protein subunit alpha-1 (CAPZA1).	[12]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of F-actin-capping protein subunit alpha-1 (CAPZA1).	[13]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of F-actin-capping protein subunit alpha-1 (CAPZA1).	[14]

References

• [1] Using proteomic approach to identify tumor-associated proteins as biomarkers in human esophageal squamous cell carcinoma.J Proteome Res. 2011 Jun 3;10(6):2863-72. doi: 10.1021/pr200141c. Epub 2011 May 3.
• [2] Interethnic analyses of blood pressure loci in populations of East Asian and European descent.Nat Commun. 2018 Nov 28;9(1):5052. doi: 10.1038/s41467-018-07345-0.
• [3] Prognostic value of CAPZA1 overexpression in gastric cancer.Int J Oncol. 2013 May;42(5):1569-77. doi: 10.3892/ijo.2013.1867. Epub 2013 Mar 27.
• [4] Hypoxia induces actin cytoskeleton remodeling by regulating the binding of CAPZA1 to F-actin via PIP2 to drive EMT in hepatocellular carcinoma.Cancer Lett. 2019 Apr 28;448:117-127. doi: 10.1016/j.canlet.2019.01.042. Epub 2019 Feb 8.
• [5] 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.
• [6] 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.
• [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] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [9] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Annexin A3 may play an important role in ochratoxin-induced malignant transformation of human gastric epithelium cells. Toxicol Lett. 2019 Oct 1;313:150-158. doi: 10.1016/j.toxlet.2019.07.002. Epub 2019 Jul 2.
• [14] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.