Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT29P1FM)

• DOT Name: Phosphatase and actin regulator 4 (PHACTR4)
• Gene Name: PHACTR4
• Related Disease:
  Disease of orbital part of eye adnexa
  Neoplasm
• UniProt ID: PHAR4_HUMAN
• Pfam ID: PF02755
• Sequence:
  MEDPFEEADQPTTEPGMVLDSVEAGDTTPPTKRKSKFSGFGKIFKPWKWRKKKSSDKFKE
  TSEVLERKISMRKPREELVKRGVLLEDPEQGGEDPGKPSDAMLKNGHTTPIGNARSSSPV
  QVEEEPVRLASLRKAIPEEDLKKRLGSTGSQPNSEAESVPENVPKPPLLPPKRPLSSSHE
  ASEGQAKDATSSGGTARFIISTSITTAPAATTAATSLAKTVNLSVTPSPAPRTLPAAPAS
  TNTTATPSLTHMVPAKQPPIPPPKPAHRNSNPVIAELSQAINSGTLLSKPSPPLPPKRGI
  PSTSVPTLESAAAITTKTPSDEREKSTCSMGSELLPMISPRSPSPPLPTHIPPEPPRTPP
  FPAKTFQVVPEIEFPPSLDLHQEIPQQEDQKKEVPKRILDQNFGEPHIPSRLPPLPLHIR
  IQQALTSPLPMTPILEGSHRAHSLLFENSDSFSEDSSTLGRTRSLPITIEMLKVPDDEEE
  EEQTCPSTFSEEMTPTSVIPKLPQCLREEEEKESDSDSEGPIQYRDEEDEDESYQSALAN
  KVKRKDTLAMKLNHRPSEPELNLNSWPCKSKEEWNEIRHQIGNTLIRRLSQRPTPEELEQ
  RNILQPKNEADRQAEKREIKRRLTRKLSQRPTVAELLARKILRFNEYVEVTDAQDYDRRA
  DKPWTKLTPADKAAIRKELNEFKSSEMEVHEESKHFTRYHRP
• Function: Regulator of protein phosphatase 1 (PP1) required for neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development. Acts as an activator of PP1 by interacting with PPP1CA and preventing phosphorylation of PPP1CA at 'Thr-320'. During neural tube closure, localizes to the ventral neural tube and activates PP1, leading to down-regulate cell proliferation within cranial neural tissue and the neural retina. Also acts as a regulator of migration of enteric neural crest cells (ENCCs) by activating PP1, leading to dephosphorylation and subsequent activation of cofilin (COF1 or COF2) and repression of the integrin signaling through the RHO/ROCK pathway.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Disease of orbital part of eye adnexa	DISGWPWX	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Limited	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Phosphatase and actin regulator 4 (PHACTR4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatase and actin regulator 4 (PHACTR4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phosphatase and actin regulator 4 (PHACTR4).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphatase and actin regulator 4 (PHACTR4).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Phosphatase and actin regulator 4 (PHACTR4).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Phosphatase and actin regulator 4 (PHACTR4).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Phosphatase and actin regulator 4 (PHACTR4).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Phosphatase and actin regulator 4 (PHACTR4).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phosphatase and actin regulator 4 (PHACTR4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Phosphatase and actin regulator 4 (PHACTR4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phosphatase and actin regulator 4 (PHACTR4).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Phosphatase and actin regulator 4 (PHACTR4).	[7]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Phosphatase and actin regulator 4 (PHACTR4).	[7]

References

• [1] Avian Binocularity and Adaptation to Nocturnal Environments: Genomic Insights from a Highly Derived Visual Phenotype.Genome Biol Evol. 2019 Aug 1;11(8):2244-2255. doi: 10.1093/gbe/evz111.
• [2] Combinatory RNA-Sequencing Analyses Reveal a Dual Mode of Gene Regulation by ADAR1 in Gastric Cancer.Dig Dis Sci. 2018 Jul;63(7):1835-1850. doi: 10.1007/s10620-018-5081-9. Epub 2018 Apr 25.
• [3] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] 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.
• [7] 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.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] 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.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.