Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU0MVR7)

• DOT Name: Protein phosphatase 1F (PPM1F)
• Synonyms: EC 3.1.3.16; Ca(2+)/calmodulin-dependent protein kinase phosphatase; CaM-kinase phosphatase; CaMKPase; Partner of PIX 2; Protein fem-2 homolog; hFem-2
• Gene Name: PPM1F
• Related Disease:
  Neoplasm
  Advanced cancer
  Anxiety
  Anxiety disorder
  Depression
  Hepatocellular carcinoma
  Post-traumatic stress disorder
• UniProt ID: PPM1F_HUMAN
• EC Number: 3.1.3.16
• Pfam ID: PF00481
• Sequence:
  MSSGAPQKSSPMASGAEETPGFLDTLLQDFPALLNPEDPLPWKAPGTVLSQEEVEGELAE
  LAMGFLGSRKAPPPLAAALAHEAVSQLLQTDLSEFRKLPREEEEEEEDDDEEEKAPVTLL
  DAQSLAQSFFNRLWEVAGQWQKQVPLAARASQRQWLVSIHAIRNTRRKMEDRHVSLPSFN
  QLFGLSDPVNRAYFAVFDGHGGVDAARYAAVHVHTNAARQPELPTDPEGALREAFRRTDQ
  MFLRKAKRERLQSGTTGVCALIAGATLHVAWLGDSQVILVQQGQVVKLMEPHRPERQDEK
  ARIEALGGFVSHMDCWRVNGTLAVSRAIGDVFQKPYVSGEADAASRALTGSEDYLLLACD
  GFFDVVPHQEVVGLVQSHLTRQQGSGLRVAEELVAAARERGSHDNITVMVVFLRDPQELL
  EGGNQGEGDPQAEGRRQDLPSSLPEPETQAPPRS
• Function: Dephosphorylates and concomitantly deactivates CaM-kinase II activated upon autophosphorylation, and CaM-kinases IV and I activated upon phosphorylation by CaM-kinase kinase. Promotes apoptosis.
• Reactome Pathway: Negative regulation of NMDA receptor-mediated neuronal transmission (R-HSA-9617324)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Anxiety	DISIJDBA	Strong	Altered Expression	[3]
Anxiety disorder	DISBI2BT	Strong	Altered Expression	[3]
Depression	DIS3XJ69	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Post-traumatic stress disorder	DISHL1EY	Strong	Biomarker	[4]

4 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 Protein phosphatase 1F (PPM1F).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein phosphatase 1F (PPM1F).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein phosphatase 1F (PPM1F).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein phosphatase 1F (PPM1F).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Protein phosphatase 1F (PPM1F).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein phosphatase 1F (PPM1F).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Protein phosphatase 1F (PPM1F).	[10]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Protein phosphatase 1F (PPM1F).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein phosphatase 1F (PPM1F).	[12]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Protein phosphatase 1F (PPM1F).	[15]

References

• [1] The POPX2 phosphatase regulates cancer cell motility and invasiveness.Cell Cycle. 2010 Jan 1;9(1):179-87. doi: 10.4161/cc.9.1.10406. Epub 2010 Jan 22.
• [2] Functions and dysfunctions of Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP/PPM1F) and CaMKP-N/PPM1E.Arch Biochem Biophys. 2018 Feb 15;640:83-92. doi: 10.1016/j.abb.2018.01.001. Epub 2018 Jan 6.
• [3] Expression of the PPM1F Gene Is Regulated by Stress and Associated With Anxiety and Depression.Biol Psychiatry. 2018 Feb 1;83(3):284-295. doi: 10.1016/j.biopsych.2017.08.013. Epub 2017 Aug 30.
• [4] The PPM1F gene moderates the association between PTSD and cortical thickness.J Affect Disord. 2019 Dec 1;259:201-209. doi: 10.1016/j.jad.2019.08.055. Epub 2019 Aug 19.
• [5] CircSLC3A2 functions as an oncogenic factor in hepatocellular carcinoma by sponging miR-490-3p and regulating PPM1F expression.Mol Cancer. 2018 Nov 23;17(1):165. doi: 10.1186/s12943-018-0909-7.
• [6] 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.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [8] 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.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] 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.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.
• [15] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.