Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH5EXZC)

• DOT Name: Phospholipid phosphatase 4 (PLPP4)
• Synonyms: EC 3.1.3.4; EC 3.6.1.75; Phosphatidic acid phosphatase type 2 domain-containing protein 1A
• Gene Name: PLPP4
• Related Disease:
  Alzheimer disease
  Lung adenocarcinoma
  Lung carcinoma
  Lung squamous cell carcinoma
  Breast cancer
  Breast carcinoma
  Prostate carcinoma
• UniProt ID: PLPP4_HUMAN
• EC Number: 3.1.3.4; 3.6.1.75
• Pfam ID: PF01569
• Sequence:
  MRELAIEIGVRALLFGVFVFTEFLDPFQRVIQPEEIWLYKNPLVQSDNIPTRLMFAISFL
  TPLAVICVVKIIRRTDKTEIKEAFLAVSLALALNGVCTNTIKLIVGRPRPDFFYRCFPDG
  VMNSEMHCTGDPDLVSEGRKSFPSIHSSFAFSGLGFTTFYLAGKLHCFTESGRGKSWRLC
  AAILPLYCAMMIALSRMCDYKHHWQDSFVGGVIGLIFAYICYRQHYPPLANTACHKPYVS
  LRVPASLKKEERPTADSAPSLPLEGITEGPV
• Function: Magnesium-independent phospholipid phosphatase with broad substrate specificity. Preferentially catalyzes the conversion of diacylglycerol pyrophosphate into phosphatidate but can also act on phosphatidate and lysophosphatidate. Phospholipid phosphatases are involved in both the synthesis of lipids and the degradation or generation of lipid-signaling molecules like diacylglycerol.
• Tissue Specificity: Expressed mainly to the brain, kidney and testis, and to a lesser extent the bone marrow, thymus, prostate, liver and uterus.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
• Reactome Pathway: Role of phospholipids in phagocytosis (R-HSA-2029485)
• BioCyc Pathway: MetaCyc:G66-31698-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[3]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[4]

3 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 Phospholipid phosphatase 4 (PLPP4).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Phospholipid phosphatase 4 (PLPP4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Phospholipid phosphatase 4 (PLPP4).	[17]

11 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 Phospholipid phosphatase 4 (PLPP4).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipid phosphatase 4 (PLPP4).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Phospholipid phosphatase 4 (PLPP4).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Phospholipid phosphatase 4 (PLPP4).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Phospholipid phosphatase 4 (PLPP4).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Phospholipid phosphatase 4 (PLPP4).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Phospholipid phosphatase 4 (PLPP4).	[12]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Phospholipid phosphatase 4 (PLPP4).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Phospholipid phosphatase 4 (PLPP4).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phospholipid phosphatase 4 (PLPP4).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Phospholipid phosphatase 4 (PLPP4).	[18]

References

• [1] Genome-wide association study of the rate of cognitive decline in Alzheimer's disease.Alzheimers Dement. 2014 Jan;10(1):45-52. doi: 10.1016/j.jalz.2013.01.008. Epub 2013 Mar 25.
• [2] Phospholipid Phosphatase 4 promotes proliferation and tumorigenesis, and activates Ca(2+)-permeable Cationic Channel in lung carcinoma cells.Mol Cancer. 2017 Aug 29;16(1):147. doi: 10.1186/s12943-017-0717-5.
• [3] Microarray phosphatome profiling of breast cancer patients unveils a complex phosphatase regulatory role of the MAPK and PI3K pathways in estrogen receptor-negative breast cancers.Int J Oncol. 2014 Dec;45(6):2250-66. doi: 10.3892/ijo.2014.2648. Epub 2014 Sep 9.
• [4] Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy.J Natl Cancer Inst. 2020 Feb 1;112(2):179-190. doi: 10.1093/jnci/djz075.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] 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.
• [9] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] 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.
• [16] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [17] 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.
• [18] 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.