Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0BQAXX)

• DOT Name: Phospholipid phosphatase 2 (PLPP2)
• Synonyms: EC 3.1.3.-; EC 3.1.3.4; Lipid phosphate phosphohydrolase 2; PAP2-gamma; PAP2-G; Phosphatidate phosphohydrolase type 2c; Phosphatidic acid phosphatase 2c; PAP-2c; PAP2c
• Gene Name: PLPP2
• Related Disease:
  Advanced cancer
  Carcinoma
  Malignant soft tissue neoplasm
  Neoplasm
  Sarcoma
  Squamous cell carcinoma
• UniProt ID: PLPP2_HUMAN
• EC Number: 3.1.3.-; 3.1.3.4
• Pfam ID: PF01569
• Sequence:
  MQRRWVFVLLDVLCLLVASLPFAILTLVNAPYKRGFYCGDDSIRYPYRPDTITHGLMAGV
  TITATVILVSAGEAYLVYTDRLYSRSDFNNYVAAVYKVLGTFLFGAAVSQSLTDLAKYMI
  GRLRPNFLAVCDPDWSRVNCSVYVQLEKVCRGNPADVTEARLSFYSGHSSFGMYCMVFLA
  LYVQARLCWKWARLLRPTVQFFLVAFALYVGYTRVSDYKHHWSDVLVGLLQGALVAALTV
  CYISDFFKARPPQHCLKEEELERKPSLSLTLTLGEADHNHYGYPHSSS
• Function: Magnesium-independent phospholipid phosphatase that catalyzes the dephosphorylation of a variety of glycerolipid and sphingolipid phosphate esters including phosphatidate/PA, lysophosphatidate/LPA, sphingosine 1-phosphate/S1P and ceramide 1-phosphate/C1P. Has no apparent extracellular phosphatase activity and therefore most probably acts intracellularly. Also acts on N-oleoyl ethanolamine phosphate/N-(9Z-octadecenoyl)-ethanolamine phosphate, a potential physiological compound. Through dephosphorylation of these bioactive lipid mediators produces new bioactive compounds and may regulate signal transduction in different cellular processes (Probable). Indirectly regulates, for instance, cell cycle G1/S phase transition through its phospholipid phosphatase activity.
• Tissue Specificity: Found mainly in brain, pancreas and placenta.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
  Ether lipid metabolism (hsa00565)
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Phospholipase D sig.ling pathway (hsa04072)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Fat digestion and absorption (hsa04975)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway: Sphingolipid metabolism (R-HSA-428157)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[1]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Sarcoma	DISZDG3U	Strong	Altered Expression	[1]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Phospholipid phosphatase 2 (PLPP2) decreases the response to substance of Arsenic trioxide.	[19]

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 Phospholipid phosphatase 2 (PLPP2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Phospholipid phosphatase 2 (PLPP2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phospholipid phosphatase 2 (PLPP2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phospholipid phosphatase 2 (PLPP2).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Phospholipid phosphatase 2 (PLPP2).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Phospholipid phosphatase 2 (PLPP2).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Phospholipid phosphatase 2 (PLPP2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Phospholipid phosphatase 2 (PLPP2).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Phospholipid phosphatase 2 (PLPP2).	[10]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Phospholipid phosphatase 2 (PLPP2).	[11]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Phospholipid phosphatase 2 (PLPP2).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phospholipid phosphatase 2 (PLPP2).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Phospholipid phosphatase 2 (PLPP2).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phospholipid phosphatase 2 (PLPP2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phospholipid phosphatase 2 (PLPP2).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phospholipid phosphatase 2 (PLPP2).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phospholipid phosphatase 2 (PLPP2).	[17]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Phospholipid phosphatase 2 (PLPP2).	[18]

References

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• [2] Altered expression of sphingosine-1-phosphate metabolizing enzymes in oral cancer correlate with clinicopathological attributes. Cancer Invest. 2017 Feb 7;35(2):139-141.
• [3] 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.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [6] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [11] Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
• [12] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [19] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.