Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYBM4PK)

• DOT Name: Plastin-3 (PLS3)
• Synonyms: T-plastin
• Gene Name: PLS3
• Related Disease:
  X-linked osteoporosis with fractures
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Bone disease
  Cerebellar ataxia
  Colon cancer
  Colon carcinoma
  Neoplasm
  Osteogenesis imperfecta
  Osteogenesis imperfecta type 1
  Osteoporosis
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Gastric cancer
  Osteoarthritis
  Primary cutaneous T-cell lymphoma
  Spinal muscular atrophy
  Stomach cancer
• UniProt ID: PLST_HUMAN
• PDB ID: 1AOA; 1WJO; 7R94; 7SX8; 7SX9; 7SXA
• Pfam ID: PF00307 ; PF13499
• Sequence:
  MDEMATTQISKDELDELKEAFAKVDLNSNGFICDYELHELFKEANMPLPGYKVREIIQKL
  MLDGDRNKDGKISFDEFVYIFQEVKSSDIAKTFRKAINRKEGICALGGTSELSSEGTQHS
  YSEEEKYAFVNWINKALENDPDCRHVIPMNPNTDDLFKAVGDGIVLCKMINLSVPDTIDE
  RAINKKKLTPFIIQENLNLALNSASAIGCHVVNIGAEDLRAGKPHLVLGLLWQIIKIGLF
  ADIELSRNEALAALLRDGETLEELMKLSPEELLLRWANFHLENSGWQKINNFSADIKDSK
  AYFHLLNQIAPKGQKEGEPRIDINMSGFNETDDLKRAESMLQQADKLGCRQFVTPADVVS
  GNPKLNLAFVANLFNKYPALTKPENQDIDWTLLEGETREERTFRNWMNSLGVNPHVNHLY
  ADLQDALVILQLYERIKVPVDWSKVNKPPYPKLGANMKKLENCNYAVELGKHPAKFSLVG
  IGGQDLNDGNQTLTLALVWQLMRRYTLNVLEDLGDGQKANDDIIVNWVNRTLSEAGKSTS
  IQSFKDKTISSSLAVVDLIDAIQPGCINYDLVKSGNLTEDDKHNNAKYAVSMARRIGARV
  YALPEDLVEVKPKMVMTVFACLMGRGMKRV
• Function: Actin-bundling protein found in intestinal microvilli, hair cell stereocilia, and fibroblast filopodia. May play a role in the regulation of bone development.
• Tissue Specificity: Expressed in a variety of organs, including muscle, brain, uterus and esophagus.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked osteoporosis with fractures	DISD1P75	Definitive	X-linked	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bone disease	DISE1F82	Strong	Genetic Variation	[4]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Genetic Variation	[6]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Osteogenesis imperfecta	DIS7XQSD	Strong	Biomarker	[8]
Osteogenesis imperfecta type 1	DISPEDS3	Strong	Genetic Variation	[9]
Osteoporosis	DISF2JE0	Strong	Biomarker	[10]
Breast cancer	DIS7DPX1	Limited	Biomarker	[11]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[12]
Gastric cancer	DISXGOUK	Limited	Biomarker	[13]
Osteoarthritis	DIS05URM	Limited	Biomarker	[14]
Primary cutaneous T-cell lymphoma	DIS35WVW	Limited	Altered Expression	[15]
Spinal muscular atrophy	DISTLKOB	Limited	Biomarker	[5]
Stomach cancer	DISKIJSX	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Plastin-3 (PLS3) increases the response to substance of Arsenic.	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Plastin-3 (PLS3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Plastin-3 (PLS3).	[27]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Plastin-3 (PLS3).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Plastin-3 (PLS3).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin affects the expression of Plastin-3 (PLS3).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Plastin-3 (PLS3).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Plastin-3 (PLS3).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Plastin-3 (PLS3).	[21]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Plastin-3 (PLS3).	[22]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Plastin-3 (PLS3).	[23]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Plastin-3 (PLS3).	[24]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Plastin-3 (PLS3).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Plastin-3 (PLS3).	[25]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Plastin-3 (PLS3).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Plastin-3 (PLS3).	[26]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Plastin-3 (PLS3).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Plastin-3 (PLS3).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Plastin-3 (PLS3).	[25]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Plastin-3 (PLS3).	[31]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Plastin-3 (PLS3).	[32]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Plastin-3 (PLS3).	[33]

References

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• [5] PLS3 Overexpression Delays Ataxia in Chp1 Mutant Mice.Front Neurosci. 2019 Sep 19;13:993. doi: 10.3389/fnins.2019.00993. eCollection 2019.
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• [8] NOVEL MUTATIONS IN THE WNT1, TMEM38B, P4HB, AND PLS3 GENES IN FOUR UNRELATED CHINESE FAMILIES WITH OSTEOGENESIS IMPERFECTA. Endocr Pract. 2019 Mar;25(3):230-241. doi: 10.4158/EP-2018-0443.
• [9] PLS3 mutations in X-linked osteoporosis with fractures. N Engl J Med. 2013 Oct 17;369(16):1529-36. doi: 10.1056/NEJMoa1308223. Epub 2013 Oct 2.
• [10] Mice lacking plastin-3 display a specific defect of cortical bone acquisition.Bone. 2020 Jan;130:115062. doi: 10.1016/j.bone.2019.115062. Epub 2019 Oct 31.
• [11] Plastin 3 down-regulation augments the sensitivity of MDA-MB-231 cells to paclitaxel via the p38 MAPK signalling pathway.Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):685-695. doi: 10.1080/21691401.2019.1576707.
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• [16] 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.
• [17] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [18] 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.
• [19] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [25] 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.
• [26] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [27] 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.
• [28] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [29] 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.
• [30] 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.
• [31] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [32] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [33] Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. J Biol Chem. 1999 Feb 26;274(9):5830-4. doi: 10.1074/jbc.274.9.5830.
• [34] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.