Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOD5NID)

• DOT Name: Receptor-type tyrosine-protein phosphatase epsilon (PTPRE)
• Synonyms: Protein-tyrosine phosphatase epsilon; R-PTP-epsilon; EC 3.1.3.48
• Gene Name: PTPRE
• Related Disease:
  Acute myelogenous leukaemia
  Allergic asthma
  Obesity
  Asthma
• UniProt ID: PTPRE_HUMAN
• PDB ID: 2JJD; 6D3F; 6D4D; 6D4F
• EC Number: 3.1.3.48
• Pfam ID: PF00102
• Sequence:
  MEPLCPLLLVGFSLPLARALRGNETTADSNETTTTSGPPDPGASQPLLAWLLLPLLLLLL
  VLLLAAYFFRFRKQRKAVVSTSDKKMPNGILEEQEQQRVMLLSRSPSGPKKYFPIPVEHL
  EEEIRIRSADDCKQFREEFNSLPSGHIQGTFELANKEENREKNRYPNILPNDHSRVILSQ
  LDGIPCSDYINASYIDGYKEKNKFIAAQGPKQETVNDFWRMVWEQKSATIVMLTNLKERK
  EEKCHQYWPDQGCWTYGNIRVCVEDCVVLVDYTIRKFCIQPQLPDGCKAPRLVSQLHFTS
  WPDFGVPFTPIGMLKFLKKVKTLNPVHAGPIVVHCSAGVGRTGTFIVIDAMMAMMHAEQK
  VDVFEFVSRIRNQRPQMVQTDMQYTFIYQALLEYYLYGDTELDVSSLEKHLQTMHGTTTH
  FDKIGLEEEFRKLTNVRIMKENMRTGNLPANMKKARVIQIIPYDFNRVILSMKRGQEYTD
  YINASFIDGYRQKDYFIATQGPLAHTVEDFWRMIWEWKSHTIVMLTEVQEREQDKCYQYW
  PTEGSVTHGEITIEIKNDTLSEAISIRDFLVTLNQPQARQEEQVRVVRQFHFHGWPEIGI
  PAEGKGMIDLIAAVQKQQQQTGNHPITVHCSAGAGRTGTFIALSNILERVKAEGLLDVFQ
  AVKSLRLQRPHMVQTLEQYEFCYKVVQDFIDIFSDYANFK
• Function: Isoform 1 plays a critical role in signaling transduction pathways and phosphoprotein network topology in red blood cells. May play a role in osteoclast formation and function; Isoform 2 acts as a negative regulator of insulin receptor (IR) signaling in skeletal muscle. Regulates insulin-induced tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate 1 (IRS-1), phosphorylation of protein kinase B and glycogen synthase kinase-3 and insulin induced stimulation of glucose uptake; Isoform 1 and isoform 2 act as a negative regulator of FceRI-mediated signal transduction leading to cytokine production and degranulation, most likely by acting at the level of SYK to affect downstream events such as phosphorylation of SLP76 and LAT and mobilization of Ca(2+).
• Tissue Specificity: Expressed in giant cell tumor (osteoclastoma rich in multinucleated osteoclastic cells).

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
Allergic asthma	DISHF0H3	Strong	Biomarker	[2]
Obesity	DIS47Y1K	Strong	Biomarker	[3]
Asthma	DISW9QNS	moderate	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Receptor-type tyrosine-protein phosphatase epsilon (PTPRE) affects the response to substance of Mitoxantrone.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[14]
Marinol	DM70IK5	Approved	Marinol increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[15]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[19]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Receptor-type tyrosine-protein phosphatase epsilon (PTPRE).	[21]

References

• [1] Deregulation of protein phosphatase expression in acute myeloid leukemia.Med Oncol. 2013 Jun;30(2):517. doi: 10.1007/s12032-013-0517-8. Epub 2013 Feb 26.
• [2] LncRNA PTPRE-AS1 modulates M2 macrophage activation and inflammatory diseases by epigenetic promotion of PTPRE.Sci Adv. 2019 Dec 11;5(12):eaax9230. doi: 10.1126/sciadv.aax9230. eCollection 2019 Dec.
• [3] Inter-Tissue Gene Co-Expression Networks between Metabolically Healthy and Unhealthy Obese Individuals.PLoS One. 2016 Dec 1;11(12):e0167519. doi: 10.1371/journal.pone.0167519. eCollection 2016.
• [4] Attempted replication of 50 reported asthma risk genes identifies a SNP in RAD50 as associated with childhood atopic asthma.Hum Hered. 2011;71(2):97-105. doi: 10.1159/000319536. Epub 2011 Jul 6.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [10] 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.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] 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.
• [13] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [14] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [15] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [16] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [17] Resveratrol attenuates constitutive STAT3 and STAT5 activation through induction of PTP and SHP-2 tyrosine phosphatases and potentiates sorafenib-induced apoptosis in renal cell carcinoma. BMC Nephrol. 2016 Feb 25;17:19. doi: 10.1186/s12882-016-0233-7.
• [18] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [21] 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.
• [22] 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.
• [23] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.