Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0S09B3)

• DOT Name: Tyrosine-protein phosphatase non-receptor type 18 (PTPN18)
• Synonyms: EC 3.1.3.48; Brain-derived phosphatase
• Gene Name: PTPN18
• Related Disease:
  Endometrial cancer
  Endometrial carcinoma
  Gastrointestinal stromal tumour
  Pyogenic arthritis-pyoderma gangrenosum-acne syndrome
  Hepatocellular carcinoma
• UniProt ID: PTN18_HUMAN
• PDB ID: 2OC3; 4GFU; 4GFV; 4NND
• EC Number: 3.1.3.48
• Pfam ID: PF00102
• Sequence:
  MSRSLDSARSFLERLEARGGREGAVLAGEFSDIQACSAAWKADGVCSTVAGSRPENVRKN
  RYKDVLPYDQTRVILSLLQEEGHSDYINGNFIRGVDGSLAYIATQGPLPHTLLDFWRLVW
  EFGVKVILMACREIENGRKRCERYWAQEQEPLQTGLFCITLIKEKWLNEDIMLRTLKVTF
  QKESRSVYQLQYMSWPDRGVPSSPDHMLAMVEEARRLQGSGPEPLCVHCSAGCGRTGVLC
  TVDYVRQLLLTQMIPPDFSLFDVVLKMRKQRPAAVQTEEQYRFLYHTVAQMFCSTLQNAS
  PHYQNIKENCAPLYDDALFLRTPQALLAIPRPPGGVLRSISVPGSPGHAMADTYAVVQKR
  GAPAGAGSGTQTGTGTGTGARSAEEAPLYSKVTPRAQRPGAHAEDARGTLPGRVPADQSP
  AGSGAYEDVAGGAQTGGLGFNLRIGRPKGPRDPPAEWTRV
• Function: Differentially dephosphorylate autophosphorylated tyrosine kinases which are known to be overexpressed in tumor tissues.
• Tissue Specificity: Expressed in brain, colon and several tumor-derived cell lines.
• Reactome Pathway:
  Interleukin-37 signaling (R-HSA-9008059)
  Downregulation of ERBB2 signaling (R-HSA-8863795)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Endometrial cancer	DISW0LMR	Strong	Biomarker	[1]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[1]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[2]
Pyogenic arthritis-pyoderma gangrenosum-acne syndrome	DIS7E15X	Strong	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[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 Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tyrosine-protein phosphatase non-receptor type 18 (PTPN18).	[15]

References

• [1] Downregulation of PTPN18 can inhibit proliferation and metastasis and promote apoptosis of endometrial cancer.Clin Exp Pharmacol Physiol. 2019 Aug;46(8):734-742. doi: 10.1111/1440-1681.13098. Epub 2019 May 30.
• [2] miR-125a-5p regulation increases phosphorylation of FAK that contributes to imatinib resistance in gastrointestinal stromal tumors.Exp Cell Res. 2018 Oct 1;371(1):287-296. doi: 10.1016/j.yexcr.2018.08.028. Epub 2018 Aug 24.
• [3] PEST family phosphatases in immunity, autoimmunity, and autoinflammatory disorders.Immunol Rev. 2009 Mar;228(1):312-24. doi: 10.1111/j.1600-065X.2008.00747.x.
• [4] Prognostic Value of Phosphotyrosine Phosphatases in Hepatocellular Carcinoma.Cell Physiol Biochem. 2018;46(6):2335-2346. doi: 10.1159/000489625. Epub 2018 May 4.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] 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.
• [9] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] 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.
• [13] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] 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.