Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNAR1I2)

• DOT Name: Tyrosine-protein phosphatase non-receptor type 9 (PTPN9)
• Synonyms: EC 3.1.3.48; Protein-tyrosine phosphatase MEG2; PTPase MEG2
• Gene Name: PTPN9
• Related Disease:
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Esophageal squamous cell carcinoma
  Gastric cancer
  Glioma
  Neoplasm
  Non-insulin dependent diabetes
  Polycythemia vera
  Stomach cancer
  Colorectal carcinoma
  Hepatocellular carcinoma
  Glaucoma/ocular hypertension
  Hyperglycemia
• UniProt ID: PTN9_HUMAN
• PDB ID: 2PA5; 4GE2; 4GE5; 4GE6; 4ICZ; 6KZQ; 6L03
• EC Number: 3.1.3.48
• Pfam ID: PF00650 ; PF00102
• Sequence:
  MEPATAPRPDMAPELTPEEEQATKQFLEEINKWTVQYNVSPLSWNVAVKFLMARKFDVLR
  AIELFHSYRETRRKEGIVKLKPHEEPLRSEILSGKFTILNVRDPTGASIALFTARLHHPH
  KSVQHVVLQALFYLLDRAVDSFETQRNGLVFIYDMCGSNYANFELDLGKKVLNLLKGAFP
  ARLKKVLIVGAPIWFRVPYSIISLLLKDKVRERIQILKTSEVTQHLPRECLPENLGGYVK
  IDLATWNFQFLPQVNGHPDPFDEIILFSLPPALDWDSVHVPGPHAMTIQELVDYVNARQK
  QGIYEEYEDIRRENPVGTFHCSMSPGNLEKNRYGDVPCLDQTRVKLTKRSGHTQTDYINA
  SFMDGYKQKNAYIGTQGPLENTYRDFWLMVWEQKVLVIVMTTRFEEGGRRKCGQYWPLEK
  DSRIRFGFLTVTNLGVENMNHYKKTTLEIHNTEERQKRQVTHFQFLSWPDYGVPSSAASL
  IDFLRVVRNQQSLAVSNMGARSKGQCPEPPIVVHCSAGIGRTGTFCSLDICLAQLEELGT
  LNVFQTVSRMRTQRAFSIQTPEQYYFCYKAILEFAEKEGMVSSGQNLLAVESQ
• Function: Protein-tyrosine phosphatase that could participate in the transfer of hydrophobic ligands or in functions of the Golgi apparatus.
• Reactome Pathway: Interleukin-37 signaling (R-HSA-9008059)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Cervical cancer	DISFSHPF	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
Glioma	DIS5RPEH	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[8]
Polycythemia vera	DISB5FPO	Strong	Altered Expression	[9]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[10]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Genetic Variation	[11]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Tyrosine-protein phosphatase non-receptor type 9 (PTPN9).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tyrosine-protein phosphatase non-receptor type 9 (PTPN9).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tyrosine-protein phosphatase non-receptor type 9 (PTPN9).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tyrosine-protein phosphatase non-receptor type 9 (PTPN9).	[16]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Tyrosine-protein phosphatase non-receptor type 9 (PTPN9).	[18]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of Tyrosine-protein phosphatase non-receptor type 9 (PTPN9).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Tyrosine-protein phosphatase non-receptor type 9 (PTPN9).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine-protein phosphatase non-receptor type 9 (PTPN9).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tyrosine-protein phosphatase non-receptor type 9 (PTPN9).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Tyrosine-protein phosphatase non-receptor type 9 (PTPN9).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Tyrosine-protein phosphatase non-receptor type 9 (PTPN9).	[23]

References

• [1] Downregulated Expression of PTPN9 Contributes to Human Hepatocellular Carcinoma Growth and Progression.Pathol Oncol Res. 2016 Jul;22(3):555-65. doi: 10.1007/s12253-015-0038-1. Epub 2015 Dec 29.
• [2] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [3] MiR-613 promotes cell proliferation and invasion in cervical cancer via targeting PTPN9.Eur Rev Med Pharmacol Sci. 2018 Jul;22(13):4107-4114. doi: 10.26355/eurrev_201807_15402.
• [4] PTPN9 promotes cell proliferation and invasion in Eca109 cells and is negatively regulated by microRNA-126.Oncol Lett. 2017 Aug;14(2):1419-1426. doi: 10.3892/ol.2017.6315. Epub 2017 Jun 6.
• [5] MEG2 is regulated by miR-181a-5p and functions as a tumour suppressor gene to suppress the proliferation and migration of gastric cancer cells.Mol Cancer. 2017 Jul 26;16(1):133. doi: 10.1186/s12943-017-0695-7.
• [6] EGFR blockade prevents glioma escape from BRAFV600E targeted therapy.Oncotarget. 2015 Sep 8;6(26):21993-2005. doi: 10.18632/oncotarget.4014.
• [7] PTPN9 induces cell apoptosis by mitigating the activation of Stat3 and acts as a tumor suppressor in colorectal cancer.Cancer Manag Res. 2019 Feb 8;11:1309-1319. doi: 10.2147/CMAR.S187001. eCollection 2019.
• [8] Design, synthesis, biological evaluation and molecular dynamics studies of 4-thiazolinone derivatives as protein tyrosine phosphatase 1B (PTP1B) inhibitors.J Biomol Struct Dyn. 2020 Aug;38(13):3814-3824. doi: 10.1080/07391102.2019.1664333. Epub 2019 Sep 19.
• [9] PTP-MEG2 is activated in polycythemia vera erythroid progenitor cells and is required for growth and expansion of erythroid cells.Blood. 2003 Dec 15;102(13):4354-60. doi: 10.1182/blood-2003-04-1308. Epub 2003 Aug 14.
• [10] MEG2 inhibits the growth and metastasis of hepatocellular carcinoma by inhibiting AKT pathway.Gene. 2019 Mar 1;687:1-8. doi: 10.1016/j.gene.2018.11.003. Epub 2018 Nov 3.
• [11] Heterozygous Meg2 Ablation Causes Intraocular Pressure Elevation and Progressive Glaucomatous Neurodegeneration.Mol Neurobiol. 2019 Jun;56(6):4322-4345. doi: 10.1007/s12035-018-1376-2. Epub 2018 Oct 12.
• [12] Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling.Cell Metab. 2006 May;3(5):367-78. doi: 10.1016/j.cmet.2006.03.006.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [18] DNA methylation inhibits p53-mediated survivin repression. Oncogene. 2009 May 14;28(19):2046-50. doi: 10.1038/onc.2009.62. Epub 2009 Apr 13.
• [19] The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. Clin Cancer Res. 2016 May 15;22(10):2534-44. doi: 10.1158/1078-0432.CCR-15-1666. Epub 2016 Jan 5.
• [20] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [21] 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.
• [22] 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.
• [23] 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.