Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV4VJGE)

• DOT Name: Tyrosine-protein phosphatase non-receptor type 2 (PTPN2)
• Synonyms: EC 3.1.3.48; T-cell protein-tyrosine phosphatase; TCPTP
• Gene Name: PTPN2
• UniProt ID: PTN2_HUMAN
• PDB ID: 1L8K; 6ZZ4; 7F5N; 7F5O; 7UAD
• EC Number: 3.1.3.48
• Pfam ID: PF00102
• Sequence:
  MPTTIEREFEELDTQRRWQPLYLEIRNESHDYPHRVAKFPENRNRNRYRDVSPYDHSRVK
  LQNAENDYINASLVDIEEAQRSYILTQGPLPNTCCHFWLMVWQQKTKAVVMLNRIVEKES
  VKCAQYWPTDDQEMLFKETGFSVKLLSEDVKSYYTVHLLQLENINSGETRTISHFHYTTW
  PDFGVPESPASFLNFLFKVRESGSLNPDHGPAVIHCSAGIGRSGTFSLVDTCLVLMEKGD
  DINIKQVLLNMRKYRMGLIQTPDQLRFSYMAIIEGAKCIKGDSSIQKRWKELSKEDLSPA
  FDHSPNKIMTEKYNGNRIGLEEEKLTGDRCTGLSSKMQDTMEENSESALRKRIREDRKAT
  TAQKVQQMKQRLNENERKRKRWLYWQPILTKMGFMSVILVGAFVGWTLFFQQNAL
• Function: Non-receptor type tyrosine-specific phosphatase that dephosphorylates receptor protein tyrosine kinases including INSR, EGFR, CSF1R, PDGFR. Also dephosphorylates non-receptor protein tyrosine kinases like JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3 and STAT6 either in the nucleus or the cytoplasm. Negatively regulates numerous signaling pathways and biological processes like hematopoiesis, inflammatory response, cell proliferation and differentiation, and glucose homeostasis. Plays a multifaceted and important role in the development of the immune system. Functions in T-cell receptor signaling through dephosphorylation of FYN and LCK to control T-cells differentiation and activation. Dephosphorylates CSF1R, negatively regulating its downstream signaling and macrophage differentiation. Negatively regulates cytokine (IL2/interleukin-2 and interferon)-mediated signaling through dephosphorylation of the cytoplasmic kinases JAK1, JAK3 and their substrate STAT1, that propagate signaling downstream of the cytokine receptors. Also regulates the IL6/interleukin-6 and IL4/interleukin-4 cytokine signaling through dephosphorylation of STAT3 and STAT6 respectively. In addition to the immune system, it is involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth. Activated by the integrin ITGA1/ITGB1, it dephosphorylates EGFR and negatively regulates EGF signaling. Dephosphorylates PDGFRB and negatively regulates platelet-derived growth factor receptor-beta signaling pathway and therefore cell proliferation. Negatively regulates tumor necrosis factor-mediated signaling downstream via MAPK through SRC dephosphorylation. May also regulate the hepatocyte growth factor receptor signaling pathway through dephosphorylation of the hepatocyte growth factor receptor MET. Also plays an important role in glucose homeostasis. For instance, negatively regulates the insulin receptor signaling pathway through the dephosphorylation of INSR and control gluconeogenesis and liver glucose production through negative regulation of the IL6 signaling pathways. May also bind DNA.
• Tissue Specificity: Ubiquitously expressed. Isoform 2 is probably the major isoform. Isoform 1 is expressed in T-cells and in placenta.
• KEGG Pathway: JAK-STAT sig.ling pathway (hsa04630)
• Reactome Pathway:
  Interleukin-37 signaling (R-HSA-9008059)
  PKR-mediated signaling (R-HSA-9833482)
  Negative regulation of MET activity (R-HSA-6807004)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
4-nitrophenyl phosphate	DMBX4UJ	Investigative	Tyrosine-protein phosphatase non-receptor type 2 (PTPN2) increases the hydrolysis of 4-nitrophenyl phosphate.	[7]

2 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 Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[1]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[4]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[5]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[6]
Benzoic acid	DMKB9FI	Approved	Benzoic acid decreases the activity of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[9]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[4]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Tyrosine-protein phosphatase non-receptor type 2 (PTPN2).	[12]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [5] Ouabain at pathological concentrations might induce damage in human vascular endothelial cells. Acta Pharmacol Sin. 2006 Feb;27(2):165-72. doi: 10.1111/j.1745-7254.2006.00244.x.
• [6] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [7] Synthesis, biological activity and structure-activity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells. Eur J Med Chem. 2014 Jan;71:112-27. doi: 10.1016/j.ejmech.2013.11.001. Epub 2013 Nov 11.
• [8] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [9] 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.
• [10] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [11] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] 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.