Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT33XNZM)

• DOT Name: Tyrosine-protein phosphatase non-receptor type 6 (PTPN6)
• Synonyms: EC 3.1.3.48; Hematopoietic cell protein-tyrosine phosphatase; Protein-tyrosine phosphatase 1C; PTP-1C; Protein-tyrosine phosphatase SHP-1; SH-PTP1
• Gene Name: PTPN6
• UniProt ID: PTN6_HUMAN
• PDB ID: 1FPR; 1GWZ; 1X6C; 2B3O; 2RMX; 2YU7; 3PS5; 4GRY; 4GRZ; 4GS0; 4HJP; 4HJQ; 6SM5
• EC Number: 3.1.3.48
• Pfam ID: PF00017 ; PF00102
• Sequence:
  MVRWFHRDLSGLDAETLLKGRGVHGSFLARPSRKNQGDFSLSVRVGDQVTHIRIQNSGDF
  YDLYGGEKFATLTELVEYYTQQQGVLQDRDGTIIHLKYPLNCSDPTSERWYHGHMSGGQA
  ETLLQAKGEPWTFLVRESLSQPGDFVLSVLSDQPKAGPGSPLRVTHIKVMCEGGRYTVGG
  LETFDSLTDLVEHFKKTGIEEASGAFVYLRQPYYATRVNAADIENRVLELNKKQESEDTA
  KAGFWEEFESLQKQEVKNLHQRLEGQRPENKGKNRYKNILPFDHSRVILQGRDSNIPGSD
  YINANYIKNQLLGPDENAKTYIASQGCLEATVNDFWQMAWQENSRVIVMTTREVEKGRNK
  CVPYWPEVGMQRAYGPYSVTNCGEHDTTEYKLRTLQVSPLDNGDLIREIWHYQYLSWPDH
  GVPSEPGGVLSFLDQINQRQESLPHAGPIIVHCSAGIGRTGTIIVIDMLMENISTKGLDC
  DIDIQKTIQMVRAQRSGMVQTEAQYKFIYVAIAQFIETTKKKLEVLQSQKGQESEYGNIT
  YPPAMKNAHAKASRTSSKHKEDVYENLHTKNKREEKVKKQRSADKEKSKGSLKRK
• Function: Modulates signaling by tyrosine phosphorylated cell surface receptors such as KIT and the EGF receptor/EGFR. The SH2 regions may interact with other cellular components to modulate its own phosphatase activity against interacting substrates. Together with MTUS1, induces UBE2V2 expression upon angiotensin II stimulation. Plays a key role in hematopoiesis.
• Tissue Specificity: Isoform 1 is expressed in hematopoietic cells. Isoform 2 is expressed in non-hematopoietic cells.
• KEGG Pathway:
  Efferocytosis (hsa04148)
  Adherens junction (hsa04520)
  JAK-STAT sig.ling pathway (hsa04630)
  .tural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Pathogenic Escherichia coli infection (hsa05130)
  Leishmaniasis (hsa05140)
  Proteoglycans in cancer (hsa05205)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway:
  Regulation of KIT signaling (R-HSA-1433559)
  Signaling by ALK (R-HSA-201556)
  PECAM1 interactions (R-HSA-210990)
  Costimulation by the CD28 family (R-HSA-388841)
  PD-1 signaling (R-HSA-389948)
  Signal regulatory protein family interactions (R-HSA-391160)
  Platelet sensitization by LDL (R-HSA-432142)
  Interleukin-3, Interleukin-5 and GM-CSF signaling (R-HSA-512988)
  CD22 mediated BCR regulation (R-HSA-5690714)
  Neutrophil degranulation (R-HSA-6798695)
  Interferon gamma signaling (R-HSA-877300)
  Regulation of IFNG signaling (R-HSA-877312)
  Interleukin-37 signaling (R-HSA-9008059)
  Interferon alpha/beta signaling (R-HSA-909733)
  Interleukin receptor SHC signaling (R-HSA-912526)
  Regulation of IFNA/IFNB signaling (R-HSA-912694)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Growth hormone receptor signaling (R-HSA-982772)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

4 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 6 (PTPN6).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[23]

22 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 6 (PTPN6).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[12]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[13]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[14]
Sodium chloride	DMM3950	Approved	Sodium chloride decreases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[15]
Digitoxin	DMWVIGP	Approved	Digitoxin increases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[16]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[17]
Rigosertib	DMOSTXF	Phase 3	Rigosertib decreases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[12]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the activity of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[19]
Sodium stibogluconate	DMH5MVE	Phase 2	Sodium stibogluconate decreases the activity of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[22]
EMODIN	DMAEDQG	Terminated	EMODIN increases the expression of Tyrosine-protein phosphatase non-receptor type 6 (PTPN6).	[24]

References

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• [9] 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.
• [10] [SHP-1 gene's methylation status of Daudi lymphoma cell and the demethylation effect of 5-aza-2'-deoxycytidine]. Zhonghua Xue Ye Xue Za Zhi. 2006 Oct;27(10):670-4.
• [11] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [12] 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.
• [13] Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. Leuk Res. 2008 Feb;32(2):275-85. doi: 10.1016/j.leukres.2007.05.024. Epub 2007 Jul 19.
• [14] 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.
• [15] Neoplastic-like transformation effect of single-walled and multi-walled carbon nanotubes compared to asbestos on human lung small airway epithelial cells. Nanotoxicology. 2014 Aug;8(5):485-507.
• [16] Digitoxin promotes apoptosis and inhibits proliferation and migration by reducing HIF-1 and STAT3 in KRAS mutant human colon cancer cells. Chem Biol Interact. 2022 Jan 5;351:109729. doi: 10.1016/j.cbi.2021.109729. Epub 2021 Oct 28.
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• [18] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [19] Regulation of growth hormone signaling by selective estrogen receptor modulators occurs through suppression of protein tyrosine phosphatases. Endocrinology. 2007 May;148(5):2417-23. doi: 10.1210/en.2006-1305. Epub 2007 Feb 1.
• [20] Effects of sodium stibogluconate on differentiation and proliferation of human myeloid leukemia cell lines in vitro. Leukemia. 2002 Nov;16(11):2285-91. doi: 10.1038/sj.leu.2402692.
• [21] 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.
• [22] 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.
• [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.
• [24] Emodin inhibits growth and induces apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of STAT3. Br J Pharmacol. 2013 Oct;170(4):807-21. doi: 10.1111/bph.12302.