Details of Drug Off-Target (DOT)

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

• DOT Name: Receptor-type tyrosine-protein phosphatase O (PTPRO)
• Synonyms: R-PTP-O; EC 3.1.3.48; Glomerular epithelial protein 1; Protein tyrosine phosphatase U2; PTP-U2; PTPase U2
• Gene Name: PTPRO
• Related Disease:
  Nephrotic syndrome, type 2
  Acute lymphocytic leukaemia
  B-cell lymphoma
  Breast neoplasm
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Focal segmental glomerulosclerosis
  Hepatocellular carcinoma
  High blood pressure
  leukaemia
  Leukemia
  Liver cancer
  Lung neoplasm
  Melanoma
  Neoplasm
  Nephritis
  Nephrotic syndrome, type 6
  Small lymphocytic lymphoma
  Breast cancer
  Breast carcinoma
  Nephrotic syndrome
  Phospholipid syndrome
  Pulmonary emphysema
  Familial idiopathic steroid-resistant nephrotic syndrome
  HER2/NEU overexpressing breast cancer
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Hepatitis
  Lymphoma
• UniProt ID: PTPRO_HUMAN
• PDB ID: 2G59; 2GJT
• EC Number: 3.1.3.48
• Pfam ID: PF00041 ; PF00102
• Sequence:
  MGHLPTGIHGARRLLPLLWLFVLFKNATAFHVTVQDDNNIVVSLEASDVISPASVYVVKI
  TGESKNYFFEFEEFNSTLPPPVIFKASYHGLYYIITLVVVNGNVVTKPSRSITVLTKPLP
  VTSVSIYDYKPSPETGVLFEIHYPEKYNVFTRVNISYWEGKDFRTMLYKDFFKGKTVFNH
  WLPGMCYSNITFQLVSEATFNKSTLVEYSGVSHEPKQHRTAPYPPQNISVRIVNLNKNNW
  EEQSGNFPEESFMRSQDTIGKEKLFHFTEETPEIPSGNISSGWPDFNSSDYETTSQPYWW
  DSASAAPESEDEFVSVLPMEYENNSTLSETEKSTSGSFSFFPVQMILTWLPPKPPTAFDG
  FHIHIEREENFTEYLMVDEEAHEFVAELKEPGKYKLSVTTFSSSGSCETRKSQSAKSLSF
  YISPSGEWIEELTEKPQHVSVHVLSSTTALMSWTSSQENYNSTIVSVVSLTCQKQKESQR
  LEKQYCTQVNSSKPIIENLVPGAQYQVVIYLRKGPLIGPPSDPVTFAIVPTGIKDLMLYP
  LGPTAVVLSWTRPYLGVFRKYVVEMFYFNPATMTSEWTTYYEIAATVSLTASVRIANLLP
  AWYYNFRVTMVTWGDPELSCCDSSTISFITAPVAPEITSVEYFNSLLYISWTYGDDTTDL
  SHSRMLHWMVVAEGKKKIKKSVTRNVMTAILSLPPGDIYNLSVTACTERGSNTSMLRLVK
  LEPAPPKSLFAVNKTQTSVTLLWVEEGVADFFEVFCQQVGSSQKTKLQEPVAVSSHVVTI
  SSLLPATAYNCSVTSFSHDSPSVPTFIAVSTMVTEMNPNVVVISVLAILSTLLIGLLLVT
  LIILRKKHLQMARECGAGTFVNFASLERDGKLPYNWRRSIFAFLTLLPSCLWTDYLLAFY
  INPWSKNGLKKRKLTNPVQLDDFDAYIKDMAKDSDYKFSLQFEELKLIGLDIPHFAADLP
  LNRCKNRYTNILPYDFSRVRLVSMNEEEGADYINANYIPGYNSPQEYIATQGPLPETRND
  FWKMVLQQKSQIIVMLTQCNEKRRVKCDHYWPFTEEPIAYGDITVEMISEEEQDDWACRH
  FRINYADEMQDVMHFNYTAWPDHGVPTANAAESILQFVHMVRQQATKSKGPMIIHCSAGV
  GRTGTFIALDRLLQHIRDHEFVDILGLVSEMRSYRMSMVQTEEQYIFIHQCVQLMWMKKK
  QQFCISDVIYENVSKS
• Function: Possesses tyrosine phosphatase activity. Plays a role in regulating the glomerular pressure/filtration rate relationship through an effect on podocyte structure and function.
• Tissue Specificity: Glomerulus of kidney. Also detected in brain, lung and placenta.
• Reactome Pathway: Signaling by NTRK3 (TRKC) (R-HSA-9034015)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephrotic syndrome, type 2	DISIRFO1	Definitive	GermlineCausalMutation	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[2]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
High blood pressure	DISY2OHH	Strong	Biomarker	[9]
leukaemia	DISS7D1V	Strong	Genetic Variation	[10]
Leukemia	DISNAKFL	Strong	Genetic Variation	[10]
Liver cancer	DISDE4BI	Strong	Biomarker	[11]
Lung neoplasm	DISVARNB	Strong	Posttranslational Modification	[12]
Melanoma	DIS1RRCY	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Nephritis	DISQZQ70	Strong	Biomarker	[14]
Nephrotic syndrome, type 6	DIS15COB	Strong	Autosomal recessive	[9]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[15]
Breast cancer	DIS7DPX1	moderate	Biomarker	[16]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[16]
Nephrotic syndrome	DISSPSC2	moderate	Genetic Variation	[1]
Phospholipid syndrome	DISPI49U	moderate	Genetic Variation	[17]
Pulmonary emphysema	DIS5M7HZ	moderate	Genetic Variation	[18]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[1]
HER2/NEU overexpressing breast cancer	DISYKID5	Disputed	Posttranslational Modification	[19]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[11]
Hepatitis	DISXXX35	Limited	Biomarker	[11]
Lymphoma	DISN6V4S	Limited	Altered Expression	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Receptor-type tyrosine-protein phosphatase O (PTPRO) decreases the response to substance of Camptothecin.	[31]

10 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 Receptor-type tyrosine-protein phosphatase O (PTPRO).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[22]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[24]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[25]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[26]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Receptor-type tyrosine-protein phosphatase O (PTPRO).	[27]

References

• [1] Disruption of PTPRO causes childhood-onset nephrotic syndrome. Am J Hum Genet. 2011 Jul 15;89(1):139-47. doi: 10.1016/j.ajhg.2011.05.026. Epub 2011 Jun 30.
• [2] DNA methylation of membrane-bound tyrosine phosphatase genes in acute lymphoblastic leukaemia.Leukemia. 2014 Apr;28(4):787-93. doi: 10.1038/leu.2013.270. Epub 2013 Sep 18.
• [3] MiR-17-92 represses PTPROt and PP2A phosphatases and amplifies tonic BCR signaling in DLBCL cells.Exp Hematol. 2017 Feb;46:56-61.e1. doi: 10.1016/j.exphem.2016.09.011. Epub 2016 Oct 6.
• [4] Estrogen-mediated suppression of the gene encoding protein tyrosine phosphatase PTPRO in human breast cancer: mechanism and role in tamoxifen sensitivity.Mol Endocrinol. 2009 Feb;23(2):176-87. doi: 10.1210/me.2008-0211. Epub 2008 Dec 18.
• [5] MiR-6803-5p Promotes Cancer Cell Proliferation and Invasion via PTPRO/NF-B Axis in Colorectal Cancer.Mediators Inflamm. 2019 Nov 20;2019:8128501. doi: 10.1155/2019/8128501. eCollection 2019.
• [6] Aberrant methylation of the PTPRO gene in peripheral blood as a potential biomarker in esophageal squamous cell carcinoma patients.Cancer Lett. 2012 Feb 28;315(2):138-44. doi: 10.1016/j.canlet.2011.08.032. Epub 2011 Sep 12.
• [7] Activation of the TGF-beta/Smad signaling pathway in focal segmental glomerulosclerosis.Kidney Int. 2003 Nov;64(5):1715-21. doi: 10.1046/j.1523-1755.2003.00288.x.
• [8] Estrogen-sensitive PTPRO expression represses hepatocellular carcinoma progression by control of STAT3.Hepatology. 2013 Feb;57(2):678-88. doi: 10.1002/hep.25980. Epub 2012 Oct 30.
• [9] Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate. J Clin Invest. 2000 Nov;106(10):1281-90. doi: 10.1172/JCI7236.
• [10] AP-1 elements and TCL1 protein regulate expression of the gene encoding protein tyrosine phosphatase PTPROt in leukemia.Blood. 2011 Dec 1;118(23):6132-40. doi: 10.1182/blood-2011-01-323147. Epub 2011 Oct 14.
• [11] Survival and inflammation promotion effect of PTPRO in fulminant hepatitis is associated with NF-B activation.J Immunol. 2014 Nov 15;193(10):5161-70. doi: 10.4049/jimmunol.1303354. Epub 2014 Oct 22.
• [12] Methylation and silencing of protein tyrosine phosphatase receptor type O in chronic lymphocytic leukemia.Clin Cancer Res. 2007 Jun 1;13(11):3174-81. doi: 10.1158/1078-0432.CCR-06-1720.
• [13] Exome sequencing identifies GRIN2A as frequently mutated in melanoma.Nat Genet. 2011 May;43(5):442-6. doi: 10.1038/ng.810. Epub 2011 Apr 15.
• [14] Glomerular epithelial protein 1 and podocalyxin-like protein 1 in inflammatory glomerular disease (crescentic nephritis) in rabbit and man.Lab Invest. 1996 Mar;74(3):571-84.
• [15] The PTPROt tyrosine phosphatase functions as an obligate haploinsufficient tumor suppressor in vivo in B-cell chronic lymphocytic leukemia.Oncogene. 2017 Jun 29;36(26):3686-3694. doi: 10.1038/onc.2016.523. Epub 2017 Feb 6.
• [16] PTPRO represses ERBB2-driven breast oncogenesis by dephosphorylation and endosomal internalization of ERBB2.Oncogene. 2017 Jan 19;36(3):410-422. doi: 10.1038/onc.2016.213. Epub 2016 Jun 27.
• [17] The first genome-wide association study identifying new susceptibility loci for obstetric antiphospholipid syndrome.J Hum Genet. 2017 Sep;62(9):831-838. doi: 10.1038/jhg.2017.46. Epub 2017 Apr 20.
• [18] Extreme Trait Whole-Genome Sequencing Identifies PTPRO as a Novel Candidate Gene in Emphysema with Severe Airflow Obstruction.Am J Respir Crit Care Med. 2017 Jul 15;196(2):159-171. doi: 10.1164/rccm.201606-1147OC.
• [19] PTPRO promoter methylation is predictive of poorer outcome for HER2-positive breast cancer: indication for personalized therapy.J Transl Med. 2013 Oct 3;11:245. doi: 10.1186/1479-5876-11-245.
• [20] Protein tyrosine phosphatase receptor-type O truncated (PTPROt) regulates SYK phosphorylation, proximal B-cell-receptor signaling, and cellular proliferation.Blood. 2006 Nov 15;108(10):3428-33. doi: 10.1182/blood-2006-03-013821. Epub 2006 Aug 3.
• [21] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [22] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [23] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [24] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [25] 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.
• [26] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [27] 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.
• [28] 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.
• [29] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [31] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.