Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT10OKOF)

• DOT Name: Receptor-type tyrosine-protein phosphatase eta (PTPRJ)
• Synonyms: Protein-tyrosine phosphatase eta; R-PTP-eta; EC 3.1.3.48; Density-enhanced phosphatase 1; DEP-1; HPTP eta; Protein-tyrosine phosphatase receptor type J; R-PTP-J; CD antigen CD148
• Gene Name: PTPRJ
• Related Disease:
  Hereditary nonpolyposis colon cancer
  Colorectal cancer
• UniProt ID: PTPRJ_HUMAN
• PDB ID: 2CFV; 2DLE; 2NZ6; 7U01; 7U08
• EC Number: 3.1.3.48
• Pfam ID: PF00041 ; PF18861 ; PF00102
• Sequence:
  MKPAAREARLPPRSPGLRWALPLLLLLLRLGQILCAGGTPSPIPDPSVATVATGENGITQ
  ISSTAESFHKQNGTGTPQVETNTSEDGESSGANDSLRTPEQGSNGTDGASQKTPSSTGPS
  PVFDIKAVSISPTNVILTWKSNDTAASEYKYVVKHKMENEKTITVVHQPWCNITGLRPAT
  SYVFSITPGIGNETWGDPRVIKVITEPIPVSDLRVALTGVRKAALSWSNGNGTASCRVLL
  ESIGSHEELTQDSRLQVNISGLKPGVQYNINPYLLQSNKTKGDPLGTEGGLDASNTERSR
  AGSPTAPVHDESLVGPVDPSSGQQSRDTEVLLVGLEPGTRYNATVYSQAANGTEGQPQAI
  EFRTNAIQVFDVTAVNISATSLTLIWKVSDNESSSNYTYKIHVAGETDSSNLNVSEPRAV
  IPGLRSSTFYNITVCPVLGDIEGTPGFLQVHTPPVPVSDFRVTVVSTTEIGLAWSSHDAE
  SFQMHITQEGAGNSRVEITTNQSIIIGGLFPGTKYCFEIVPKGPNGTEGASRTVCNRTVP
  SAVFDIHVVYVTTTEMWLDWKSPDGASEYVYHLVIESKHGSNHTSTYDKAITLQGLIPGT
  LYNITISPEVDHVWGDPNSTAQYTRPSNVSNIDVSTNTTAATLSWQNFDDASPTYSYCLL
  IEKAGNSSNATQVVTDIGITDATVTELIPGSSYTVEIFAQVGDGIKSLEPGRKSFCTDPA
  SMASFDCEVVPKEPALVLKWTCPPGANAGFELEVSSGAWNNATHLESCSSENGTEYRTEV
  TYLNFSTSYNISITTVSCGKMAAPTRNTCTTGITDPPPPDGSPNITSVSHNSVKVKFSGF
  EASHGPIKAYAVILTTGEAGHPSADVLKYTYEDFKKGASDTYVTYLIRTEEKGRSQSLSE
  VLKYEIDVGNESTTLGYYNGKLEPLGSYRACVAGFTNITFHPQNKGLIDGAESYVSFSRY
  SDAVSLPQDPGVICGAVFGCIFGALVIVTVGGFIFWRKKRKDAKNNEVSFSQIKPKKSKL
  IRVENFEAYFKKQQADSNCGFAEEYEDLKLVGISQPKYAAELAENRGKNRYNNVLPYDIS
  RVKLSVQTHSTDDYINANYMPGYHSKKDFIATQGPLPNTLKDFWRMVWEKNVYAIIMLTK
  CVEQGRTKCEEYWPSKQAQDYGDITVAMTSEIVLPEWTIRDFTVKNIQTSESHPLRQFHF
  TSWPDHGVPDTTDLLINFRYLVRDYMKQSPPESPILVHCSAGVGRTGTFIAIDRLIYQIE
  NENTVDVYGIVYDLRMHRPLMVQTEDQYVFLNQCVLDIVRSQKDSKVDLIYQNTTAMTIY
  ENLAPVTTFGKTNGYIA
• Function: Tyrosine phosphatase which dephosphorylates or contributes to the dephosphorylation of CTNND1, FLT3, PDGFRB, MET, KDR, LYN, SRC, MAPK1, MAPK3, EGFR, TJP1, OCLN, PIK3R1 and PIK3R2. Plays a role in cell adhesion, migration, proliferation and differentiation. Involved in vascular development. Regulator of macrophage adhesion and spreading. Positively affects cell-matrix adhesion. Positive regulator of platelet activation and thrombosis. Negative regulator of cell proliferation. Negative regulator of PDGF-stimulated cell migration; through dephosphorylation of PDGFR. Positive regulator of endothelial cell survival, as well as of VEGF-induced SRC and AKT activation; through KDR dephosphorylation. Negative regulator of EGFR signaling pathway; through EGFR dephosphorylation. Enhances the barrier function of epithelial junctions during reassembly. Negatively regulates T-cell receptor (TCR) signaling. Upon T-cell TCR activation, it is up-regulated and excluded from the immunological synapses, while upon T-cell-antigen presenting cells (APC) disengagement, it is no longer excluded and can dephosphorylate PLCG1 and LAT to down-regulate prolongation of signaling ; [Isoform 2]: Activates angiogenesis and cell migration. Downregulates the expression of the endothelial adhesion molecules ICAM1 and VCAM1.
• Tissue Specificity: Expressed in the promyelocytic cell line HL-60, the granulocyte-macrophage colony-stimulating factor-dependent leukemic cell line F-36P, and the IL3 and erythropoietin-dependent leukemic cell line F-36E. Expressed predominantly in epithelial cells and lymphocytes. Enhanced expression at high cell density.; [Isoform 2]: Expressed in the brain.
• KEGG Pathway:
  Adherens junction (hsa04520)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Negative regulation of MET activity (R-HSA-6807004)
  Negative regulation of FLT3 (R-HSA-9706369)
  Phosphorylation of CD3 and TCR zeta chains (R-HSA-202427)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary nonpolyposis colon cancer	DISPA49R	Limited	Autosomal dominant	[1]
Colorectal cancer	DISNH7P9	No Known	Unknown	[2]

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 Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[9]

11 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 Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[14]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Receptor-type tyrosine-protein phosphatase eta (PTPRJ).	[15]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] 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.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [12] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] 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.
• [15] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.