Details of Drug Off-Target (DOT)

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

• DOT Name: Receptor-type tyrosine-protein phosphatase H (PTPRH)
• Synonyms: R-PTP-H; EC 3.1.3.48; Stomach cancer-associated protein tyrosine phosphatase 1; SAP-1; Transmembrane-type protein-tyrosine phosphatase type H
• Gene Name: PTPRH
• Related Disease:
  Candidiasis
  Colitis
  Colorectal carcinoma
  Colorectal neoplasm
  Gastric cancer
  Hepatitis B virus infection
  Hepatocellular carcinoma
  HIV infectious disease
  Inflammatory bowel disease
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Oral candidiasis
  Peutz-Jeghers syndrome
  Progressive multifocal leukoencephalopathy
  Stomach cancer
  Vaginal infection
  Metachromatic leukodystrophy
  Vulvovaginal Candidiasis
  Malaria
• UniProt ID: PTPRH_HUMAN
• PDB ID: 7XC0
• EC Number: 3.1.3.48
• Pfam ID: PF00041 ; PF00102
• Sequence:
  MAGAGGGLGVWGNLVLLGLCSWTGARAPAPNPGRNLTVETQTTSSISLSWEVPDGLDSQN
  SNYWVQCTGDGGTTETRNTTATNVTVDGLGPGSLYTCSVWVEKDGVNSSVGTVTTATAPN
  PVRNLRVEAQTNSSIALTWEVPDGPDPQNSTYGVEYTGDGGRAGTRSTAHTNITVDGLEP
  GCLYAFSMWVGKNGINSSRETRNATTAHNPVRNLRVEAQTTSSISLSWEVPDGTDPQNST
  YCVQCTGDGGRTETRNTTDTRVTVDGLGPGSLYTCSVWVEKDGVNSSVEIVTSATAPNPV
  RNLTVEAQTNSSIALTWEVPDGPDPQNSTYGVEYTGDGGRAGTRSTAHTNITVDRLEPGC
  LYVFSVWVGKNGINSSRETRNATTAPNPVRNLHMETQTNSSIALCWEVPDGPYPQDYTYW
  VEYTGDGGGTETRNTTNTSVTAERLEPGTLYTFSVWAEKNGARGSRQNVSISTVPNAVTS
  LSKQDWTNSTIALRWTAPQGPGQSSYSYWVSWVREGMTDPRTQSTSGTDITLKELEAGSL
  YHLTVWAERNEVRGYNSTLTAATAPNEVTDLQNETQTKNSVMLWWKAPGDPHSQLYVYWV
  QWASKGHPRRGQDPQANWVNQTSRTNETWYKVEALEPGTLYNFTVWAERNDVASSTQSLC
  ASTYPDTVTITSCVSTSAGYGVNLIWSCPQGGYEAFELEVGGQRGSQDRSSCGEAVSVLG
  LGPARSYPATITTIWDGMKVVSHSVVCHTESAGVIAGAFVGILLFLILVGLLIFFLKRRN
  KKKQQKPELRDLVFSSPGDIPAEDFADHVRKNERDSNCGFADEYQQLSLVGHSQSQMVAS
  ASENNAKNRYRNVLPYDWSRVPLKPIHEEPGSDYINASFMPGLWSPQEFIATQGPLPQTV
  GDFWRLVWEQQSHTLVMLTNCMEAGRVKCEHYWPLDSQPCTHGHLRVTLVGEEVMENWTV
  RELLLLQVEEQKTLSVRQFHYQAWPDHGVPSSPDTLLAFWRMLRQWLDQTMEGGPPIVHC
  SAGVGRTGTLIALDVLLRQLQSEGLLGPFSFVRKMRESRPLMVQTEAQYVFLHQCILRFL
  QQSAQAPAEKEVPYEDVENLIYENVAAIQAHKLEV
• Function: Protein phosphatase that may contribute to contact inhibition of cell growth and motility by mediating the dephosphorylation of focal adhesion-associated substrates and thus negatively regulating integrin-promoted signaling processes. Induces apoptotic cell death by at least two distinct mechanisms: inhibition of cell survival signaling mediated by PI 3-kinase, Akt, and ILK and activation of a caspase-dependent proapoptotic pathway. Inhibits the basal activity of LCK and its activation in response to TCR stimulation and TCR-induced activation of MAP kinase and surface expression of CD69. Inhibits TCR-induced tyrosine phosphorylation of LAT and ZAP70. Inhibits both basal activity of DOK1 and its CD2-induced tyrosine phosphorylation. Induces dephosphorylation of BCAR1, focal adhesion kinase and SRC. Reduces migratory activity of activity of Jurkat cells. Reduces tyrosine phosphorylation of CEACAM20 and thereby contributes to suppress the intestinal immune response CEACAM20.
• Tissue Specificity: Expressed at high levels in the brain, spleen and liver and at lower levels in the heart and stomach. Expressed in pancreatic and colorectal cancer cells, but not in normal pancreas or colon. Expression in hepatocellular carcinoma is related to the differentiation status of the tumor and expression is inversely related to tumor aggressiveness.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Candidiasis	DISIRYMU	Strong	Altered Expression	[1]
Colitis	DISAF7DD	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
HIV infectious disease	DISO97HC	Strong	Biomarker	[7]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Posttranslational Modification	[8]
Lung cancer	DISCM4YA	Strong	Altered Expression	[8]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[8]
Oral candidiasis	DISAVKAH	Strong	Biomarker	[10]
Peutz-Jeghers syndrome	DISF27ZJ	Strong	Genetic Variation	[11]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[12]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Vaginal infection	DISVXFB7	Strong	Biomarker	[13]
Metachromatic leukodystrophy	DIS3OMWS	moderate	Biomarker	[14]
Vulvovaginal Candidiasis	DISRCR6D	moderate	Biomarker	[15]
Malaria	DISQ9Y50	Disputed	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Receptor-type tyrosine-protein phosphatase H (PTPRH) affects the response to substance of Doxorubicin.	[31]

2 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 Receptor-type tyrosine-protein phosphatase H (PTPRH).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[26]

13 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 H (PTPRH).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[18]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[21]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[22]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[23]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[28]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Receptor-type tyrosine-protein phosphatase H (PTPRH).	[30]

References

• [1] Quantitative expression of the Candida albicans secreted aspartyl proteinase gene family in human oral and vaginal candidiasis.Microbiology (Reading). 2008 Nov;154(Pt 11):3266-3280. doi: 10.1099/mic.0.2008/022293-0.
• [2] Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium.Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4264-71. doi: 10.1073/pnas.1510167112. Epub 2015 Jul 20.
• [3] Downregulation of PTPRH (Sap-1) in colorectal tumors.Int J Oncol. 2017 Sep;51(3):841-850. doi: 10.3892/ijo.2017.4068. Epub 2017 Jul 5.
• [4] Molecular cloning of a human transmembrane-type protein tyrosine phosphatase and its expression in gastrointestinal cancers.J Biol Chem. 1994 Jan 21;269(3):2075-81.
• [5] Replication of clinical hepatitis B virus isolate and its application for selecting antiviral agents for chronic hepatitis B patients.World J Gastroenterol. 2008 Jun 14;14(22):3490-6. doi: 10.3748/wjg.14.3490.
• [6] Downregulation of stomach cancer-associated protein tyrosine phosphatase-1 (SAP-1) in advanced human hepatocellular carcinoma.Oncogene. 2003 Jul 24;22(30):4656-63. doi: 10.1038/sj.onc.1206588.
• [7] Elevated aspartic proteinase secretion and experimental pathogenicity of Candida albicans isolates from oral cavities of subjects infected with human immunodeficiency virus.Infect Immun. 1996 Feb;64(2):466-71. doi: 10.1128/iai.64.2.466-471.1996.
• [8] Prognostic implication of PTPRH hypomethylation in non-small cell lung cancer.Oncol Rep. 2015 Sep;34(3):1137-45. doi: 10.3892/or.2015.4082. Epub 2015 Jun 25.
• [9] Integrated analyses of murine breast cancer models reveal critical parallels with human disease.Nat Commun. 2019 Jul 22;10(1):3261. doi: 10.1038/s41467-019-11236-3.
• [10] In vivo analysis of secreted aspartyl proteinase expression in human oral candidiasis.Infect Immun. 1999 May;67(5):2482-90. doi: 10.1128/IAI.67.5.2482-2490.1999.
• [11] Gene for the human transmembrane-type protein tyrosine phosphatase H (PTPRH): genomic structure, fine-mapping and its exclusion as a candidate for Peutz-Jeghers syndrome.Cytogenet Cell Genet. 2001;92(3-4):213-6. doi: 10.1159/000056905.
• [12] Molecular characterization of a JC virus (Sap-1) clone derived from a cerebellar form of progressive multifocal leukoencephalopathy.Acta Neuropathol. 1992;83(2):105-12. doi: 10.1007/BF00308469.
• [13] The secreted aspartyl proteinases Sap1 and Sap2 cause tissue damage in an in vitro model of vaginal candidiasis based on reconstituted human vaginal epithelium.Infect Immun. 2003 Jun;71(6):3227-34. doi: 10.1128/IAI.71.6.3227-3234.2003.
• [14] The mechanism for a 33-nucleotide insertion in mRNA causing sphingolipid activator protein (SAP-1)-deficient metachromatic leukodystrophy.Hum Genet. 1991 Jun;87(2):211-5. doi: 10.1007/BF00204185.
• [15] Differential expression of Candida albicans secreted aspartyl proteinase in human vulvovaginal candidiasis.Mycoses. 2007 Sep;50(5):383-90. doi: 10.1111/j.1439-0507.2007.01384.x.
• [16] Targeted deletion of SAP1 abolishes the expression of infectivity factors necessary for successful malaria parasite liver infection.Mol Microbiol. 2008 Jul;69(1):152-63. doi: 10.1111/j.1365-2958.2008.06271.x. Epub 2008 May 5.
• [17] 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.
• [18] 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.
• [19] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [24] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] 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.
• [29] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [30] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [31] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.