Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAP7NOL)

• DOT Name: Receptor-type tyrosine-protein phosphatase-like N (PTPRN)
• Synonyms: R-PTP-N; Islet cell antigen 512; ICA 512; Islet cell autoantigen 3; PTP IA-2
• Gene Name: PTPRN
• Related Disease:
  Endometrial carcinoma
  Insulinoma
  Autoimmune disease
  Carcinoid tumor
  Endometrial cancer
  Maturity-onset diabetes of the young
  Multiple sclerosis
  Non-insulin dependent diabetes
  Type-1/2 diabetes
  Amyotrophic lateral sclerosis
  Enterovirus infection
  Hepatocellular carcinoma
  Hyperglycemia
• UniProt ID: PTPRN_HUMAN
• PDB ID: 2I1Y; 2QT7; 3N01; 3N4W; 3NG8; 3NP5
• Pfam ID: PF11548 ; PF14948 ; PF00102
• Sequence:
  MRRPRRPGGLGGSGGLRLLLCLLLLSSRPGGCSAVSAHGCLFDRRLCSHLEVCIQDGLFG
  QCQVGVGQARPLLQVTSPVLQRLQGVLRQLMSQGLSWHDDLTQYVISQEMERIPRLRPPE
  PRPRDRSGLAPKRPGPAGELLLQDIPTGSAPAAQHRLPQPPVGKGGAGASSSLSPLQAEL
  LPPLLEHLLLPPQPPHPSLSYEPALLQPYLFHQFGSRDGSRVSEGSPGMVSVGPLPKAEA
  PALFSRTASKGIFGDHPGHSYGDLPGPSPAQLFQDSGLLYLAQELPAPSRARVPRLPEQG
  SSSRAEDSPEGYEKEGLGDRGEKPASPAVQPDAALQRLAAVLAGYGVELRQLTPEQLSTL
  LTLLQLLPKGAGRNPGGVVNVGADIKKTMEGPVEGRDTAELPARTSPMPGHPTASPTSSE
  VQQVPSPVSSEPPKAARPPVTPVLLEKKSPLGQSQPTVAGQPSARPAAEEYGYIVTDQKP
  LSLAAGVKLLEILAEHVHMSSGSFINISVVGPALTFRIRHNEQNLSLADVTQQAGLVKSE
  LEAQTGLQILQTGVGQREEAAAVLPQTAHSTSPMRSVLLTLVALAGVAGLLVALAVALCV
  RQHARQQDKERLAALGPEGAHGDTTFEYQDLCRQHMATKSLFNRAEGPPEPSRVSSVSSQ
  FSDAAQASPSSHSSTPSWCEEPAQANMDISTGHMILAYMEDHLRNRDRLAKEWQALCAYQ
  AEPNTCATAQGEGNIKKNRHPDFLPYDHARIKLKVESSPSRSDYINASPIIEHDPRMPAY
  IATQGPLSHTIADFWQMVWESGCTVIVMLTPLVEDGVKQCDRYWPDEGASLYHVYEVNLV
  SEHIWCEDFLVRSFYLKNVQTQETRTLTQFHFLSWPAEGTPASTRPLLDFRRKVNKCYRG
  RSCPIIVHCSDGAGRTGTYILIDMVLNRMAKGVKEIDIAATLEHVRDQRPGLVRSKDQFE
  FALTAVAEEVNAILKALPQ
• Function: Plays a role in vesicle-mediated secretory processes. Required for normal accumulation of secretory vesicles in hippocampus, pituitary and pancreatic islets. Required for the accumulation of normal levels of insulin-containing vesicles and preventing their degradation. Plays a role in insulin secretion in response to glucose stimuli. Required for normal accumulation of the neurotransmitters norepinephrine, dopamine and serotonin in the brain. In females, but not in males, required for normal accumulation and secretion of pituitary hormones, such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Required to maintain normal levels of renin expression and renin release. Seems to lack intrinsic enzyme activity. May regulate catalytic active protein-tyrosine phosphatases such as PTPRA through dimerization; [ICA512-transmembrane fragment]: ICA512-TMF regulates dynamics and exocytosis of insulin secretory granules (SGs); binding of ICA512-TMF to SNTB2/beta-2-syntrophin is proposed to restrain SGs mobility and exocytosis by tethering them to the actin cytoskeleton depending on UTRN; the function is inhibited by cytoplasmic ICA512-CFF dimerizing with ICA512-TMF and displacing SNTB2; [ICA512-cleaved cytosolic fragment]: ICA512-CCF translocated to the nucleus promotes expression of insulin and other granule-related genes; the function implicates binding to and regulating activity of STAT5B probably by preventing its dephosphorylation and potentially by inducing its sumoylation by recruiting PIAS4. Enhances pancreatic beta-cell proliferation by converging with signaling by STAT5B and STAT3. ICA512-CCF located in the cytoplasm regulates dynamics and exocytosis of insulin secretory granules (SGs) by dimerizing with ICA512-TMF and displacing SNTB2 thus enhancing SGs mobility and exocytosis.
• Tissue Specificity: Expression is restricted to neuroendocrine cells. Found in pancreas, brain and pituitary.
• KEGG Pathway: Type I diabetes mellitus (hsa04940)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Endometrial carcinoma	DISXR5CY	Definitive	Biomarker	[1]
Insulinoma	DISIU1JS	Definitive	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Biomarker	[3]
Carcinoid tumor	DISMNRDC	Strong	Altered Expression	[4]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[1]
Maturity-onset diabetes of the young	DISG75M5	Strong	Biomarker	[5]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[7]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[8]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[9]
Enterovirus infection	DISH2UDP	Limited	Altered Expression	[10]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[11]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[12]

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-like N (PTPRN).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Receptor-type tyrosine-protein phosphatase-like N (PTPRN).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Receptor-type tyrosine-protein phosphatase-like N (PTPRN).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Receptor-type tyrosine-protein phosphatase-like N (PTPRN).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Receptor-type tyrosine-protein phosphatase-like N (PTPRN).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Receptor-type tyrosine-protein phosphatase-like N (PTPRN).	[17]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Receptor-type tyrosine-protein phosphatase-like N (PTPRN).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Receptor-type tyrosine-protein phosphatase-like N (PTPRN).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Receptor-type tyrosine-protein phosphatase-like N (PTPRN).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Receptor-type tyrosine-protein phosphatase-like N (PTPRN).	[21]

References

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• [2] ICA512 RESP18 homology domain is a protein-condensing factor and insulin fibrillation inhibitor.J Biol Chem. 2019 May 24;294(21):8564-8576. doi: 10.1074/jbc.RA119.007607. Epub 2019 Apr 12.
• [3] Diabetes Antibody Standardization Program: evaluation of assays for autoantibodies to glutamic acid decarboxylase and islet antigen-2.Diabetologia. 2008 May;51(5):846-52. doi: 10.1007/s00125-008-0967-2. Epub 2008 Mar 29.
• [4] Transmembrane protein tyrosine phosphatase IA-2 (ICA512) is expressed in human midgut carcinoids but is not detectable in normal enterochromaffin cells.J Endocrinol. 2000 Mar;164(3):315-22. doi: 10.1677/joe.0.1640315.
• [5] The role of late-onset autoimmune diabetes in white familial NIDDM pedigrees.Diabetes Care. 1997 Aug;20(8):1248-51. doi: 10.2337/diacare.20.8.1248.
• [6] Human fibrocytes express multiple antigens associated with autoimmune endocrine diseases.J Clin Endocrinol Metab. 2014 May;99(5):E796-803. doi: 10.1210/jc.2013-3072. Epub 2014 Feb 11.
• [7] Measuring gene-gene interaction using Kullback-Leibler divergence.Ann Hum Genet. 2019 Nov;83(6):405-417. doi: 10.1111/ahg.12324. Epub 2019 Jun 17.
• [8] Identification of Unique Antigenic Determinants in the Amino Terminus of IA-2 (ICA512) in Childhood and Adult Autoimmune Diabetes: New Biomarker Development.Diabetes Care. 2017 Apr;40(4):561-568. doi: 10.2337/dc16-1527. Epub 2017 Feb 7.
• [9] Degeneration of proprioceptive sensory nerve endings in mice harboring amyotrophic lateral sclerosis-causing mutations.J Comp Neurol. 2015 Dec 1;523(17):2477-94. doi: 10.1002/cne.23848. Epub 2015 Jul 21.
• [10] Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) Study Group.J Med Virol. 2000 Jun;61(2):214-20.
• [11] Prognostic Value of Phosphotyrosine Phosphatases in Hepatocellular Carcinoma.Cell Physiol Biochem. 2018;46(6):2335-2346. doi: 10.1159/000489625. Epub 2018 May 4.
• [12] Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes.Diabetologia. 2005 Apr;48(4):687-94. doi: 10.1007/s00125-005-1702-x. Epub 2005 Mar 9.
• [13] 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.
• [14] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [15] 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.
• [16] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [17] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [18] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [19] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [20] 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.
• [21] 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.