Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF4S7NE)

• DOT Name: Polypyrimidine tract-binding protein 2 (PTBP2)
• Synonyms: Neural polypyrimidine tract-binding protein; Neurally-enriched homolog of PTB; PTB-like protein
• Gene Name: PTBP2
• Related Disease:
  Glioma
  Neoplasm
  Alzheimer disease
  Breast cancer
  Breast neoplasm
  Bronchopulmonary dysplasia
  Carney complex
  Colorectal carcinoma
  Congenital alveolar dysplasia
  Extrapulmonary tuberculosis
  Hepatitis C virus infection
  HIV infectious disease
  Hypercholesterolemia, familial, 4
  Immunodeficiency
  Melanoma
  Myocardial infarction
  Oculocerebrorenal syndrome
  Polycystic ovarian syndrome
  Pulmonary tuberculosis
  Tuberculosis
  Breast carcinoma
  Epithelial ovarian cancer
  Frontotemporal dementia
  Lung cancer
  Lung carcinoma
  Neuroblastoma
  Ovarian cancer
  Ovarian neoplasm
  Pick disease
  Adult glioblastoma
  Cryptorchidism
  Glioblastoma multiforme
  Hyperglycemia
  Obesity
  Tauopathy
• UniProt ID: PTBP2_HUMAN
• PDB ID: 2CQ1; 2MJU; 4CQ1
• Pfam ID: PF00076 ; PF13893 ; PF11835
• Sequence:
  MDGIVTEVAVGVKRGSDELLSGSVLSSPNSNMSSMVVTANGNDSKKFKGEDKMDGAPSRV
  LHIRKLPGEVTETEVIALGLPFGKVTNILMLKGKNQAFLELATEEAAITMVNYYSAVTPH
  LRNQPIYIQYSNHKELKTDNTLNQRAQAVLQAVTAVQTANTPLSGTTVSESAVTPAQSPV
  LRIIIDNMYYPVTLDVLHQIFSKFGAVLKIITFTKNNQFQALLQYGDPVNAQQAKLALDG
  QNIYNACCTLRIDFSKLVNLNVKYNNDKSRDYTRPDLPSGDGQPALDPAIAAAFAKETSL
  LAVPGALSPLAIPNAAAAAAAAAAGRVGMPGVSAGGNTVLLVSNLNEEMVTPQSLFTLFG
  VYGDVQRVKILYNKKDSALIQMADGNQSQLAMNHLNGQKMYGKIIRVTLSKHQTVQLPRE
  GLDDQGLTKDFGNSPLHRFKKPGSKNFQNIFPPSATLHLSNIPPSVAEEDLRTLFANTGG
  TVKAFKFFQDHKMALLQMATVEEAIQALIDLHNYNLGENHHLRVSFSKSTI
• Function: RNA-binding protein which binds to intronic polypyrimidine tracts and mediates negative regulation of exons splicing. May antagonize in a tissue-specific manner the ability of NOVA1 to activate exon selection. In addition to its function in pre-mRNA splicing, plays also a role in the regulation of translation; [Isoform 5]: Reduced affinity for RNA.
• Tissue Specificity: Mainly expressed in brain although also detected in other tissues like heart and skeletal muscle. Isoform 1 and isoform 2 are specifically expressed in neuronal tissues. Isoform 3 and isoform 4 are expressed in non-neuronal tissues. Isoform 5 and isoform 6 are truncated forms expressed in non-neuronal tissues.

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Altered Expression	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Genetic Variation	[5]
Carney complex	DISVL3IP	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Congenital alveolar dysplasia	DIS1IYUN	Strong	Biomarker	[5]
Extrapulmonary tuberculosis	DIS6KM28	Strong	Genetic Variation	[8]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[9]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[10]
Hypercholesterolemia, familial, 4	DISFLNLI	Strong	Genetic Variation	[11]
Immunodeficiency	DIS093I0	Strong	Biomarker	[12]
Melanoma	DIS1RRCY	Strong	Altered Expression	[13]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[14]
Oculocerebrorenal syndrome	DIS8TEDY	Strong	Biomarker	[15]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[16]
Pulmonary tuberculosis	DIS6FLUM	Strong	Biomarker	[17]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[18]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[19]
Epithelial ovarian cancer	DIS56MH2	moderate	Altered Expression	[20]
Frontotemporal dementia	DISKYHXL	moderate	Biomarker	[21]
Lung cancer	DISCM4YA	moderate	Biomarker	[17]
Lung carcinoma	DISTR26C	moderate	Biomarker	[17]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[22]
Ovarian cancer	DISZJHAP	moderate	Altered Expression	[20]
Ovarian neoplasm	DISEAFTY	moderate	Altered Expression	[20]
Pick disease	DISP6X50	moderate	Biomarker	[21]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[23]
Cryptorchidism	DISYUD2P	Limited	Biomarker	[24]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[23]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[25]
Obesity	DIS47Y1K	Limited	Altered Expression	[26]
Tauopathy	DISY2IPA	Limited	Biomarker	[27]

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 Polypyrimidine tract-binding protein 2 (PTBP2).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Polypyrimidine tract-binding protein 2 (PTBP2).	[40]

11 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 Polypyrimidine tract-binding protein 2 (PTBP2).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Polypyrimidine tract-binding protein 2 (PTBP2).	[30]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Polypyrimidine tract-binding protein 2 (PTBP2).	[31]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Polypyrimidine tract-binding protein 2 (PTBP2).	[32]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Polypyrimidine tract-binding protein 2 (PTBP2).	[33]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Polypyrimidine tract-binding protein 2 (PTBP2).	[34]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Polypyrimidine tract-binding protein 2 (PTBP2).	[35]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Polypyrimidine tract-binding protein 2 (PTBP2).	[36]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Polypyrimidine tract-binding protein 2 (PTBP2).	[37]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Polypyrimidine tract-binding protein 2 (PTBP2).	[38]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Polypyrimidine tract-binding protein 2 (PTBP2).	[39]

References

• [1] Splicing factors PTBP1 and PTBP2 promote proliferation and migration of glioma cell lines.Brain. 2009 Aug;132(Pt 8):2277-88. doi: 10.1093/brain/awp153. Epub 2009 Jun 8.
• [2] Evaluation of Tumor Budding in Primary Colorectal Cancer and Corresponding Liver Metastases Based on H&E and Pancytokeratin Staining.Front Med (Lausanne). 2019 Oct 31;6:247. doi: 10.3389/fmed.2019.00247. eCollection 2019.
• [3] Evidence for altered Numb isoform levels in Alzheimer's disease patients and a triple transgenic mouse model.J Alzheimers Dis. 2011;24(2):349-61. doi: 10.3233/JAD-2011-101797.
• [4] Integration of Distinct ShcA Signaling Complexes Promotes Breast Tumor Growth and Tyrosine Kinase Inhibitor Resistance.Mol Cancer Res. 2018 May;16(5):894-908. doi: 10.1158/1541-7786.MCR-17-0623. Epub 2018 Feb 16.
• [5] Genetic associations of surfactant protein D and angiotensin-converting enzyme with lung disease in preterm neonates.J Perinatol. 2012 May;32(5):349-55. doi: 10.1038/jp.2011.104. Epub 2011 Sep 29.
• [6] Molecular cloning and characterization of human PTB-like protein: a possible retinal autoantigen of cancer-associated retinopathy.J Neuroimmunol. 2001 Nov 1;120(1-2):161-9. doi: 10.1016/s0165-5728(01)00427-1.
• [7] Cell Line Derived Xenograft Mouse Models Are a Suitable in vivo Model for Studying Tumor Budding in Colorectal Cancer.Front Med (Lausanne). 2019 Jun 27;6:139. doi: 10.3389/fmed.2019.00139. eCollection 2019.
• [8] Plasma levels of C-reactive protein, matrix metalloproteinase-7 and lipopolysaccharide-binding protein distinguish active pulmonary or extrapulmonary tuberculosis from uninfected controls in children.Cytokine. 2019 Nov;123:154773. doi: 10.1016/j.cyto.2019.154773. Epub 2019 Jul 9.
• [9] MEAN inhibits hepatitis C virus replication by interfering with a polypyrimidine tract-binding protein.J Cell Mol Med. 2016 Jul;20(7):1255-65. doi: 10.1111/jcmm.12798. Epub 2016 Mar 1.
• [10] Haplotype analysis of HLA-A, -B antigens and -DRB1 alleles in south Indian HIV-1-infected patients with and without pulmonary tuberculosis.Int J Immunogenet. 2009 Jun;36(3):129-33. doi: 10.1111/j.1744-313X.2009.00835.x.
• [11] A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia.Hum Genet. 2005 Jan;116(1-2):114-20. doi: 10.1007/s00439-004-1192-9. Epub 2004 Nov 17.
• [12] Provider-initiated HIV testing & counselling in incident tuberculosis cases under National TB Programme conditions at a tertiary care teaching hospital in Tirupati, south India.Indian J Med Res. 2017 Dec;146(6):774-779. doi: 10.4103/ijmr.IJMR_639_15.
• [13] RaLP, a new member of the Src homology and collagen family, regulates cell migration and tumor growth of metastatic melanomas.Cancer Res. 2007 Apr 1;67(7):3064-73. doi: 10.1158/0008-5472.CAN-06-2301.
• [14] Automated detection and localization system of myocardial infarction in single-beat ECG using Dual-Q TQWT and wavelet packet tensor decomposition.Comput Methods Programs Biomed. 2020 Feb;184:105120. doi: 10.1016/j.cmpb.2019.105120. Epub 2019 Oct 5.
• [15] Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1.Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3511-6. doi: 10.1073/pnas.0914658107. Epub 2010 Feb 2.
• [16] Evidence for decreased expression of APPL1 associated with reduced insulin and adiponectin receptors expression in PCOS patients.J Endocrinol Invest. 2016 Sep;39(9):1075-82. doi: 10.1007/s40618-016-0468-y. Epub 2016 Apr 13.
• [17] Diagnostic Accuracy of Interleukin-27 in Bronchoalveolar Lavage Fluids for Pulmonary Tuberculosis.Infect Drug Resist. 2019 Dec 2;12:3755-3763. doi: 10.2147/IDR.S231215. eCollection 2019.
• [18] Evaluation of facility and community-based active household tuberculosis contact investigation in Ethiopia: a cross-sectional study.BMC Health Serv Res. 2019 Apr 22;19(1):234. doi: 10.1186/s12913-019-4074-5.
• [19] The ShcA PTB domain functions as a biological sensor of phosphotyrosine signaling during breast cancer progression.Cancer Res. 2013 Jul 15;73(14):4521-32. doi: 10.1158/0008-5472.CAN-12-4178. Epub 2013 May 21.
• [20] Alternative splicing of the multidrug resistance protein 1/ATP binding cassette transporter subfamily gene in ovarian cancer creates functional splice variants and is associated with increased expression of the splicing factors PTB and SRp20.Clin Cancer Res. 2004 Jul 15;10(14):4652-60. doi: 10.1158/1078-0432.CCR-03-0439.
• [21] TDP-43 functions within a network of hnRNP proteins to inhibit the production of a truncated human SORT1 receptor.Hum Mol Genet. 2016 Feb 1;25(3):534-45. doi: 10.1093/hmg/ddv491. Epub 2015 Nov 27.
• [22] Activation of anaplastic lymphoma kinase is responsible for hyperphosphorylation of ShcC in neuroblastoma cell lines.Oncogene. 2002 Aug 29;21(38):5823-34. doi: 10.1038/sj.onc.1205735.
• [23] Oncogenic miR?32 sustains proliferation and selfrenewal potential by inhibition of polypyrimidine tractbinding protein 2 in glioblastoma cells.Mol Med Rep. 2017 Nov;16(5):7221-7228. doi: 10.3892/mmr.2017.7572. Epub 2017 Sep 21.
• [24] Association between RNA-binding protein Ptbp2 and germ cell injury in an experimentally-induced unilateral cryptorchidism murine model.PLoS One. 2017 Oct 18;12(10):e0186654. doi: 10.1371/journal.pone.0186654. eCollection 2017.
• [25] Inflammation and hyperglycemia mediate Deaf1 splicing in the pancreatic lymph nodes via distinct pathways during type 1 diabetes.Diabetes. 2015 Feb;64(2):604-17. doi: 10.2337/db14-0803. Epub 2014 Sep 3.
• [26] Identification of a 1p21 independent functional variant for abdominal obesity.Int J Obes (Lond). 2019 Dec;43(12):2480-2490. doi: 10.1038/s41366-019-0350-z. Epub 2019 Apr 3.
• [27] MicroRNA-132 loss is associated with tau exon 10 inclusion in progressive supranuclear palsy.Hum Mol Genet. 2011 Oct 15;20(20):4016-24. doi: 10.1093/hmg/ddr330. Epub 2011 Aug 1.
• [28] 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.
• [29] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [30] 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.
• [31] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [32] 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.
• [33] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [34] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [35] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [36] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [37] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [38] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [39] 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.
• [40] 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.