Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2H1KDK)

• DOT Name: Tyrosine-protein phosphatase non-receptor type 5 (PTPN5)
• Synonyms: EC 3.1.3.48; Neural-specific protein-tyrosine phosphatase; Striatum-enriched protein-tyrosine phosphatase; STEP
• Gene Name: PTPN5
• Related Disease:
  Cognitive impairment
  Short bowel syndrome
  Alzheimer disease
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Depression
  Fragile X syndrome
  Huntington disease
  Knee osteoarthritis
  Mental disorder
  Mixed anxiety and depressive disorder
  Movement disorder
  Neoplasm
  Non-insulin dependent diabetes
  High blood pressure
  Hypotrichosis simplex
  Neurodegenerative disease
  Schizophrenia
  Neuroblastoma
  Advanced cancer
  Myopia
  Parkinson disease
• UniProt ID: PTN5_HUMAN
• PDB ID: 2BIJ; 2BV5; 2CJZ; 5OVR; 5OVX; 5OW1; 6H8R; 8SLS; 8SLT; 8SLU
• EC Number: 3.1.3.48
• Pfam ID: PF00102
• Sequence:
  MNYEGARSERENHAADDSEGGALDMCCSERLPGLPQPIVMEALDEAEGLQDSQREMPPPP
  PPSPPSDPAQKPPPRGAGSHSLTVRSSLCLFAASQFLLACGVLWFSGYGHIWSQNATNLV
  SSLLTLLKQLEPTAWLDSGTWGVPSLLLVFLSVGLVLVTTLVWHLLRTPPEPPTPLPPED
  RRQSVSRQPSFTYSEWMEEKIEDDFLDLDPVPETPVFDCVMDIKPEADPTSLTVKSMGLQ
  ERRGSNVSLTLDMCTPGCNEEGFGYLMSPREESAREYLLSASRVLQAEELHEKALDPFLL
  QAEFFEIPMNFVDPKEYDIPGLVRKNRYKTILPNPHSRVCLTSPDPDDPLSSYINANYIR
  GYGGEEKVYIATQGPIVSTVADFWRMVWQEHTPIIVMITNIEEMNEKCTEYWPEEQVAYD
  GVEITVQKVIHTEDYRLRLISLKSGTEERGLKHYWFTSWPDQKTPDRAPPLLHLVREVEE
  AAQQEGPHCAPIIVHCSAGIGRTGCFIATSICCQQLRQEGVVDILKTTCQLRQDRGGMIQ
  TCEQYQFVHHVMSLYEKQLSHQSPE
• Function: May regulate the activity of several effector molecules involved in synaptic plasticity and neuronal cell survival, including MAPKs, Src family kinases and NMDA receptors.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)
• Reactome Pathway: Interleukin-37 signaling (R-HSA-9008059)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Definitive	Genetic Variation	[1]
Short bowel syndrome	DISMB5FU	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Bipolar disorder	DISAM7J2	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[7]
Huntington disease	DISQPLA4	Strong	Biomarker	[1]
Knee osteoarthritis	DISLSNBJ	Strong	Biomarker	[8]
Mental disorder	DIS3J5R8	Strong	Altered Expression	[9]
Mixed anxiety and depressive disorder	DISV809X	Strong	Biomarker	[10]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[11]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[12]
High blood pressure	DISY2OHH	moderate	Biomarker	[13]
Hypotrichosis simplex	DIS8WHDJ	moderate	Genetic Variation	[14]
Neurodegenerative disease	DISM20FF	moderate	Biomarker	[15]
Schizophrenia	DISSRV2N	moderate	Biomarker	[16]
Neuroblastoma	DISVZBI4	Disputed	Altered Expression	[17]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[18]
Myopia	DISK5S60	Limited	Genetic Variation	[19]
Parkinson disease	DISQVHKL	Limited	Biomarker	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Tyrosine-protein phosphatase non-receptor type 5 (PTPN5) increases the Neutropenia ADR of Cisplatin.	[27]

6 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 Tyrosine-protein phosphatase non-receptor type 5 (PTPN5).	[21]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Tyrosine-protein phosphatase non-receptor type 5 (PTPN5).	[22]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Tyrosine-protein phosphatase non-receptor type 5 (PTPN5).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Tyrosine-protein phosphatase non-receptor type 5 (PTPN5).	[23]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Tyrosine-protein phosphatase non-receptor type 5 (PTPN5).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Tyrosine-protein phosphatase non-receptor type 5 (PTPN5).	[26]

2 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 Tyrosine-protein phosphatase non-receptor type 5 (PTPN5).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tyrosine-protein phosphatase non-receptor type 5 (PTPN5).	[25]

References

• [1] Pharmacogenetic modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.Neurobiol Dis. 2018 Dec;120:88-97. doi: 10.1016/j.nbd.2018.08.024. Epub 2018 Aug 31.
• [2] Retracing our STEPs: Four decades of progress in intestinal lengthening procedures for short bowel syndrome.Am J Surg. 2019 Apr;217(4):772-782. doi: 10.1016/j.amjsurg.2018.11.025. Epub 2018 Nov 27.
• [3] X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors.J Med Chem. 2017 Nov 22;60(22):9299-9319. doi: 10.1021/acs.jmedchem.7b01292. Epub 2017 Nov 8.
• [4] Protein expression of targets of the FMRP regulon is altered in brains of subjects with schizophrenia and mood disorders.Schizophr Res. 2015 Jul;165(2-3):201-11. doi: 10.1016/j.schres.2015.04.012. Epub 2015 May 5.
• [5] Reprogramming of the estrogen responsive transcriptome contributes to tamoxifen-dependent protection against tumorigenesis in the p53 null mammary epithelial cells.PLoS One. 2018 Mar 28;13(3):e0194913. doi: 10.1371/journal.pone.0194913. eCollection 2018.
• [6] Inhibitor of Striatal-Enriched Protein Tyrosine Phosphatase, 8-(Trifluoromethyl)-1,2,3,4,5-Benzopentathiepin-6-Amine hydrochloride (TC-2153), Produces Antidepressant-Like Effect and Decreases Functional Activity and Protein Level of 5-HT(2A) Receptor in the Brain.Neuroscience. 2018 Dec 1;394:220-231. doi: 10.1016/j.neuroscience.2018.10.031. Epub 2018 Oct 24.
• [7] STEP inhibition reverses behavioral, electrophysiologic, and synaptic abnormalities in Fmr1 KO mice.Neuropharmacology. 2018 Jan;128:43-53. doi: 10.1016/j.neuropharm.2017.09.026. Epub 2017 Sep 21.
• [8] STepped exercise program for patients with knee OsteoArthritis (STEP-KOA): protocol for a randomized controlled trial.BMC Musculoskelet Disord. 2019 May 28;20(1):254. doi: 10.1186/s12891-019-2627-8.
• [9] Social Memory and Social Patterns Alterations in the Absence of STriatal-Enriched Protein Tyrosine Phosphatase.Front Behav Neurosci. 2019 Jan 25;12:317. doi: 10.3389/fnbeh.2018.00317. eCollection 2018.
• [10] Child STEPs in California: A cluster randomized effectiveness trial comparing modular treatment with community implemented treatment for youth with anxiety, depression, conduct problems, or traumatic stress.J Consult Clin Psychol. 2017 Jan;85(1):13-25. doi: 10.1037/ccp0000133. Epub 2016 Aug 22.
• [11] The Past, Present, and Future of Neurorehabilitation: From NUSTEP Through IV STEP and Beyond.J Neurol Phys Ther. 2017 Jul;41 Suppl 3:S3-S9. doi: 10.1097/NPT.0000000000000193.
• [12] Artefactual inflation of type 2 diabetes prevalence in WHO STEP surveys.Trop Med Int Health. 2019 Apr;24(4):477-483. doi: 10.1111/tmi.13213. Epub 2019 Feb 17.
• [13] Burden of hypertension in The Gambia: evidence from a national World Health Organization (WHO) STEP survey.Int J Epidemiol. 2018 Jun 1;47(3):860-871. doi: 10.1093/ije/dyx279.
• [14] Missense Variant in MAPK Inactivator PTPN5 Is Associated with Decreased Severity of Post-Burn Hypertrophic Scarring.PLoS One. 2016 Feb 12;11(2):e0149206. doi: 10.1371/journal.pone.0149206. eCollection 2016.
• [15] Status epilepticus-induced somatostatinergic hilar interneuron degeneration is regulated by striatal enriched protein tyrosine phosphatase.J Neurosci. 2007 Mar 14;27(11):2999-3009. doi: 10.1523/JNEUROSCI.4913-06.2007.
• [16] Synaptic NMDA Receptor Activation Induces Ubiquitination and Degradation of STEP(61).Mol Neurobiol. 2018 Apr;55(4):3096-3111. doi: 10.1007/s12035-017-0555-x. Epub 2017 May 2.
• [17] The activity of the Striatal-enriched protein tyrosine phosphatase in neuronal cells is modulated by adenosine A(2A) receptor.J Neurochem. 2020 Feb;152(3):284-298. doi: 10.1111/jnc.14866. Epub 2019 Oct 10.
• [18] Development and validation of simple step protein precipitation UHPLC-MS/MS methods for quantitation of temozolomide in cancer patient plasma samples.J Pharm Biomed Anal. 2019 Jan 5;162:164-170. doi: 10.1016/j.jpba.2018.09.019. Epub 2018 Sep 8.
• [19] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [20] STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease.Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1202-7. doi: 10.1073/pnas.1417423112. Epub 2015 Jan 12.
• [21] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [22] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [27] Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. Cancer Sci. 2013 Aug;104(8):1074-82. doi: 10.1111/cas.12186. Epub 2013 Jun 10.