Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDCNTC3)

• DOT Name: Tyrosine-protein phosphatase non-receptor type 22 (PTPN22)
• Synonyms: EC 3.1.3.48; Hematopoietic cell protein-tyrosine phosphatase 70Z-PEP; Lymphoid phosphatase; LyP; PEST-domain phosphatase; PEP
• Gene Name: PTPN22
• Related Disease:
  Addison disease
  Classic Hodgkin lymphoma
  Advanced cancer
  Alopecia
  Alopecia areata
  Ankylosing spondylitis
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease, susceptibility to, 6
  Autoimmune hepatitis
  Breast cancer
  Breast carcinoma
  Endometriosis
  Giant cell arteritis
  HIV infectious disease
  Hypothyroidism
  Immune system disorder
  Juvenile idiopathic arthritis
  Lupus
  Myasthenia gravis
  Myositis disease
  Obesity
  Parkinson disease
  Pulmonary tuberculosis
  Rabies
  STAT3-related early-onset multisystem autoimmune disease
  Tuberculosis
  Arthritis
  Asthma
  Purpura
  Arrhythmia
  Basal cell carcinoma
  Basal cell neoplasm
  Colitis
  Polymyositis
  Rheumatoid arthritis
  Sclerosing cholangitis
  Stroke
  Triple negative breast cancer
  Type 1 diabetes mellitus 1
  Vitiligo
• UniProt ID: PTN22_HUMAN
• PDB ID: 2P6X; 2QCJ; 2QCT; 3BRH; 3H2X; 3OLR; 3OMH; 4J51; 7AAM
• EC Number: 3.1.3.48
• Pfam ID: PF00102
• Sequence:
  MDQREILQKFLDEAQSKKITKEEFANEFLKLKRQSTKYKADKTYPTTVAEKPKNIKKNRY
  KDILPYDYSRVELSLITSDEDSSYINANFIKGVYGPKAYIATQGPLSTTLLDFWRMIWEY
  SVLIIVMACMEYEMGKKKCERYWAEPGEMQLEFGPFSVSCEAEKRKSDYIIRTLKVKFNS
  ETRTIYQFHYKNWPDHDVPSSIDPILELIWDVRCYQEDDSVPICIHCSAGCGRTGVICAI
  DYTWMLLKDGIIPENFSVFSLIREMRTQRPSLVQTQEQYELVYNAVLELFKRQMDVIRDK
  HSGTESQAKHCIPEKNHTLQADSYSPNLPKSTTKAAKMMNQQRTKMEIKESSSFDFRTSE
  ISAKEELVLHPAKSSTSFDFLELNYSFDKNADTTMKWQTKAFPIVGEPLQKHQSLDLGSL
  LFEGCSNSKPVNAAGRYFNSKVPITRTKSTPFELIQQRETKEVDSKENFSYLESQPHDSC
  FVEMQAQKVMHVSSAELNYSLPYDSKHQIRNASNVKHHDSSALGVYSYIPLVENPYFSSW
  PPSGTSSKMSLDLPEKQDGTVFPSSLLPTSSTSLFSYYNSHDSLSLNSPTNISSLLNQES
  AVLATAPRIDDEIPPPLPVRTPESFIVVEEAGEFSPNVPKSLSSAVKVKIGTSLEWGGTS
  EPKKFDDSVILRPSKSVKLRSPKSELHQDRSSPPPPLPERTLESFFLADEDCMQAQSIET
  YSTSYPDTMENSTSSKQTLKTPGKSFTRSKSLKILRNMKKSICNSCPPNKPAESVQSNNS
  SSFLNFGFANRFSKPKGPRNPPPTWNI
• Function: Acts as a negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules. Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue. Dephosphorylates ZAP70 at its activating 'Tyr-493' residue. Dephosphorylates the immune system activator SKAP2. Positively regulates toll-like receptor (TLR)-induced type 1 interferon production. Promotes host antiviral responses mediated by type 1 interferon. Regulates NOD2-induced pro-inflammatory cytokine secretion and autophagy. Acts as an activator of NLRP3 inflammasome assembly by mediating dephosphorylation of 'Tyr-861' of NLRP3. Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to anandamide (also called N-arachidonoylethanolamide).
• Tissue Specificity: Expressed in bone marrow, B and T-cells, PBMCs, natural killer cells, monocytes, dendritic cells and neutrophils . Both isoform 1 and 4 are predominantly expressed in lymphoid tissues and cells. Isoform 1 is expressed in thymocytes and both mature B and T-cells.
• Reactome Pathway:
  Translocation of ZAP-70 to Immunological synapse (R-HSA-202430)
  Phosphorylation of CD3 and TCR zeta chains (R-HSA-202427)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Addison disease	DIS7HNOH	Definitive	Genetic Variation	[1]
Classic Hodgkin lymphoma	DISV1LU6	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alopecia	DIS37HU4	Strong	Genetic Variation	[4]
Alopecia areata	DIS0XXBJ	Strong	Genetic Variation	[4]
Ankylosing spondylitis	DISRC6IR	Strong	Genetic Variation	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[7]
Autoimmune hepatitis	DISOX03Q	Strong	Genetic Variation	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[9]
Giant cell arteritis	DISSP87T	Strong	SusceptibilityMutation	[10]
HIV infectious disease	DISO97HC	Strong	Biomarker	[11]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[7]
Immune system disorder	DISAEGPH	Strong	Biomarker	[12]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Genetic Variation	[13]
Lupus	DISOKJWA	Strong	Biomarker	[14]
Myasthenia gravis	DISELRCI	Strong	Genetic Variation	[15]
Myositis disease	DISCIXF0	Strong	Genetic Variation	[16]
Obesity	DIS47Y1K	Strong	Genetic Variation	[17]
Parkinson disease	DISQVHKL	Strong	Biomarker	[18]
Pulmonary tuberculosis	DIS6FLUM	Strong	Genetic Variation	[19]
Rabies	DISSC4V5	Strong	Biomarker	[20]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[7]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[21]
Arthritis	DIST1YEL	moderate	Genetic Variation	[22]
Asthma	DISW9QNS	moderate	Genetic Variation	[23]
Purpura	DISWPOOE	moderate	Genetic Variation	[24]
Arrhythmia	DISFF2NI	Limited	Genetic Variation	[25]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[26]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[26]
Colitis	DISAF7DD	Limited	Biomarker	[27]
Polymyositis	DIS5DHFP	Limited	Genetic Variation	[28]
Rheumatoid arthritis	DISTSB4J	Limited	Unknown	[29]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[30]
Stroke	DISX6UHX	Limited	Biomarker	[31]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[32]
Type 1 diabetes mellitus 1	DIS3Y2GA	Limited	Autosomal recessive	[29]
Vitiligo	DISR05SL	Limited	Genetic Variation	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[34]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[35]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[37]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[38]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[39]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[40]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[41]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[42]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[43]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[45]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[46]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[47]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tyrosine-protein phosphatase non-receptor type 22 (PTPN22).	[44]

References

• [1] Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue.Genes Immun. 2012 Dec;13(8):641-52. doi: 10.1038/gene.2012.46. Epub 2012 Oct 18.
• [2] Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma.Blood. 2018 Nov 8;132(19):2040-2052. doi: 10.1182/blood-2018-06-855296. Epub 2018 Sep 7.
• [3] Efficacy of a novel LyP-1-containing self-microemulsifying drug delivery system (SMEDDS) for active targeting to breast cancer.Eur J Pharm Biopharm. 2019 Mar;136:138-146. doi: 10.1016/j.ejpb.2019.01.017. Epub 2019 Jan 22.
• [4] The association between rs2476601 polymorphism in PTPN22 gene and risk of alopecia areata: A meta-analysis of case-control studies.Medicine (Baltimore). 2019 May;98(20):e15448. doi: 10.1097/MD.0000000000015448.
• [5] Association Between Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Polymorphisms and Risk of Ankylosing Spondylitis: A Meta-analysis.Med Sci Monit. 2017 May 30;23:2619-2624. doi: 10.12659/msm.901083.
• [6] PTPN22 Gene Polymorphisms Are Associated with Susceptibility to Large Artery Atherosclerotic Stroke and Microembolic Signals.Dis Markers. 2019 May 5;2019:2193835. doi: 10.1155/2019/2193835. eCollection 2019.
• [7] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [8] Association of STAT4, TGF1, SH2B3 and PTPN22 polymorphisms with autoimmune hepatitis.Exp Mol Pathol. 2018 Dec;105(3):279-284. doi: 10.1016/j.yexmp.2018.10.001. Epub 2018 Oct 3.
• [9] The effect of ACP1, ADA6 and PTPN22 genetic polymorphisms on the association between p53 codon 72 polymorphism and endometriosis.Arch Gynecol Obstet. 2016 Feb;293(2):399-402. doi: 10.1007/s00404-015-3827-6. Epub 2015 Jul 28.
• [10] Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis.Ann Rheum Dis. 2013 Nov;72(11):1882-1886. doi: 10.1136/annrheumdis-2013-203641. Epub 2013 Aug 14.
• [11] Updates on HIV nonoccupational postexposure prophylaxis.Curr Opin Pediatr. 2019 Aug;31(4):454-461. doi: 10.1097/MOP.0000000000000775.
• [12] The Contribution of PTPN22 to Rheumatic Disease.Arthritis Rheumatol. 2019 Apr;71(4):486-495. doi: 10.1002/art.40790. Epub 2019 Mar 2.
• [13] STAT4 rs7574865 G/T and PTPN22 rs2488457 G/C polymorphisms influence the risk of developing juvenile idiopathic arthritis in Han Chinese patients.PLoS One. 2015 Mar 17;10(3):e0117389. doi: 10.1371/journal.pone.0117389. eCollection 2015.
• [14] IRF5, PTPN22, CD28, IL2RA, KIF5A, BLK and TNFAIP3 genes polymorphisms and lupus susceptibility in a cohort from the Egypt Delta; relation to other ethnic groups.Hum Immunol. 2015 Jul;76(7):525-31. doi: 10.1016/j.humimm.2015.06.001. Epub 2015 Jun 17.
• [15] PTPN22 R620W Polymorphism is Associated with Myasthenia Gravis Risk: A Systematic Review and Meta-Analysis.Med Sci Monit. 2015 Aug 30;21:2567-71. doi: 10.12659/MSM.894307.
• [16] Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases.Ann Rheum Dis. 2019 Mar;78(3):311-319. doi: 10.1136/annrheumdis-2018-214127. Epub 2018 Dec 20.
• [17] Hypolipidemic Effect of Arthrospira (Spirulina) maxima Supplementation and a Systematic Physical Exercise Program in Overweight and Obese Men: A Double-Blind, Randomized, and Crossover Controlled Trial.Mar Drugs. 2019 May 7;17(5):270. doi: 10.3390/md17050270.
• [18] PEP-1-PEA-15 protects against toxin-induced neuronal damage in a mouse model of Parkinson's disease.Biochim Biophys Acta. 2014 Jun;1840(6):1686-700. doi: 10.1016/j.bbagen.2014.01.004. Epub 2014 Jan 8.
• [19] Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene single nucleotide polymorphisms and its interaction with T2DM on pulmonary tuberculosis in Chinese Uygur population.Oncotarget. 2017 Jul 15;8(39):65601-65608. doi: 10.18632/oncotarget.19274. eCollection 2017 Sep 12.
• [20] Comparative Immunogenicity and Safety Trial of 2 Different Schedules of Single-visit Intradermal Rabies Postexposure Vaccination.Clin Infect Dis. 2019 Aug 16;69(5):797-804. doi: 10.1093/cid/ciy983.
• [21] Association between the PTPN22 1858C/T gene polymorphism and tuberculosis resistance.Infect Genet Evol. 2013 Jun;16:310-3. doi: 10.1016/j.meegid.2013.02.019. Epub 2013 Mar 14.
• [22] Frequency of human leukocyte antigens class II-DR alleles (HLA-DRB1) in Argentinian patients with early arthritis.Clin Rheumatol. 2019 Mar;38(3):675-681. doi: 10.1007/s10067-018-4319-4. Epub 2018 Oct 10.
• [23] Association between PTPN22/CTLA-4 Gene Polymorphism and Allergic Rhinitis with Asthma in Children.Iran J Allergy Asthma Immunol. 2016 Oct;15(5):413-419.
• [24] Lack of association of a functional single nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with susceptibility to Henoch-Schnlein purpura.Clin Exp Rheumatol. 2007 Sep-Oct;25(5):750-3.
• [25] Cardiac autonomic functioning and post-traumatic stress: A preliminary study in youth at-risk for PTSD.Psychiatry Res. 2020 Feb;284:112684. doi: 10.1016/j.psychres.2019.112684. Epub 2019 Nov 7.
• [26] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [27] Experimental colitis in IL-10-deficient mice ameliorates in the absence of PTPN22.Clin Exp Immunol. 2019 Sep;197(3):263-275. doi: 10.1111/cei.13339. Epub 2019 Jul 10.
• [28] Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups.Ann Rheum Dis. 2016 Aug;75(8):1558-66. doi: 10.1136/annrheumdis-2015-208119. Epub 2015 Sep 11.
• [29] 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.
• [30] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [31] TAT-PEP Enhanced Neurobehavioral Functional Recovery by Facilitating Axonal Regeneration and Corticospinal Tract Projection After Stroke.Mol Neurobiol. 2018 Jan;55(1):652-667. doi: 10.1007/s12035-016-0301-9. Epub 2016 Dec 16.
• [32] (99m)Tc-Labeled LyP-1 for SPECT Imaging of Triple Negative Breast Cancer.Contrast Media Mol Imaging. 2019 Sep 25;2019:9502712. doi: 10.1155/2019/9502712. eCollection 2019.
• [33] Association of PTPN22 gene polymorphism with non-segmental vitiligo in South Indian Tamils.Postepy Dermatol Alergol. 2018 Jun;35(3):280-285. doi: 10.5114/ada.2018.76225. Epub 2018 Jun 18.
• [34] 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.
• [35] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [36] 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.
• [37] 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.
• [38] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [39] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [40] 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.
• [41] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [42] Capsaicin inhibits the migration, invasion and EMT of renal cancer cells by inducing AMPK/mTOR-mediated autophagy. Chem Biol Interact. 2022 Oct 1;366:110043. doi: 10.1016/j.cbi.2022.110043. Epub 2022 Aug 28.
• [43] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [44] 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.
• [45] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [46] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [47] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.