protein tyrosine phosphatase non-receptor type 22 | Protein tyrosine phosphatases non-receptor type (PTPN) | IUPHAR Guide to IMMUNOPHARMACOLOGY

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protein tyrosine phosphatase non-receptor type 22

  Target has curated data in GtoImmuPdb

Target id: 3084

Nomenclature: protein tyrosine phosphatase non-receptor type 22

Abbreviated Name: LYP

Systematic Nomenclature: PTPN22

Family: Protein tyrosine phosphatases non-receptor type (PTPN)

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 807 1p13.2 PTPN22 protein tyrosine phosphatase non-receptor type 22 4
Mouse - 802 Ch 3, 45.52 cM; 3 F2.2 Ptpn22 protein tyrosine phosphatase, non-receptor type 22 (lymphoid)
Rat - 804 2q34 Ptpn22 protein tyrosine phosphatase
Gene and Protein Information Comments
Alternatively spliced transcript variants encoding distinct isoforms have been described for the human gene.
Previous and Unofficial Names
protein tyrosine phosphatase, non-receptor type 22 | Lyp1 | Lyp2 (85 kDa splice variant) [4] | protein tyrosine phosphatase, non-receptor type 8 | PTPN8 | 70zPEP (mouse homologue)
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 3.1.3.48
Description Reaction Reference
H2O + O-phospho-L-tyrosyl-[protein] = L-tyrosyl-[protein] + phosphate 13

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
I-C11 Hs Inhibition 5.5 pKi 14
pKi 5.5 (Ki 2.9x10-6 M) [14]
NC1 Hs Inhibition 5.4 pKi 9
pKi 5.4 (Ki 4.3x10-6 M) [9]
compound 8a [PMID: 23713581] Hs Inhibition 6.8 pIC50 7
pIC50 6.8 (IC50 1.71x10-7 M) [7]
I-C11 Hs Inhibition 5.3 pIC50 14
pIC50 5.3 (IC50 4.6x10-6 M) [14]
Description: In vitro measurement of PTPN22-catalysed substrate dephosphorylation, using pNPP as a substrate at pH 7.0, 25°C, and ionic strength of 0.15 M.
Immunopharmacology Comments
PTPN22 is a lymphoid-specific, inducible protein tyrosine phosphatase [4]. It negatively regulates T-cell receptor (TCR) signalling via direct dephosphorylation of phospho-tyrosines on a number of key signalling proteins, including LCK [13], FYN, and ZAP70 [12] (kinases), ITAM domains of the TCRζ/CD3 complex, and several other signalling proteins [11-12,14]. Biochemical studies suggest that dephosphorylation of the TCR-associated LCK and ZAP70 tyrosine kinases is the principal PTPN22 mechanism that contributes to inhibiting T cell activation [3,6,12]. The Arg620Trp (R620W) variant of PTPN22, which exhibits more active phosphatease activity, is highly correlated with a spectrum of autoimmune diseases. Selective inhibitors of PTPN22 are currently being sought as tool compounds to extend functional characterisation studies of PTPN22 in human diseases.
Cell Type Associations
Immuno Cell Type:  B cells
Cell Ontology Term:   mature B cell (CL:0000785)
References:  4
Immuno Cell Type:  T cells
Comment:  Expressed in mature T cells. Expression can be induced in resting peripheral T cells that are activated by phytohemagglutinin or anti-CD3 antibody.
References:  4
Immuno Process Associations
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 10 GO processes
GO:0030217 T cell differentiation ISS
GO:0032817 regulation of natural killer cell proliferation IDA
GO:0034141 positive regulation of toll-like receptor 3 signaling pathway IMP
GO:0034145 positive regulation of toll-like receptor 4 signaling pathway IMP
GO:0050852 T cell receptor signaling pathway TAS
GO:0050855 regulation of B cell receptor signaling pathway NAS
GO:0050860 negative regulation of T cell receptor signaling pathway IDA
GO:0050868 negative regulation of T cell activation IMP
GO:0070433 negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway IMP
GO:1902523 positive regulation of protein K63-linked ubiquitination IMP
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0050868 negative regulation of T cell activation IMP
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 5 GO processes
GO:0032481 positive regulation of type I interferon production IMP
GO:0032720 negative regulation of tumor necrosis factor production IMP
GO:1900165 negative regulation of interleukin-6 secretion IMP
GO:1902715 positive regulation of interferon-gamma secretion IMP
GO:2000483 negative regulation of interleukin-8 secretion IMP
Immuno Process:  Immune regulation
GO Annotations:  Associated to 9 GO processes
GO:0032817 regulation of natural killer cell proliferation IDA
GO:0034141 positive regulation of toll-like receptor 3 signaling pathway IMP
GO:0034145 positive regulation of toll-like receptor 4 signaling pathway IMP
GO:0045088 regulation of innate immune response IC
GO:0050852 T cell receptor signaling pathway TAS
GO:0050855 regulation of B cell receptor signaling pathway NAS
GO:0050860 negative regulation of T cell receptor signaling pathway IDA
GO:0050868 negative regulation of T cell activation IMP
GO:0070433 negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway IMP
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes
GO:0030217 T cell differentiation ISS
Immuno Process:  Inflammation
GO Annotations:  Associated to 4 GO processes
GO:0034141 positive regulation of toll-like receptor 3 signaling pathway IMP
GO:0034145 positive regulation of toll-like receptor 4 signaling pathway IMP
GO:0045088 regulation of innate immune response IC
GO:0070433 negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway IMP
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0030217 T cell differentiation ISS
GO:0050868 negative regulation of T cell activation IMP
Biologically Significant Variants
Type:  Missense mutation
Species:  Human
Description:  A natural intronic mutation that causes a missense variant found in patients with T1DM, RA, SLE, Graves' disease, Hashimoto thyroiditis and Addison's disease. This variant disrupts the P1 proline-rich motif that is important for PTPN22's interaction with Csk, and is suggested to elevate the overall reactivity of the immune system.
Amino acid change:  R620W
Nucleotide change:  C1858T
SNP accession: 
References:  1-2,5,8,10

References

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1. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM et al.. (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet., 75 (2): 330-7. [PMID:15208781]

2. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M et al.. (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet., 36 (4): 337-8. [PMID:15004560]

3. Cloutier JF, Veillette A. (1999) Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J. Exp. Med., 189 (1): 111-21. [PMID:9874568]

4. Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM. (1999) Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood, 93 (6): 2013-24. [PMID:10068674]

5. Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, Kern M, Moser KL, Begovich AB, Carlton VE, Li W et al.. (2005) Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am. J. Hum. Genet., 76 (4): 561-71. [PMID:15719322]

6. Gjörloff-Wingren A, Saxena M, Williams S, Hammi D, Mustelin T. (1999) Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. Eur. J. Immunol., 29 (12): 3845-54. [PMID:10601992]

7. He Y, Liu S, Menon A, Stanford S, Oppong E, Gunawan AM, Wu L, Wu DJ, Barrios AM, Bottini N et al.. (2013) A potent and selective small-molecule inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases. J. Med. Chem., 56 (12): 4990-5008. [PMID:23713581]

8. Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, Chang M, Ramos P, Baechler EC, Batliwalla FM et al.. (2004) Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am. J. Hum. Genet., 75 (3): 504-7. [PMID:15273934]

9. Li K, Hou X, Li R, Bi W, Yang F, Chen X, Xiao P, Liu T, Lu T, Zhou Y et al.. (2019) Identification and structure-function analyses of an allosteric inhibitor of the tyrosine phosphatase PTPN22. J. Biol. Chem., [Epub ahead of print]. DOI: 10.1074/jbc.RA118.007129 [PMID:30979725]

10. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT, Ball SG, James RA, Quinton R, Perros P et al.. (2004) The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease. J. Clin. Endocrinol. Metab., 89 (11): 5862-5. [PMID:15531553]

11. Wang Y, Shaked I, Stanford SM, Zhou W, Curtsinger JM, Mikulski Z, Shaheen ZR, Cheng G, Sawatzke K, Campbell AM et al.. (2013) The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity. Immunity, 39 (1): 111-22. [PMID:23871208]

12. Wu J, Katrekar A, Honigberg LA, Smith AM, Conn MT, Tang J, Jeffery D, Mortara K, Sampang J, Williams SR et al.. (2006) Identification of substrates of human protein-tyrosine phosphatase PTPN22. J. Biol. Chem., 281 (16): 11002-10. [PMID:16461343]

13. Yu X, Chen M, Zhang S, Yu ZH, Sun JP, Wang L, Liu S, Imasaki T, Takagi Y, Zhang ZY. (2011) Substrate specificity of lymphoid-specific tyrosine phosphatase (Lyp) and identification of Src kinase-associated protein of 55 kDa homolog (SKAP-HOM) as a Lyp substrate. J. Biol. Chem., 286 (35): 30526-34. [PMID:21719704]

14. Yu X, Sun JP, He Y, Guo X, Liu S, Zhou B, Hudmon A, Zhang ZY. (2007) Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases. Proc. Natl. Acad. Sci. U.S.A., 104 (50): 19767-72. [PMID:18056643]

How to cite this page

Protein tyrosine phosphatases non-receptor type (PTPN): protein tyrosine phosphatase non-receptor type 22. Last modified on 06/05/2019. Accessed on 26/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=3084.