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protein tyrosine phosphatase non-receptor type 22

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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)

Contents:

Gene and Protein Information Click here for help
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 3 F2.2 Ptpn22 protein tyrosine phosphatase, non-receptor type 22 (lymphoid)
Rat - 804 2q34 Ptpn22 protein tyrosine phosphatase, non-receptor type 22
Gene and Protein Information Comments
Alternatively spliced transcript variants encoding distinct isoforms have been described for the human gene.
Previous and Unofficial Names Click here for help
protein tyrosine phosphatase, non-receptor type 22 | protein tyrosine phosphatase, non-receptor type 22 (lymphoid) | protein tyrosine phosphatase | Lyp1 | Lyp2 (85 kDa splice variant) [4] | protein tyrosine phosphatase, non-receptor type 8 | PTPN8 | 70zPEP (mouse homologue)
Database Links Click here for help
Alphafold Q9Y2R2 (Hs), P29352 (Mm)
BRENDA 3.1.3.48
ChEMBL Target CHEMBL2889 (Hs), CHEMBL2157855 (Mm)
Ensembl Gene ENSG00000134242 (Hs), ENSMUSG00000027843 (Mm), ENSRNOG00000019614 (Rn)
Entrez Gene 26191 (Hs), 19260 (Mm), 295338 (Rn)
Human Protein Atlas ENSG00000134242 (Hs)
KEGG Enzyme 3.1.3.48
KEGG Gene hsa:26191 (Hs), mmu:19260 (Mm), rno:295338 (Rn)
OMIM 600716 (Hs)
Pharos Q9Y2R2 (Hs)
RefSeq Nucleotide NM_015967 (Hs), NM_008979 (Mm), NM_001106460 (Rn)
RefSeq Protein NP_057051 (Hs), NP_033005 (Mm), NP_001099930 (Rn)
UniProtKB Q9Y2R2 (Hs), P29352 (Mm)
Wikipedia PTPN22 (Hs)
Enzyme Reaction Click here for help
EC Number: 3.1.3.48
Description Reaction Reference
H2O + O-phospho-L-tyrosyl-[protein] = L-tyrosyl-[protein] + phosphate 14

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
I-C11 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.5 pKi 15
⤷ pKi 5.5 (Ki 2.9x10-6 M) [15]
NC1 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.4 pKi 10
⤷ pKi 5.4 (Ki 4.3x10-6 M) [10]
compound 8a [PMID: 23713581] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.8 pIC50 7
⤷ pIC50 6.8 (IC50 1.71x10-7 M) [7]
I-C11 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.3 pIC50 15
⤷ pIC50 5.3 (IC50 4.6x10-6 M) [15]
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 [14], FYN, and ZAP70 [13] (kinases), ITAM domains of the TCRζ/CD3 complex, and several other signalling proteins [12-13,15]. 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 [3,6,13]. The Arg620Trp (R620W) variant of PTPN22, which exhibits more active phosphatease activity, is highly correlated with a spectrum of autoimmune diseases. In mice, reduced PTPN22 activity augments antitumour activity by increasing infiltration and activation of macrophages, natural killer cells, and T cells within the tumour mocroenvironment [8]. This information suggests that PTPN22 can be considered as a target for cancer immunotherapy. 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
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cytokine production & signalling
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Biologically Significant Variants Click here for help
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:  rs2476601
References:  1-2,5,9,11

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. Ho WJ, Croessmann S, Lin J, Phyo ZH, Charmsaz S, Danilova L, Mohan AA, Gross NE, Chen F, Dong J et al.. (2021) Systemic inhibition of PTPN22 augments anticancer immunity. J Clin Invest, 131 (17) [Epub ahead of print]. [PMID:34283806]

9. 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]

10. 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, 294 (21): 8653-8663. [PMID:30979725]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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 USA, 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 26/07/2021. Accessed on 04/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3084.