PTPN22

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Protein tyrosine phosphatase, non-receptor type 22 (lymphoid)
Protein PTPN22 PDB 2p6x.png
PDB rendering based on 2p6x.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PTPN22 ; LYP; LYP1; LYP2; PEP; PTPN8
External IDs OMIM600716 MGI107170 HomoloGene7498 ChEMBL: 2889 GeneCards: PTPN22 Gene
EC number 3.1.3.48
RNA expression pattern
PBB GE PTPN22 206060 s at tn.png
PBB GE PTPN22 208010 s at tn.png
PBB GE PTPN22 208011 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 26191 19260
Ensembl ENSG00000134242 ENSMUSG00000027843
UniProt Q9Y2R2 P29352
RefSeq (mRNA) NM_001193431 NM_008979
RefSeq (protein) NP_001180360 NP_033005
Location (UCSC) Chr 1:
114.36 – 114.41 Mb
Chr 3:
103.86 – 103.91 Mb
PubMed search [1] [2]

Protein tyrosine phosphatase, non-receptor type 22 (lymphoid), also known as PTPN22, is a protein that in humans is encoded by the PTPN22 gene.[1][2][3] This gene can be expressed in different forms. PTPN22 affects the responsiveness of T and B cell receptors, and mutations are associated with increases or decreases in risks of autoimmune diseases.

Molecular biology[edit]

The gene is located on the short arm of Chromosome 1 near the end (telomere) (1p13.2) on the Crick (minus) strand. It is 57,898 bases in length and encodes a protein of 807 amino acids (molecular weight 91,705 Da). There are 24 exons in the gene and 21 transcript variants encoding 10 distinct proteins are known. The proteins are located in the cytoplasm.[citation needed]

Function[edit]

This gene encodes a protein tyrosine phosphatase which is expressed primarily in lymphoid tissues. This enzyme is involved in several signalling pathways associated with the immune response. Based on models of the murine phosphatase,[4][5] structural identification,[6] and human genetics[7] the phosphatase forms complexes with C-src tyrosine kinase (Csk), associated with the control of Src family members. The mutation Arg620Trp disrupts binding to Csk, alters the responsiveness of T and B cell receptors, and is associated with autoimmune diseases. There are other suggestions that the phosphatase regulates CBL function in the T cell receptor signaling pathway.[1] Other interactions are likely.

Disease association[edit]

The common 1858T (rs2476601) Arg620Trp nonsynonymous single nucleotide polymorphism located in the PTPN22 gene has been associated with autoimmune disorders, including an increased risk of Type 1 Diabetes, rheumatoid arthritis, Systemic Lupus Erythematosus, Vitiligo and Graves' disease, but a decreased risk of Crohn's disease.[8][9]

A recent study suggests that the mutation does not, on a population basis, reduce life span.[10] The mutation may be conserved in human evolution because it may provide a hyper-immune response to infectious disease.[11]

Mutations in CCND3 are implicated in cases of breast cancer.[12]

References[edit]

  1. ^ a b EntrezGene 26191
  2. ^ Matthews RJ, Bowne DB, Flores E, Thomas ML (May 1992). "Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences". Mol. Cell. Biol. 12 (5): 2396–405. PMC 364412. PMID 1373816.  edit
  3. ^ Cohen, S. (March 1999). "Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp". Blood 93 (6): 2013–2024. PMID 10068674.  edit
  4. ^ Cloutier JF, Veillette A (September 1996). "Association of inhibitory tyrosine protein kinase p50csk with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells". EMBO J. 15 (18): 4909–18. PMC 452228. PMID 8890164.  edit
  5. ^ Gregorieff A, Cloutier JF, Veillette A; Cloutier; Veillette (May 1998). "Sequence requirements for association of protein-tyrosine phosphatase PEP with the Src homology 3 domain of inhibitory tyrosine protein kinase p50(csk)". J. Biol. Chem. 273 (21): 13217–22. doi:10.1074/jbc.273.21.13217. PMID 9582365.  edit
  6. ^ Ghose, R.; Shekhtman, A.; Goger, M. J.; Ji, H.; Cowburn, D. (November 2001). "A novel, specific interaction involving the Csk SH3 domain and its natural ligand". Nat. Struct. Biol. 8 (11): 998–1004. doi:10.1038/nsb1101-998. PMID 11685249.  edit
  7. ^ Vang, T.; Miletic, A. V.; Bottini, N.; Mustelin, T. (September 2007). "Protein tyrosine phosphatase PTPN22 in human autoimmunity". Autoimmunity 40 (6): 453–461. doi:10.1080/08916930701464897. PMID 17729039.  edit
  8. ^ "Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study". J. Med. Genet. 42 (3): 266–270. March 2005. doi:10.1136/jmg.2004.026971. PMC 1736025. PMID 15744042.  edit
  9. ^ Vang, T.; Congia, M.; Macis, M. D.; Musumeci, L.; Orrú, V.; Zavattari, P.; Nika, K.; Tautz, L.; Taskén, K.; Cucca, F.; Mustelin, T.; Bottini, N. (December 2005). "Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant". Nat. Genet. 37 (12): 1317–1319. doi:10.1038/ng1673. PMID 16273109.  edit
  10. ^ Napolioni, V.; Natali, A.; Saccucci, P.; Lucarini, N. (August 2011). "PTPN22 1858C>T (R620W) functional polymorphism and human longevity". Mol. Biol. Rep. 38 (6): 4231–4235. doi:10.1007/s11033-010-0546-8. PMID 21113673.  edit
  11. ^ "PTPN22". NLM (US Gov). Retrieved 5 April 2013. 
  12. ^ The Cancer Genome Atlas Network (2012). "Comprehensive molecular portraits of human breast tumours". Nature (Nature Publishing Group) 490 (7418): 61–70. doi:10.1038/nature11412. PMC 3465532. PMID 23000897. Retrieved 24 September 2012. 

Further reading[edit]

  • Gregersen, P. K. (2005). "Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond". Immunological Reviews 204: 74–86. doi:10.1111/j.0105-2896.2005.00243.x. PMID 15790351.  edit
  • Brand, O.; Gough, S.; Heward, J. (2005). "HLA, CTLA-4 and PTPN22: The shared genetic master-key to autoimmunity?". Expert Reviews in Molecular Medicine 7 (23): 1–15. doi:10.1017/S1462399405009981. PMID 16229750.  edit
  • Bottini, N.; Vang, T.; Cucca, F.; Mustelin, T. (2006). "Role of PTPN22 in type 1 diabetes and other autoimmune diseases". Seminars in Immunology 18 (4): 207–213. doi:10.1016/j.smim.2006.03.008. PMID 16697661.  edit
  • Gjörloff-Wingren, A.; Saxena, M.; Han, S.; Wang, X.; Alonso, A.; Renedo, M.; Oh, P.; Williams, S.; Schnitzer, J.; Mustelin, T. (2000). "Subcellular localization of intracellular protein tyrosine phosphatases in T cells". European Journal of Immunology 30 (8): 2412–2421. doi:10.1002/1521-4141(2000)30:8<2412::AID-IMMU2412>3.0.CO;2-J. PMID 10940933.  edit
  • Hill, R. J.; Zozulya, S.; Lu, Y. L.; Ward, K.; Gishizky, M.; Jallal, B. (2002). "The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation". Experimental hematology 30 (3): 237–244. doi:10.1016/S0301-472X(01)00794-9. PMID 11882361.  edit
  • Chien, W.; Tidow, N.; Williamson, E. A.; Shih, L. Y.; Krug, U.; Kettenbach, A.; Fermin, A. C.; Roifman, C. M.; Koeffler, H. P. (2003). "Characterization of a Myeloid Tyrosine Phosphatase, Lyp, and Its Role in the Bcr-Abl Signal Transduction Pathway". Journal of Biological Chemistry 278 (30): 27413–27420. doi:10.1074/jbc.M304575200. PMID 12764153.  edit
  • Bottini, N.; Musumeci, L.; Alonso, A.; Rahmouni, S.; Nika, K.; Rostamkhani, M.; MacMurray, J.; Meloni, G. F.; Lucarelli, P.; Pellecchia, M.; Eisenbarth, G. S.; Comings, D.; Mustelin, T. (2004). "A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes". Nature Genetics 36 (4): 337–338. doi:10.1038/ng1323. PMID 15004560.  edit
  • Begovich, A.; Carlton, V.; Honigberg, L.; Schrodi, S.; Chokkalingam, A.; Alexander, H.; Ardlie, K.; Huang, Q.; Smith, A.; Spoerke, J.; Conn, M. T.; Chang, M.; Chang, S. Y.; Saiki, R. K.; Catanese, J. J.; Leong, D. U.; Garcia, V. E.; McAllister, L. B.; Jeffery, D. A.; Lee, A. T.; Batliwalla, F.; Remmers, E.; Criswell, L. A.; Seldin, M. F.; Kastner, D. L.; Amos, C. I.; Sninsky, J. J.; Gregersen, P. K. (2004). "A Missense Single-Nucleotide Polymorphism in a Gene Encoding a Protein Tyrosine Phosphatase (PTPN22) is Associated with Rheumatoid Arthritis". The American Journal of Human Genetics 75 (2): 330–337. doi:10.1086/422827. PMC 1216068. PMID 15208781.  edit
  • Kyogoku, C.; Ortmann, W. A.; Lee, A.; Selby, S.; Carlton, V. E. H.; Chang, M.; Ramos, P.; Baechler, E. C.; Batliwalla, F. M.; Novitzke, J.; Williams, A. H.; Gillett, C.; Rodine, P.; Graham, R. R.; Ardlie, K. G.; Gaffney, P. M.; Moser, K. L.; Petri, M.; Begovich, A. B.; Gregersen, P. K.; Langefeld, C. D.; Behrens, T. W. (2004). "Genetic Association of the R620W Polymorphism of Protein Tyrosine Phosphatase PTPN22 with Human SLE". The American Journal of Human Genetics 75 (3): 504–507. doi:10.1086/423790. PMC 1182029. PMID 15273934.  edit
  • Smyth, D.; Cooper, J. D.; Collins, J. E.; Heward, J. M.; Franklyn, J. A.; Howson, J. M.; Vella, A.; Nutland, S.; Rance, H. E.; Maier, L.; Barratt, B. J.; Guja, C.; Ionescu-Tîrgoviste, C.; Savage, D. A.; Dunger, D. B.; Widmer, B.; Strachan, D. P.; Ring, S. M.; Walker, N.; Clayton, D. G.; Twells, R. C.; Gough, S. C.; Todd, J. A. (2004). "Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus". Diabetes 53 (11): 3020–3023. doi:10.2337/diabetes.53.11.3020. PMID 15504986.  edit
  • Ladner, M. B.; Bottini, N.; Valdes, A. M.; Noble, J. A. (2005). "Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes". Human Immunology 66 (1): 60–64. doi:10.1016/j.humimm.2004.09.016. PMID 15620463.  edit
  • Orozco G, Sánchez E, González-Gay MA, López-Nevot MA, Torres B, Cáliz R, Ortego-Centeno N, Jiménez-Alonso J, Pascual-Salcedo D, Balsa A, de Pablo R, Nuñez-Roldan A, González-Escribano MF, Martín J (January 2005). "Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus". Arthritis Rheum. 52 (1): 219–24. doi:10.1002/art.20771. PMID 15641066.  edit
  • Steer, S.; Lad, B.; Grumley, J. A.; Kingsley, G. H.; Fisher, S. A. (2005). "Association of R602W in a protein tyrosine phosphatase gene with a high risk of rheumatoid arthritis in a British population: Evidence for an early onset/disease severity effect". Arthritis & Rheumatism 52 (1): 358–360. doi:10.1002/art.20737. PMID 15641088.  edit
  • Zheng, W.; She, J. X. (2005). "Genetic association between a lymphoid tyrosine phosphatase (PTPN22) and type 1 diabetes". Diabetes 54 (3): 906–908. doi:10.2337/diabetes.54.3.906. PMID 15734872.  edit
  • Zhernakova, A.; Eerligh, P.; Wijmenga, C.; Barrera, P.; Roep, B. O.; Koeleman, B. P. C. (2005). "Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population". Genes and Immunity 6 (6): 459–461. doi:10.1038/sj.gene.6364220. PMID 15875058.  edit