Protein tyrosine phosphatase, non-receptor type 22 (lymphoid), also known as PTPN22, is a protein that in humans is encoded by the PTPN22gene. 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.
The gene is located on the short arm of Chromosome 1 near the centromere (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.
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, structural identification, and human genetics 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. Other interactions are likely.
A recent study suggests that the mutation does not, on a population basis, reduce life span. The mutation may be conserved in human evolution because it may provide a hyper-immune response to infectious disease.
^Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM (March 1999). "Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp". Blood. 93 (6): 2013–24. PMID10068674.
^Gregorieff A, Cloutier JF, Veillette A (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. PMID9582365.
^Ghose R, Shekhtman A, Goger MJ, 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. PMID11685249.
Hill RJ, Zozulya S, Lu YL, 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". Exp. Hematol. 30 (3): 237–44. doi:10.1016/S0301-472X(01)00794-9. PMID11882361.
Chien W, Tidow N, Williamson EA, Shih LY, Krug U, Kettenbach A, Fermin AC, Roifman CM, Koeffler HP (2003). "Characterization of a myeloid tyrosine phosphatase, Lyp, and its role in the Bcr-Abl signal transduction pathway". J. Biol. Chem. 278 (30): 27413–20. doi:10.1074/jbc.M304575200. PMID12764153.
Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T (2004). "A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes". Nat. Genet. 36 (4): 337–8. doi:10.1038/ng1323. PMID15004560.
Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, Howson JM, Vella A, Nutland S, Rance HE, Maier L, Barratt BJ, Guja C, Ionescu-Tîrgoviste C, Savage DA, Dunger DB, Widmer B, Strachan DP, Ring SM, Walker N, Clayton DG, Twells RC, Gough SC, Todd JA (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): 3020–3. doi:10.2337/diabetes.53.11.3020. PMID15504986.
Ladner MB, Bottini N, Valdes AM, Noble JA (2005). "Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes". Hum. Immunol. 66 (1): 60–4. doi:10.1016/j.humimm.2004.09.016. PMID15620463.
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. PMID15641066.
Steer S, Lad B, Grumley JA, Kingsley GH, Fisher SA (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 Rheum. 52 (1): 358–60. doi:10.1002/art.20737. PMID15641088.
Zhernakova A, Eerligh P, Wijmenga C, Barrera P, Roep BO, Koeleman BP (2005). "Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population". Genes Immun. 6 (6): 459–61. doi:10.1038/sj.gene.6364220. PMID15875058.