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{{Infobox_gene}}
{{PBB_Controls
'''Protein tyrosine phosphatase, non-receptor type 22 (lymphoid)''', also known as '''PTPN22''', is a [[protein]] that in humans is encoded by the ''PTPN22'' [[gene]].<ref name="entrez">{{EntrezGene|26191}}</ref><ref name="pmid1373816">{{cite journal | vauthors = Matthews RJ, Bowne DB, Flores E, Thomas ML | title = 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 | journal = Mol. Cell. Biol. | volume = 12 | issue = 5 | pages = 2396–405  | date = May 1992 | pmid = 1373816 | pmc = 364412 | doi =  }}</ref><ref name="pmid10068674">{{cite journal | vauthors = Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM | title = Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp | journal = Blood | volume = 93 | issue = 6 | pages = 2013–24  | date = March 1999 | pmid = 10068674 | doi =  }}</ref> This gene can be expressed in different [[protein isoform|forms]]. PTPN22 affects the responsiveness of T and B cell receptors, and mutations are associated with increases or decreases in risks of autoimmune diseases.
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==Molecular biology==
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The gene is located on the short arm of Chromosome 1 near the centromere (1p13.2) on the Crick (minus) [[directionality (molecular biology)|strand]]. It is 57,898  bases in length and encodes a protein of 807 amino acids (molecular weight 91,705 Da). There are 24 [[exon]]s in the gene and 21 transcript variants encoding 10 distinct proteins are known. The proteins are located in the [[cytoplasm]].{{Citation needed|date=October 2011}}
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== Function ==
}}
This gene encodes a [[protein tyrosine phosphatase]] which is expressed primarily in [[lymphatic system#Lymphoid tissue|lymphoid tissue]]s. This enzyme is involved in several signalling pathways associated with the immune response.  Based on models of the murine phosphatase,<ref>{{cite journal | vauthors = Cloutier JF, Veillette A | title = Association of inhibitory tyrosine protein kinase p50csk with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells | journal = EMBO J. | volume = 15 | issue = 18 | pages = 4909–18  | date = September 1996 | pmid = 8890164 | pmc = 452228 | doi =  }}</ref><ref>{{cite journal | vauthors = Gregorieff A, Cloutier JF, Veillette A | title = Sequence requirements for association of protein-tyrosine phosphatase PEP with the Src homology 3 domain of inhibitory tyrosine protein kinase p50(csk) | journal = J. Biol. Chem. | volume = 273 | issue = 21 | pages = 13217–22  | date = May 1998 | pmid = 9582365 | doi = 10.1074/jbc.273.21.13217 }}</ref> structural identification,<ref>{{cite journal | vauthors = Ghose R, Shekhtman A, Goger MJ, Ji H, Cowburn D | title = A novel, specific interaction involving the Csk SH3 domain and its natural ligand | journal = Nat. Struct. Biol. | volume = 8 | issue = 11 | pages = 998–1004  | date = November 2001 | pmid = 11685249 | doi = 10.1038/nsb1101-998 }}</ref> and human genetics<ref>{{cite journal | vauthors = Vang T, Miletic AV, Bottini N, Mustelin T | title = Protein tyrosine phosphatase PTPN22 in human autoimmunity | journal = Autoimmunity | volume = 40 | issue = 6 | pages = 453–61  | date = September 2007 | pmid = 17729039 | doi = 10.1080/08916930701464897 }}</ref> 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 (gene)|CBL]] function in the [[T cell]] receptor signaling pathway.<ref name="entrez"/> Other interactions are likely.
 
==Disease association==
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]].<ref name="pmid15719322">{{cite journal | vauthors = Qu H, Tessier MC, Hudson TJ, Polychronakos C | title = Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study | journal = J. Med. Genet. | volume = 42 | issue = 3 | pages = 266–70  | date = March 2005 | pmid = 15744042 | pmc = 1736025 | doi = 10.1136/jmg.2004.026971 }}</ref><ref name="pmid16273109">{{cite journal | vauthors = Vang T, Congia M, Macis MD, Musumeci L, Orrú V, Zavattari P, Nika K, Tautz L, Taskén K, Cucca F, Mustelin T, Bottini N | title = Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant | journal = Nat. Genet. | volume = 37 | issue = 12 | pages = 1317–9  | date = December 2005 | pmid = 16273109 | doi = 10.1038/ng1673 }}</ref>
 
A recent study suggests that the mutation does not, on a population basis, reduce life span.<ref>{{cite journal | vauthors = Napolioni V, Natali A, Saccucci P, Lucarini N | title = PTPN22 1858C>T (R620W) functional polymorphism and human longevity | journal = Mol. Biol. Rep. | volume = 38 | issue = 6 | pages = 4231–5  | date = August 2011 | pmid = 21113673 | doi = 10.1007/s11033-010-0546-8 }}</ref> The mutation may be conserved in human evolution because it may provide a hyper-immune response to infectious disease.<ref name="Genetics Home Reference">{{cite web|title=PTPN22|url=http://ghr.nlm.nih.gov/gene/PTPN22|publisher=NLM (US Gov)|accessdate=5 April 2013}}</ref>


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
Mutations in ''PTPN22'' are over-represented in [[breast cancer]].<ref name=nature11412>{{cite journal | vauthors =  | title = Comprehensive molecular portraits of human breast tumours | journal = Nature | volume = 490 | issue = 7418 | pages = 61–70 | year = 2012 | pmid = 23000897 | pmc = 3465532 | doi = 10.1038/nature11412 | url = http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11412.html | publisher = Nature Publishing Group }}</ref>
{{GNF_Protein_box
| image = PBB_Protein_PTPN22_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2p6x.
| PDB = {{PDB2|2p6x}}
| Name = Protein tyrosine phosphatase, non-receptor type 22 (lymphoid)
  | HGNCid = 9652
| Symbol = PTPN22
| AltSymbols =; LYP; PEP; Lyp1; Lyp2; PTPN8
| OMIM = 600716
| ECnumber =
| Homologene = 7498
| MGIid = 107170
| GeneAtlas_image1 = PBB_GE_PTPN22_206060_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_PTPN22_208010_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_PTPN22_208011_at_tn.png
| Function = {{GNF_GO|id=GO:0004725 |text = protein tyrosine phosphatase activity}} {{GNF_GO|id=GO:0016787 |text = hydrolase activity}}
| Component =
| Process = {{GNF_GO|id=GO:0006470 |text = protein amino acid dephosphorylation}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0030217 |text = T cell differentiation}} {{GNF_GO|id=GO:0050852 |text = T cell receptor signaling pathway}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 26191
    | Hs_Ensembl = ENSG00000134242
    | Hs_RefseqProtein = NP_036543
    | Hs_RefseqmRNA = NM_012411
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 1
    | Hs_GenLoc_start = 114092981
    | Hs_GenLoc_end = 114215904
    | Hs_Uniprot = Q9Y2R2
    | Mm_EntrezGene = 19260
    | Mm_Ensembl = ENSMUSG00000027843
    | Mm_RefseqmRNA = NM_008979
    | Mm_RefseqProtein = NP_033005
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 3
    | Mm_GenLoc_start = 103989353
    | Mm_GenLoc_end = 104041308
    | Mm_Uniprot = Q3TEL9
  }}
}}
'''Protein tyrosine phosphatase, non-receptor type 22 (lymphoid)''', also known as '''PTPN22''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: PTPN22 protein tyrosine phosphatase, non-receptor type 22 (lymphoid)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=26191| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== References ==
{{PBB_Summary
{{Reflist|2}}
| section_title =  
| summary_text = This gene encodes a protein tyrosine phosphatase which is expressed primarily in lymphoid tissues. This enzyme associates with the molecular adapter protein CBL and may be involved in regulating CBL function in the T-cell receptor signaling pathway. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms.<ref name="entrez">{{cite web | title = Entrez Gene: PTPN22 protein tyrosine phosphatase, non-receptor type 22 (lymphoid)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=26191| accessdate = }}</ref>
}}


==References==
== Further reading ==
{{reflist|2}}
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Gregersen PK | title = Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond | journal = Immunol. Rev. | volume = 204 | pages = 74–86 | year = 2005 | pmid = 15790351 | pmc =  | doi = 10.1111/j.0105-2896.2005.00243.x }}
| citations =
* {{cite journal | vauthors = Brand O, Gough S, Heward J | title = HLA , CTLA-4 and PTPN22 : the shared genetic master-key to autoimmunity? | journal = Expert Rev Mol Med | volume = 7 | issue = 23 | pages = 1–15 | year = 2005 | pmid = 16229750 | pmc =  | doi = 10.1017/S1462399405009981 }}
*{{cite journal | author=Gregersen PK |title=Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond. |journal=Immunol. Rev. |volume=204 |issue=  |pages= 74-86 |year= 2005 |pmid= 15790351 |doi= 10.1111/j.0105-2896.2005.00243.x }}
* {{cite journal | vauthors = Bottini N, Vang T, Cucca F, Mustelin T | title = Role of PTPN22 in type 1 diabetes and other autoimmune diseases | journal = Semin. Immunol. | volume = 18 | issue = 4 | pages = 207–13 | year = 2006 | pmid = 16697661 | pmc =  | doi = 10.1016/j.smim.2006.03.008 }}
*{{cite journal | author=Brand O, Gough S, Heward J |title=HLA , CTLA-4 and PTPN22 : the shared genetic master-key to autoimmunity? |journal=Expert reviews in molecular medicine |volume=7 |issue= 23 |pages= 1-15 |year= 2007 |pmid= 16229750 |doi= 10.1017/S1462399405009981 }}
*{{Cite journal  
*{{cite journal | author=Bottini N, Vang T, Cucca F, Mustelin T |title=Role of PTPN22 in type 1 diabetes and other autoimmune diseases. |journal=Semin. Immunol. |volume=18 |issue= 4 |pages= 207-13 |year= 2007 |pmid= 16697661 |doi= 10.1016/j.smim.2006.03.008 }}
| last1 = Gjörloff-Wingren | first1 = A.  
*{{cite journal | author=Matthews RJ, Bowne DB, Flores E, Thomas ML |title=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. |journal=Mol. Cell. Biol. |volume=12 |issue= 5 |pages= 2396-405 |year= 1992 |pmid= 1373816 |doi=  }}
| last2 = Saxena | first2 = M.  
*{{cite journal  | author=Gregorieff A, Cloutier JF, Veillette A |title=Sequence requirements for association of protein-tyrosine phosphatase PEP with the Src homology 3 domain of inhibitory tyrosine protein kinase p50(csk). |journal=J. Biol. Chem. |volume=273 |issue= 21 |pages= 13217-22 |year= 1998 |pmid= 9582365 |doi=  }}
| last3 = Han | first3 = S.  
*{{cite journal  | author=Cohen S, Dadi H, Shaoul E, ''et al.'' |title=Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. |journal=Blood |volume=93 |issue= 6 |pages= 2013-24 |year= 1999 |pmid= 10068674 |doi=  }}
| last4 = Wang | first4 = X.  
*{{cite journal  | author=Gjörloff-Wingren A, Saxena M, Han S, ''et al.'' |title=Subcellular localization of intracellular protein tyrosine phosphatases in T cells. |journal=Eur. J. Immunol. |volume=30 |issue= 8 |pages= 2412-21 |year= 2000 |pmid= 10940933 |doi=  }}
| last5 = Alonso | first5 = A.  
*{{cite journal  | author=Hill RJ, Zozulya S, Lu YL, ''et al.'' |title=The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. |journal=Exp. Hematol. |volume=30 |issue= 3 |pages= 237-44 |year= 2002 |pmid= 11882361 |doi=  }}
| last6 = Renedo | first6 = M.  
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
| last7 = Oh | first7 = P.  
*{{cite journal  | author=Chien W, Tidow N, Williamson EA, ''et al.'' |title=Characterization of a myeloid tyrosine phosphatase, Lyp, and its role in the Bcr-Abl signal transduction pathway. |journal=J. Biol. Chem. |volume=278 |issue= 30 |pages= 27413-20 |year= 2003 |pmid= 12764153 |doi= 10.1074/jbc.M304575200 }}
| last8 = Williams | first8 = S.  
*{{cite journal  | author=Bottini N, Musumeci L, Alonso A, ''et al.'' |title=A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. |journal=Nat. Genet. |volume=36 |issue= 4 |pages= 337-8 |year= 2004 |pmid= 15004560 |doi= 10.1038/ng1323 }}
| last9 = Schnitzer | first9 = J.  
*{{cite journal  | author=Begovich AB, Carlton VE, Honigberg LA, ''et al.'' |title=A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. |journal=Am. J. Hum. Genet. |volume=75 |issue= 2 |pages= 330-7 |year= 2004 |pmid= 15208781 |doi= 10.1086/422827 }}
| last10 = Mustelin | first10 = T.  
*{{cite journal  | author=Kyogoku C, Langefeld CD, Ortmann WA, ''et al.'' |title=Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. |journal=Am. J. Hum. Genet. |volume=75 |issue= 3 |pages= 504-7 |year= 2004 |pmid= 15273934 |doi= 10.1086/423790 }}
| title = Subcellular localization of intracellular protein tyrosine phosphatases in T cells
*{{cite journal  | author=Smyth D, Cooper JD, Collins JE, ''et al.'' |title=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. |journal=Diabetes |volume=53 |issue= 11 |pages= 3020-3 |year= 2005 |pmid= 15504986 |doi=  }}
| journal = European Journal of Immunology
*{{cite journal  | author=Ladner MB, Bottini N, Valdes AM, Noble JA |title=Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes. |journal=Hum. Immunol. |volume=66 |issue= 1 |pages= 60-4 |year= 2005 |pmid= 15620463 |doi= 10.1016/j.humimm.2004.09.016 }}
| volume = 30
*{{cite journal  | author=Orozco G, Sánchez E, González-Gay MA, ''et al.'' |title=Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. |journal=Arthritis Rheum. |volume=52 |issue= 1 |pages= 219-24 |year= 2005 |pmid= 15641066 |doi= 10.1002/art.20771 }}
| issue = 8
*{{cite journal  | author=Steer S, Lad B, Grumley JA, ''et al.'' |title=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. |journal=Arthritis Rheum. |volume=52 |issue= 1 |pages= 358-60 |year= 2005 |pmid= 15641088 |doi= 10.1002/art.20737 }}
| pages = 2412–2421
*{{cite journal  | author=Zheng W, She JX |title=Genetic association between a lymphoid tyrosine phosphatase (PTPN22) and type 1 diabetes. |journal=Diabetes |volume=54 |issue= 3 |pages= 906-8 |year= 2005 |pmid= 15734872 |doi=  }}
| year = 2000
*{{cite journal  | author=Zhernakova A, Eerligh P, Wijmenga C, ''et al.'' |title=Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population. |journal=Genes Immun. |volume=6 |issue= 6 |pages= 459-61 |year= 2005 |pmid= 15875058 |doi= 10.1038/sj.gene.6364220 }}
| doi = 10.1002/1521-4141(2000)30:8<2412::AID-IMMU2412>3.0.CO;2-J
| pmid = 10940933
| pmc =  
}}
}}
* {{cite journal | vauthors = Hill RJ, Zozulya S, Lu YL, Ward K, Gishizky M, Jallal B | title = The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation | journal = Exp. Hematol. | volume = 30 | issue = 3 | pages = 237–44 | year = 2002 | pmid = 11882361 | doi = 10.1016/S0301-472X(01)00794-9 }}
* {{cite journal | vauthors = Chien W, Tidow N, Williamson EA, Shih LY, Krug U, Kettenbach A, Fermin AC, Roifman CM, Koeffler HP | title = Characterization of a myeloid tyrosine phosphatase, Lyp, and its role in the Bcr-Abl signal transduction pathway | journal = J. Biol. Chem. | volume = 278 | issue = 30 | pages = 27413–20 | year = 2003 | pmid = 12764153 | pmc =  | doi = 10.1074/jbc.M304575200 }}
* {{cite journal | vauthors = 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 | title = A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes | journal = Nat. Genet. | volume = 36 | issue = 4 | pages = 337–8 | year = 2004 | pmid = 15004560 | pmc =  | doi = 10.1038/ng1323 }}
* {{cite journal | vauthors = Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SY, Saiki RK, Catanese JJ, Leong DU, Garcia VE, McAllister LB, Jeffery DA, Lee AT, Batliwalla F, Remmers E, Criswell LA, Seldin MF, Kastner DL, Amos CI, Sninsky JJ, Gregersen PK | title = A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis | journal = Am. J. Hum. Genet. | volume = 75 | issue = 2 | pages = 330–7 | year = 2004 | pmid = 15208781 | pmc = 1216068 | doi = 10.1086/422827 }}
* {{cite journal | vauthors = Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, Chang M, Ramos P, Baechler EC, Batliwalla FM, Novitzke J, Williams AH, Gillett C, Rodine P, Graham RR, Ardlie KG, Gaffney PM, Moser KL, Petri M, Begovich AB, Gregersen PK, Behrens TW | title = Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE | journal = Am. J. Hum. Genet. | volume = 75 | issue = 3 | pages = 504–7 | year = 2004 | pmid = 15273934 | pmc = 1182029 | doi = 10.1086/423790 }}
* {{cite journal | vauthors = 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 | title = 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 | journal = Diabetes | volume = 53 | issue = 11 | pages = 3020–3 | year = 2004 | pmid = 15504986 | doi = 10.2337/diabetes.53.11.3020 }}
* {{cite journal | vauthors = Ladner MB, Bottini N, Valdes AM, Noble JA | title = Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes | journal = Hum. Immunol. | volume = 66 | issue = 1 | pages = 60–4 | year = 2005 | pmid = 15620463 | pmc =  | doi = 10.1016/j.humimm.2004.09.016 }}
* {{cite journal | vauthors = 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 | title = Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus | journal = Arthritis Rheum. | volume = 52 | issue = 1 | pages = 219–24  | date = January 2005 | pmid = 15641066 | doi = 10.1002/art.20771 }}
* {{cite journal | vauthors = Steer S, Lad B, Grumley JA, Kingsley GH, Fisher SA | title = 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 | journal = Arthritis Rheum. | volume = 52 | issue = 1 | pages = 358–60 | year = 2005 | pmid = 15641088 | pmc =  | doi = 10.1002/art.20737 }}
* {{cite journal | vauthors = Zheng W, She JX | title = Genetic association between a lymphoid tyrosine phosphatase (PTPN22) and type 1 diabetes | journal = Diabetes | volume = 54 | issue = 3 | pages = 906–8 | year = 2005 | pmid = 15734872 | doi = 10.2337/diabetes.54.3.906 }}
* {{cite journal | vauthors = Zhernakova A, Eerligh P, Wijmenga C, Barrera P, Roep BO, Koeleman BP | title = Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population | journal = Genes Immun. | volume = 6 | issue = 6 | pages = 459–61 | year = 2005 | pmid = 15875058 | pmc =  | doi = 10.1038/sj.gene.6364220 }}
{{refend}}
{{refend}}


{{protein-stub}}
{{PDB Gallery|geneid=26191}}
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{{Protein tyrosine phosphatases}}

Latest revision as of 23:15, 8 March 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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

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.[citation needed]

Function

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

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 PTPN22 are over-represented in breast cancer.[12]

References

  1. ↑ 1.0 1.1 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.
  3. ↑ 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. PMID 10068674.
  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.
  5. ↑ 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. PMID 9582365.
  6. ↑ 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. PMID 11685249.
  7. ↑ Vang T, Miletic AV, Bottini N, Mustelin T (September 2007). "Protein tyrosine phosphatase PTPN22 in human autoimmunity". Autoimmunity. 40 (6): 453–61. doi:10.1080/08916930701464897. PMID 17729039.
  8. ↑ Qu H, Tessier MC, Hudson TJ, Polychronakos C (March 2005). "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): 266–70. doi:10.1136/jmg.2004.026971. PMC 1736025. PMID 15744042.
  9. ↑ Vang T, Congia M, Macis MD, 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): 1317–9. doi:10.1038/ng1673. PMID 16273109.
  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): 4231–5. doi:10.1007/s11033-010-0546-8. PMID 21113673.
  11. ↑ "PTPN22". NLM (US Gov). Retrieved 5 April 2013.
  12. ↑ "Comprehensive molecular portraits of human breast tumours". Nature. Nature Publishing Group. 490 (7418): 61–70. 2012. doi:10.1038/nature11412. PMC 3465532. PMID 23000897.

Further reading

  • Gregersen PK (2005). "Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond". Immunol. Rev. 204: 74–86. doi:10.1111/j.0105-2896.2005.00243.x. PMID 15790351.
  • Brand O, Gough S, Heward J (2005). "HLA , CTLA-4 and PTPN22 : the shared genetic master-key to autoimmunity?". Expert Rev Mol Med. 7 (23): 1–15. doi:10.1017/S1462399405009981. PMID 16229750.
  • Bottini N, Vang T, Cucca F, Mustelin T (2006). "Role of PTPN22 in type 1 diabetes and other autoimmune diseases". Semin. Immunol. 18 (4): 207–13. doi:10.1016/j.smim.2006.03.008. PMID 16697661.
  • 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.
  • 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. PMID 11882361.
  • 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. PMID 12764153.
  • 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. PMID 15004560.
  • Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SY, Saiki RK, Catanese JJ, Leong DU, Garcia VE, McAllister LB, Jeffery DA, Lee AT, Batliwalla F, Remmers E, Criswell LA, Seldin MF, Kastner DL, Amos CI, Sninsky JJ, Gregersen PK (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. doi:10.1086/422827. PMC 1216068. PMID 15208781.
  • Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, Chang M, Ramos P, Baechler EC, Batliwalla FM, Novitzke J, Williams AH, Gillett C, Rodine P, Graham RR, Ardlie KG, Gaffney PM, Moser KL, Petri M, Begovich AB, Gregersen PK, Behrens TW (2004). "Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE". Am. J. Hum. Genet. 75 (3): 504–7. doi:10.1086/423790. PMC 1182029. PMID 15273934.
  • 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. PMID 15504986.
  • 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. PMID 15620463.
  • 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.
  • 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. PMID 15641088.
  • Zheng W, She JX (2005). "Genetic association between a lymphoid tyrosine phosphatase (PTPN22) and type 1 diabetes". Diabetes. 54 (3): 906–8. doi:10.2337/diabetes.54.3.906. PMID 15734872.
  • 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. PMID 15875058.
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