Affinage

PTPN22

Tyrosine-protein phosphatase non-receptor type 22 · UniProt Q9Y2R2

Length
807 aa
Mass
91.7 kDa
Annotated
2026-04-28
100 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTPN22 (LYP) is a lymphoid- and myeloid-expressed non-receptor protein tyrosine phosphatase that serves as a central negative regulator of antigen receptor and innate immune signaling across multiple hematopoietic lineages. Its catalytic domain directly dephosphorylates activating tyrosines on TCR-proximal kinases Lck (Tyr-394) and ZAP-70 (Tyr-493), as well as TCRζ, Vav, and CD3ε, thereby attenuating T cell activation; dissociation from its cytosolic partner CSK is required for PTPN22 translocation to the plasma membrane where it exerts this inhibitory function (PMID:16461343, PMID:22426112). Beyond lymphocytes, PTPN22 promotes TRAF3 K63-linked ubiquitination to enhance TLR-driven type I interferon production in myeloid cells, regulates FcγR-mediated neutrophil activation through Lyn/Syk dephosphorylation, restrains dectin-1 signaling in dendritic cells, modulates macrophage M1/M2 polarization, and negatively regulates platelet activation via dephosphorylation of PDE5A (PMID:23871208, PMID:27807193, PMID:28948613, PMID:35767715). Enzyme activity is redox-regulated through a Cys129–Cys227 disulfide bond reversible by thioredoxin, and PKC-mediated phosphorylation at Ser-35 impairs its capacity to inactivate Src-family kinases (PMID:35587260, PMID:18056643). The autoimmunity-associated R620W variant disrupts CSK binding, impairs TRAF3 ubiquitination, and confers lymphocyte hyperresponsiveness leading to autoantibody production and systemic autoimmunity in knockin mice (PMID:23619366, PMID:23871208).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 Medium

    Establishing PTPN22 as a lymphoid PTP with proline-rich SH3-binding motifs and identifying c-Cbl as an initial interaction partner and putative substrate defined the gene as a T-cell signaling phosphatase.

    Evidence Molecular cloning, co-immunoprecipitation in thymocytes and T cells, overexpression phosphorylation assays

    PMID:10068674

    Open questions at the time
    • c-Cbl as substrate was based on overexpression Co-IP without purified-protein reconstitution
    • physiological relevance of Cbl dephosphorylation not tested in loss-of-function setting
  2. 2006 High

    Substrate-trapping and in vitro reconstitution identified the precise TCR-proximal substrates — Lck Tyr-394, ZAP-70 Tyr-493, and TCRζ — establishing PTPN22 as a direct negative regulator of the earliest TCR signaling events.

    Evidence Catalytically inactive D195A/C227S substrate-trap coupled to mass spectrometry, in vitro dephosphorylation with purified proteins, 293T cell validation

    PMID:16461343

    Open questions at the time
    • relative contributions of individual substrate dephosphorylation events to TCR output not dissected
    • whether PTPN22 acts on these substrates simultaneously or sequentially in vivo unknown
  3. 2007 High

    The crystal structure revealed a Lyp-specific insert whose Ser-35 is phosphorylated by PKC, providing the first post-translational regulatory mechanism that tunes PTPN22 phosphatase activity and consequently TCR signal strength.

    Evidence X-ray crystallography, in vitro PKC kinase assay, mutagenesis, cellular TCR signaling readouts

    PMID:18056643

    Open questions at the time
    • which PKC isoform(s) phosphorylate Ser-35 in physiological settings not defined
    • structural basis for how Ser-35 phosphorylation alters catalytic activity not resolved
  4. 2012 High

    Live-cell imaging resolved a longstanding question about how PTPN22 accesses its membrane-proximal substrates: dissociation from the cytosolic CSK complex is required for PTPN22 membrane recruitment, and the R620W variant, constitutively free of CSK, is hyperactive at the membrane.

    Evidence Live-cell imaging of LYP-CSK dynamics, selective chemical LYP inhibitor, T-cell activation assays

    PMID:22426112

    Open questions at the time
    • signals triggering CSK-PTPN22 dissociation upon TCR engagement not identified
    • whether additional scaffolds recruit free PTPN22 to the membrane unknown
  5. 2012 Medium

    Characterization of R263Q and R266W variants as loss-of-function alleles demonstrated that structural integrity of the Q-loop/WPD-loop region is essential for catalytic activity, establishing a structure-function framework for disease-associated variants.

    Evidence In vitro kinetic assays with purified recombinant variants, structural modeling, T-cell signaling assays

    PMID:22952725

    Open questions at the time
    • no crystal structures of these variants obtained
    • population-level disease associations for R263Q/R266W not established
  6. 2013 High

    The R619W knockin mouse (ortholog of human R620W) provided definitive in vivo evidence that the variant causes lymphocyte hyperresponsiveness, disrupted B cell selection, and spontaneous autoimmunity, directly linking PTPN22 loss-of-interaction to autoimmune pathogenesis.

    Evidence Knockin mouse, flow cytometry, phosphoproteomic profiling, autoantibody detection

    PMID:23619366

    Open questions at the time
    • which specific phosphoproteomic changes are causally responsible for autoimmunity not determined
    • epistatic modifiers required for penetrant disease not identified
  7. 2013 High

    Discovery that PTPN22 promotes TRAF3 K63-ubiquitination to enhance type I IFN production established a phosphatase-independent scaffolding function in myeloid innate immunity, fundamentally expanding PTPN22's role beyond TCR signaling.

    Evidence Co-immunoprecipitation, ubiquitination assays, Ptpn22-KO mice stimulated with TLR agonists, colitis and arthritis models

    PMID:23871208

    Open questions at the time
    • E3 ligase catalyzing TRAF3 K63-ubiquitination recruited by PTPN22 not identified
    • whether the phosphatase domain is entirely dispensable for this function not tested
  8. 2013 Medium

    The finding that PTPN22 suppresses M1 macrophage polarization and promotes M2 gene expression extended its innate immune role to macrophage functional polarization, with therapeutic implications for inflammatory bowel disease.

    Evidence Ptpn22-KO mice in DSS colitis model, M1/M2 gene expression analysis, human macrophage knockdown

    PMID:23913970

    Open questions at the time
    • direct substrates mediating M1/M2 skewing not identified
    • whether this reflects phosphatase activity or scaffolding unknown
  9. 2016 High

    Demonstration that PTPN22 is required for full FcγR-mediated neutrophil activation via Lyn/Syk dephosphorylation revealed a context-dependent positive regulatory role — opposite to its inhibitory function in T cells — and provided protection from immune complex arthritis.

    Evidence Ptpn22-KO neutrophil functional assays, Lyn/Syk phosphorylation analysis, serum transfer arthritis model

    PMID:27807193

    Open questions at the time
    • mechanism by which PTPN22-mediated Lyn/Syk dephosphorylation promotes rather than inhibits neutrophil activation not fully explained
    • whether specific Lyn/Syk tyrosine sites differ from those in T cells not mapped
  10. 2017 Medium

    TRAF3 was shown to reciprocally regulate PTPN22 by controlling its membrane recruitment and CSK association, establishing a bidirectional TRAF3–PTPN22 regulatory axis in T cells.

    Evidence Co-immunoprecipitation, membrane fractionation of TRAF3-deficient T cells, Lck phosphorylation analysis

    PMID:28522807

    Open questions at the time
    • structural basis of TRAF3-PTPN22 interaction not defined
    • whether TRAF3 regulation of PTPN22 localization operates in myeloid cells unknown
  11. 2020 Medium

    Identification of EB1 as a PTPN22 substrate dephosphorylated at Tyr-247 revealed a non-canonical mechanism linking PTPN22 to microtubule-associated signaling and T cell activation, expanding its substrate repertoire beyond canonical TCR kinases.

    Evidence Yeast two-hybrid, mass spectrometry, in vitro dephosphorylation, T-cell activation assays

    PMID:32469452

    Open questions at the time
    • physiological consequence of EB1-Tyr247 dephosphorylation on microtubule dynamics not tested
    • in vivo relevance using loss-of-function models not established
  12. 2022 High

    Redox regulation of PTPN22 via a Cys129–Cys227 disulfide bond, reversible by thioredoxin and dependent on NOX2/Ncf1-generated ROS, established reactive oxygen species as physiological modulators of PTPN22 activity and TCR signaling strength.

    Evidence C129S knock-in mouse, Ncf1 epistasis, in vitro thioredoxin reductase assay with purified protein, autoimmune arthritis model

    PMID:35587260

    Open questions at the time
    • kinetics and spatial dynamics of disulfide formation/reduction in intact T cells not measured
    • whether other PTPs in the same signaling cascade are co-regulated by the same ROS pool unknown
  13. 2022 High

    Discovery that PTPN22 dephosphorylates PDE5A at Ser-92 in platelets — exhibiting serine phosphatase activity — and negatively regulates platelet aggregation and thrombus formation extended its function to hemostasis and revealed unexpected dual-specificity catalysis.

    Evidence PTPN22-KO mouse platelets, phosphoproteomic analysis, in vitro phosphatase assay with purified PTPN22 and C227S mutant, arterial thrombosis model

    PMID:35767715

    Open questions at the time
    • structural basis for serine phosphatase activity in a classical tyrosine phosphatase not resolved
    • whether dual-specificity activity extends to other substrates unknown
    • platelet phenotype relevance to human thrombotic disease not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the signals that trigger CSK-PTPN22 dissociation upon receptor engagement, the structural basis for PTPN22's dual tyrosine/serine phosphatase activity, the identity of the E3 ligase mediating TRAF3 ubiquitination downstream of PTPN22, and how context-dependent switching between positive and negative regulation is achieved across cell types.
  • no structural model of PTPN22-CSK or PTPN22-TRAF3 complexes
  • mechanism of cell-type-specific functional polarity (inhibitory in T cells, activating in neutrophils) not explained
  • therapeutic targeting strategies remain preclinical

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0098772 molecular function regulator activity 4
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 2 R-HSA-109582 Hemostasis 1
Partners
CSKLCKLYNMAPK1E1PDE5ASYKTRAF3ZAP70

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 LYP/PTPN22 is an intracellular protein tyrosine phosphatase expressed predominantly in lymphoid tissues; it contains a single catalytic PTP domain and four proline-rich SH3-binding motifs; it is constitutively associated with the proto-oncogene c-Cbl in thymocytes and T cells, and overexpression of LYP reduces Cbl tyrosine phosphorylation, indicating Cbl is a substrate. Molecular cloning, co-immunoprecipitation, overexpression in T cells with phosphorylation assays Blood Medium 10068674
2006 PTPN22 directly dephosphorylates the activating tyrosines of Lck (Tyr-394) and Zap70 (Tyr-493), but not their regulatory tyrosines; TCRζ is also a direct substrate dephosphorylated by PTPN22 both in vitro and in cells; additional substrates include Vav, CD3ε, and valosin-containing protein, identified by substrate-trapping mass spectrometry. Substrate trapping with catalytically inactive PTPN22-D195A/C227S mutant coupled to mass spectrometry, in vitro dephosphorylation assays with purified recombinant proteins, co-immunoprecipitation in 293T cells The Journal of biological chemistry High 16461343
2007 Crystal structure of LYP (PTPN22) reveals a Lyp-specific insert region (S35TKYKADK42) that can adopt loop or helical conformations; PKC phosphorylates LYP exclusively at Ser-35 both in vitro and in vivo, and Ser-35 phosphorylation impairs LYP's ability to inactivate Src family kinases and down-regulate TCR signaling; a bidentate salicylic acid-based inhibitor I-C11 was identified that binds both the active site and a peripheral site unique to LYP. X-ray crystallography, in vitro kinase assay (PKC phosphorylation of Ser-35), site-directed mutagenesis, cellular TCR signaling assays, small-molecule inhibitor characterization Proceedings of the National Academy of Sciences of the United States of America High 18056643
2012 LYP inhibits T-cell activation when dissociated from CSK; dissociation of the LYP-CSK complex is required for recruitment of LYP to the plasma membrane where it downmodulates TCR signaling; the disease-associated R620W variant, which cannot bind CSK, shows reduced TCR-mediated signaling consistent with constitutive LYP activity at the membrane. Live-cell imaging of LYP-CSK complex spatiotemporal dynamics, selective chemical LYP inhibitor, T-cell activation assays Nature chemical biology High 22426112
2013 PTPN22 directly associates with TRAF3 and promotes TRAF3 lysine-63-linked ubiquitination, selectively enhancing TLR-driven type I interferon production in myeloid cells; the disease-associated PTPN22-R620W variant fails to promote TRAF3 ubiquitination and type I IFN upregulation. Co-immunoprecipitation of PTPN22 with TRAF3, ubiquitination assays, Ptpn22-knockout mouse studies with TLR agonist stimulation, colitis and arthritis models Immunity High 23871208
2013 The disease-linked PEP-R619W knockin variant (mouse ortholog of human LYP-R620W) renders lymphocytes hyperresponsive to antigen-receptor engagement with a distinct phosphotyrosine substrate profile, promotes effector T cell and B cell expansion, disrupts B cell selection, and leads to development of autoantibodies and systemic autoimmunity in aged mice. Knockin mouse generation, flow cytometric immunophenotyping, antigen-receptor stimulation assays, phosphoproteomic profiling, autoantibody detection The Journal of clinical investigation High 23619366
2003 LYP/PTPN22 is expressed in myeloid cells (granulocytes, monocytes) in addition to lymphocytes and localizes to the cytosol; overexpression of LYP reduces phosphorylation of Cbl, Bcr-Abl, Erk1/2, and CrkL and suppresses anchorage-independent growth of CML cells, suggesting LYP antagonizes Bcr-Abl signaling. RT-PCR expression profiling, subcellular fractionation, overexpression in CML cell lines with phosphorylation assays, colony formation assay The Journal of biological chemistry Medium 12764153
2012 An alternative splice isoform of PTPN22, PTPN22.6, lacks nearly the entire phosphatase domain and functions as a dominant-negative isoform of full-length PTPN22; expression of the W620 variant of PTPN22.6 (but not PTPN22.1-W620) leads to hyperactivation of human T cells. Identification of splice variant by cloning, dominant-negative overexpression assays in T cells, T-cell activation readouts PloS one Medium 22427951
2013 PTPN22 suppresses M1 macrophage polarization and reciprocally promotes M2-associated gene expression; PTPN22-deficient mice develop more severe dextran sulfate sodium-induced colitis with increased M1 macrophage polarization in the intestine; PTPN22 also suppresses its own expression in M1 but not M2 macrophages (autoinhibition). Ptpn22-knockout mice, dextran sulfate sodium colitis model, gene expression analysis of M1/M2 markers, PTPN22 knockdown in human macrophages Journal of immunology Medium 23913970
2016 PTPN22 is required for full FcγR-mediated neutrophil activation; Ptpn22-/- neutrophils show reduced adhesion, ROS production, and degranulation upon immune complex stimulation; PTPN22 regulates tyrosine phosphorylation of Lyn and Syk in neutrophils; Ptpn22-/- mice are protected from immune complex-mediated arthritis. Ptpn22-knockout mouse neutrophil functional assays (adhesion, ROS, degranulation), phosphorylation analysis of Lyn and Syk, serum transfer arthritis model Journal of immunology High 27807193
2016 Loss of PTPN22 increases the size of the regulatory T cell (Treg) compartment by upregulating GITR expression and enhancing GITR signaling, leading to prolonged Treg survival rather than accelerated division; GITR ligand blockade prevents Treg expansion caused by Ptpn22 knockdown. Ptpn22 siRNA knockdown in mice, GITR ligand blockade, apoptosis and proliferation assays of Treg cells, flow cytometric phenotyping Journal of immunology Medium 26810223
2017 TRAF3 associates with PTPN22 and regulates its recruitment to the TCR/CD28 complex; loss of TRAF3 results in increased amounts of PTPN22 in T cell membrane fractions and decreased association of PTPN22 with CSK, thereby reducing activating phosphorylation of Lck. Co-immunoprecipitation of TRAF3 with PTPN22 and CSK, membrane fractionation of TRAF3-deficient T cells, phosphorylation analysis of Lck Scientific reports Medium 28522807
2017 PTPN22 negatively regulates dectin-1 signaling in dendritic cells by restraining Syk and Erk phosphorylation; Ptpn22-/- BMDCs show enhanced IL-1β secretion and drive increased IL-17 T-cell responses upon dectin-1 stimulation; the Ptpn22-R619W variant also increases IL-1β secretion in this context, acting as a loss-of-function allele for dectin-1 regulation. Ptpn22-/- and Ptpn22-R619W knockin bone marrow-derived dendritic cells, dectin-1 agonist (curdlan) stimulation, Syk/Erk immunoblotting, in vitro and in vivo T-cell co-culture assays European journal of immunology Medium 28948613
2018 PTPN22 negatively regulates LFA-1-dependent Th1 responses through two mechanisms: (1) a T cell-intrinsic mechanism whereby Ptpn22-/- T cells have enhanced ability to engage ICAM-1 at the immune synapse; (2) a T cell-extrinsic mechanism whereby Ptpn22-/- dendritic cells enhance Th1 development in an LFA-1/ICAM-dependent manner. Ptpn22-/- mice, planar lipid bilayer immune synapse assays, DC-T cell conjugate formation assays, in vitro and in vivo Th1 differentiation assays with LFA-1 blockade Journal of autoimmunity Medium 30054208
2018 PTPN22 negatively regulates FcγR-mediated antigen presentation in dendritic cells; Ptpn22-/- BMDCs show enhanced uptake and presentation of immune complex-derived antigens and form more DC-T cell conjugates, leading to enhanced T cell proliferation. Ptpn22-/- bone marrow-derived DCs pulsed with ovalbumin:anti-ovalbumin immune complexes, T cell co-culture proliferation assays, DC-T cell conjugate quantification Scientific reports Medium 30139951
2020 PTPN22 interacts with end-binding protein 1 (EB1) via the P1 proline-rich domain of PTPN22 (competing with CSK binding); PTPN22 dephosphorylates EB1 at tyrosine-247, which reduces expression of T cell activation markers CD25 and CD69, decreases phosphorylation of ZAP-70, LAT, and Erk, and reduces NFAT activation and IL-2 secretion; the R620W variant does not affect EB1 association. Yeast two-hybrid screen, mass spectrometry, co-immunoprecipitation, site-directed mutagenesis, in vitro dephosphorylation assay, T-cell activation assays FASEB journal Medium 32469452
2022 PTPN22 activity is redox-regulated through the non-catalytic Cys129 residue, which forms a disulfide with catalytic Cys227; a C129S knock-in mouse shows enhanced TCR signaling, stronger T-cell-dependent inflammation, and more severe autoimmune arthritis; thioredoxin can directly reduce the native PTPN22 disulfide to reactivate the enzyme; the functional effects depend on the NOX2 component Ncf1. C129S knock-in mouse, Ncf1-mutant double-mutant epistasis, in vitro activity assays with purified PTPN22 proteins, thioredoxin reductase assays, autoimmune arthritis model eLife High 35587260
2022 PTPN22 is expressed in human and mouse platelets and negatively regulates platelet function; PTPN22-deficient mice show enhanced platelet aggregation, granule secretion, calcium mobilization, and accelerated arterial thrombus formation; PTPN22 interacts with phosphorylated PDE5A (Ser92) and dephosphorylates it, modulating cGMP signaling; purified PTPN22 (but not catalytic-dead C227S mutant) has intrinsic serine phosphatase activity toward PDE5A. PTPN22-/- mouse model, phosphoproteomic analysis, co-immunoprecipitation of PTPN22 with phospho-PDE5A, in vitro phosphatase assay with purified proteins and C227S mutant, arterial thrombosis model Blood High 35767715
2013 LYP (encoded by PTPN22) interacts with CSK through its P1 and P2 proline-rich motifs and CSK's SH3 and SH2 domains; this interaction is inducible upon TCR stimulation rather than constitutive; abrogating LYP/CSK interaction does not preclude regulation of TCR signaling by these proteins. Co-immunoprecipitation, domain mapping with truncation mutants, TCR stimulation time-course experiments PloS one Medium 23359562
2012 The Lyp variants R263Q and R266W both have significantly reduced phosphatase activity compared to wild-type Lyp; R266W severely impairs catalytic activity likely by perturbing the Q-loop or WPD loop; both are loss-of-function variants in T cell signaling assays. In vitro kinetic phosphatase assays with purified recombinant Lyp variants, structural modeling, T cell signaling functional assays PloS one Medium 22952725

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 385 15504986
2006 The PTPN22 C1858T functional polymorphism and autoimmune diseases--a meta-analysis. Rheumatology (Oxford, England) 264 16760194
1999 Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood 261 10068674
2006 Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Seminars in immunology 257 16697661
2006 Identification of substrates of human protein-tyrosine phosphatase PTPN22. The Journal of biological chemistry 212 16461343
2014 PTPN22: the archetypal non-HLA autoimmunity gene. Nature reviews. Rheumatology 182 25003765
2011 Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? FEBS letters 178 21515266
2013 Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annual review of immunology 174 24364806
2013 The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity. Immunity 171 23871208
2013 A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models. The Journal of clinical investigation 155 23619366
2009 CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cells. Immunological reviews 138 19290935
2007 Protein tyrosine phosphatase PTPN22 in human autoimmunity. Autoimmunity 128 17729039
2007 Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases. Proceedings of the National Academy of Sciences of the United States of America 128 18056643
2012 LYP inhibits T-cell activation when dissociated from CSK. Nature chemical biology 116 22426112
2011 Protein cage nanoparticles bearing the LyP-1 peptide for enhanced imaging of macrophage-rich vascular lesions. ACS nano 89 21391720
2006 Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population. Rheumatology (Oxford, England) 89 16690758
2012 Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue. Genes and immunity 87 23076337
2007 PTPN22: its role in SLE and autoimmunity. Autoimmunity 84 18075792
2006 Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes. Diabetologia 82 16614815
2008 Mutation screening of PTPN22: association of the 1858T-allele with Addison's disease. European journal of human genetics : EJHG 72 18301444
2010 Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis. Annals of the rheumatic diseases 70 21131644
2005 HLA , CTLA-4 and PTPN22 : the shared genetic master-key to autoimmunity? Expert reviews in molecular medicine 69 16229750
1993 Cloning and sequencing of the Saccharomyces cerevisiae gene LYP1 coding for a lysine-specific permease. Yeast (Chichester, England) 67 8368011
2008 Reduced CD4+T cell activation in children with type 1 diabetes carrying the PTPN22/Lyp 620Trp variant. Journal of autoimmunity 65 18299186
2011 Therapeutic ultrasonic microbubbles carrying paclitaxel and LyP-1 peptide: preparation, characterization and application to ultrasound-assisted chemotherapy in breast cancer cells. Ultrasound in medicine & biology 64 21458148
2015 Genetic Variations of PTPN2 and PTPN22: Role in the Pathogenesis of Type 1 Diabetes and Crohn's Disease. Frontiers in cellular and infection microbiology 62 26734582
2013 PTPN22 modulates macrophage polarization and susceptibility to dextran sulfate sodium-induced colitis. Journal of immunology (Baltimore, Md. : 1950) 60 23913970
2001 BB rat lyp mutation and Type 1 diabetes. Immunological reviews 58 12086310
2012 LyP-1 modification to enhance delivery of artemisinin or fluorescent probe loaded polymeric micelles to highly metastatic tumor and its lymphatics. Molecular pharmaceutics 57 22853186
2005 Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond. Immunological reviews 56 15790351
2012 The putative role of the C1858T polymorphism of protein tyrosine phosphatase PTPN22 gene in autoimmunity. Autoimmunity reviews 53 23261816
2021 The role of PTPN22 in the pathogenesis of autoimmune diseases: A comprehensive review. Seminars in arthritis and rheumatism 51 33866147
2007 PTPN22 R620W functional variant in type 1 diabetes and autoimmunity related traits. Diabetes 51 17259401
2013 Roles of the protein tyrosine phosphatase PTPN22 in immunity and autoimmunity. Clinical immunology (Orlando, Fla.) 48 24269925
2021 Systemic inhibition of PTPN22 augments anticancer immunity. The Journal of clinical investigation 47 34283806
2019 The Contribution of PTPN22 to Rheumatic Disease. Arthritis & rheumatology (Hoboken, N.J.) 45 30507064
2006 Association of the PTPN22/LYP gene with type 1 diabetes. Pediatric diabetes 45 17054449
2013 Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis. Annals of the rheumatic diseases 43 23946333
2020 Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy. Journal for immunotherapy of cancer 42 33127657
2019 Recent progress in LyP-1-based strategies for targeted imaging and therapy. Drug delivery 42 30905205
2018 Regulation of autoimmune and anti-tumour T-cell responses by PTPN22. Immunology 41 29512901
2017 Identification of PTPN22, ST6GAL1 and JAZF1 as psoriasis risk genes demonstrates shared pathogenesis between psoriasis and diabetes. Experimental dermatology 40 28603863
2020 Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset. Frontiers in immunology 39 32328064
2008 The tryptophan 620 allele of the lymphoid tyrosine phosphatase (PTPN22) gene predisposes to autoimmune Addison's disease. Clinical endocrinology 39 18710467
2021 Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease. Frontiers in immunology 34 33717184
2013 The role of PTPN22 in autoimmunity: learning from mice. Autoimmunity reviews 34 24189282
2012 PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis. PloS one 34 22427951
2010 PTPN22, PDCD1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Polish patients. International journal of immunogenetics 32 20518841
2016 Magnetic mesoporous nanospheres anchored with LyP-1 as an efficient pancreatic cancer probe. Biomaterials 30 27871003
2022 Protein tyrosine phosphatase PTPN22 negatively modulates platelet function and thrombus formation. Blood 29 35767715
2019 Deletion of PTPN22 improves effector and memory CD8+ T cell responses to tumors. JCI insight 29 31335326
2017 TRAF3 enhances TCR signaling by regulating the inhibitors Csk and PTPN22. Scientific reports 29 28522807
2016 PTPN22 Is a Critical Regulator of Fcγ Receptor-Mediated Neutrophil Activation. Journal of immunology (Baltimore, Md. : 1950) 29 27807193
2007 Gender-specific association of the PTPN22 C1858T polymorphism with achalasia. Human immunology 29 17961776
2016 Genetic Association of PTPN22 Polymorphisms with Autoimmune Hepatitis and Primary Biliary Cholangitis in Japan. Scientific reports 28 27406031
2013 PTPN22 gene polymorphism (C1858T) is associated with susceptibility to type 1 diabetes: a meta-analysis of 19,495 cases and 25,341 controls. Annals of human genetics 27 23438410
2015 Association of PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with rheumatoid arthritis: A meta-analysis update. Immunobiology 24 25963842
2012 Association of Protein Tyrosine Phosphatase Nonreceptor 22 (PTPN22) C1858T gene polymorphism with susceptibility to autoimmune thyroid diseases: a meta-analysis. Endocrine journal 24 22374238
2017 The lysin motif-containing proteins, Lyp1, Lyk7 and LysMe3, play important roles in chitin perception and defense against Verticillium dahliae in cotton. BMC plant biology 22 28870172
2016 Ptpn22 Modifies Regulatory T Cell Homeostasis via GITR Upregulation. Journal of immunology (Baltimore, Md. : 1950) 22 26810223
2013 Variants in PTPN22 and SMOC2 genes and the risk of thyroid disease in the Jordanian Arab population. Endocrine 22 23463390
2013 Association between the PTPN22 1858C/T gene polymorphism and tuberculosis resistance. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 22 23499775
2022 Genetic Polymorphism of PTPN22 in Autoimmune Diseases: A Comprehensive Review. Medicina (Kaunas, Lithuania) 21 36013501
2016 Loss of the Protein Tyrosine Phosphatase PTPN22 Reduces Mannan-Induced Autoimmune Arthritis in SKG Mice. Journal of immunology (Baltimore, Md. : 1950) 21 27288531
2013 The PTPN22 C1858T polymorphism and rheumatoid arthritis: a meta-analysis. Rheumatology international 21 23370857
2003 Characterization of a myeloid tyrosine phosphatase, Lyp, and its role in the Bcr-Abl signal transduction pathway. The Journal of biological chemistry 21 12764153
2022 PTPN22: structure, function, and developments in inhibitor discovery with applications for immunotherapy. Expert opinion on drug discovery 20 35637605
2019 Experimental colitis in IL-10-deficient mice ameliorates in the absence of PTPN22. Clinical and experimental immunology 20 31194881
2015 Association between PTPN22 C1858T polymorphism and alopecia areata risk. Experimental and therapeutic medicine 20 26640579
2013 PTPN22 in autoimmunity: different cell and different way. Immunity 20 23890067
2022 Redox regulation of PTPN22 affects the severity of T-cell-dependent autoimmune inflammation. eLife 19 35587260
2018 Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1 responses. Journal of autoimmunity 19 30054208
2018 The penetrating properties of the tumor homing peptide LyP-1 in model lipid membranes. Journal of peptide science : an official publication of the European Peptide Society 19 30588706
2014 Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells. PloS one 19 24498279
2013 The autoimmunity risk variant LYP-W620 cooperates with CSK in the regulation of TCR signaling. PloS one 19 23359562
2018 The potential of PTPN22 as a therapeutic target for rheumatoid arthritis. Expert opinion on therapeutic targets 18 30251905
2015 Distribution of PTPN22 polymorphisms in SLE from western Mexico: correlation with mRNA expression and disease activity. Clinical and experimental medicine 18 26013387
2014 Protein tyrosine phosphatase PTPN22 +1858C/T polymorphism is associated with active vitiligo. Experimental and therapeutic medicine 18 25289035
2013 Design, characterization and in vitro evaluation of SMEDDS containing an anticancer peptide, linear LyP-1. Pharmaceutical development and technology 18 23678858
2013 Associations of the PTPN22 and CTLA-4 genetic polymorphisms with Taiwanese ankylosing spondylitis. Rheumatology international 18 24212676
2010 Identification of a variant form of tyrosine phosphatase LYP. BMC molecular biology 18 21044313
2020 Membrane Lipid Requirements of the Lysine Transporter Lyp1 from Saccharomyces cerevisiae. Journal of molecular biology 17 32413406
2018 The protein tyrosine phosphatase PTPN22 negatively regulates presentation of immune complex derived antigens. Scientific reports 17 30139951
2016 Autoimmune Variant PTPN22 C1858T Is Associated With Impaired Responses to Influenza Vaccination. The Journal of infectious diseases 17 27034343
2014 A functional variant of PTPN22 confers risk for Vogt-Koyanagi-Harada syndrome but not for ankylosing spondylitis. PloS one 17 24816862
2012 Biochemical and functional studies of lymphoid-specific tyrosine phosphatase (Lyp) variants S201F and R266W. PloS one 17 22952725
2011 The role of PTPN22 gene polymorphism in childhood immune thrombocytopenic purpura. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 17 21597364
2010 LYP, a novel bestatin derivative, inhibits cell growth and suppresses APN/CD13 activity in human ovarian carcinoma cells more potently than bestatin. Investigational new drugs 17 20111888
2006 Are other protein tyrosine phosphatases than PTPN22 associated with autoimmunity? Seminars in immunology 17 16678435
1997 The lymphopenia (lyp) gene controls the intrathymic cytokine ratio in congenic BioBreeding rats. Diabetologia 17 9243099
2021 Proautoimmune Allele of Tyrosine Phosphatase, PTPN22, Enhances Tumor Immunity. Journal of immunology (Baltimore, Md. : 1950) 16 34417261
2020 PTPN22 interacts with EB1 to regulate T-cell receptor signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 32469452
2019 Efficacy of a novel LyP-1-containing self-microemulsifying drug delivery system (SMEDDS) for active targeting to breast cancer. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 16 30660694
2017 Protein tyrosine phosphatase PTPN22 regulates IL-1β dependent Th17 responses by modulating dectin-1 signaling in mice. European journal of immunology 16 28948613
2016 CD28 and PTPN22 are associated with susceptibility to rheumatoid arthritis in Egyptians. Human immunology 16 27125674
2012 Association of PTPN22 C1858T polymorphism and type 1 diabetes: a meta-analysis. Immunological investigations 16 22429252
2011 No association of PTPN22 R620W gene polymorphism with rheumatic heart disease and systemic lupus erythematosus. Molecular biology reports 16 21384170
2011 The association between the PTPN22 C1858T polymorphism and systemic sclerosis: a meta-analysis. Molecular biology reports 16 21688149
2013 Metaanalysis of the association of smoking and PTPN22 R620W genotype on autoantibody status and radiological erosions in rheumatoid arthritis. The Journal of rheumatology 15 23637320
2007 Expression of human PTPN22 alleles. Genes and immunity 15 17230194