Affinage

PTPN2

Tyrosine-protein phosphatase non-receptor type 2 · UniProt P17706

Length
415 aa
Mass
48.5 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTPN2 (also known as TC-PTP/TCPTP) is a non-receptor protein tyrosine phosphatase that serves as a central negative regulator of receptor tyrosine kinase, JAK-STAT, and Src family kinase signaling across multiple cell types. It exists as two splice isoforms—nuclear TC45 and ER-localized TC48—both of which are kept basally inactive by an autoinhibitory C-terminal intrinsically disordered tail that is displaced upon binding of activators such as the integrin-α1 cytoplasmic tail, and both share a catalytic domain whose efficiency depends on an allosteric helix α7 (PMID:35013194, PMID:34910875). PTPN2 directly dephosphorylates the insulin receptor, EGFR, VEGFR2, CSF-1R, KRAS, JAK1, SFKs, STAT1, STAT3, STAT5, ASC, and c-Fos, thereby attenuating growth factor, cytokine (IFN-γ, IL-2, IL-6, leptin), and inflammasome signaling (PMID:12612081, PMID:10488121, PMID:18840653, PMID:16705167, PMID:29444435, PMID:22000926). In the immune system, PTPN2 restrains TCR-driven T cell proliferation, controls Treg stability through STAT3 dephosphorylation, limits CD8+ T cell exhaustion differentiation, and suppresses macrophage-driven inflammation; accordingly, tumor-cell or T-cell PTPN2 deletion enhances anti-tumor immunity and responsiveness to PD-1 checkpoint blockade, and pharmacological PTPN2/PTP1B inhibition (AC484) phenocopies these effects (PMID:24445916, PMID:30620725, PMID:31527834, PMID:28723893, PMID:37794185).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Establishing that TC45 is not merely a nuclear phosphatase but exits the nucleus upon growth factor stimulation to dephosphorylate EGFR and suppress PI3K/Akt and JNK signaling resolved the question of how a predominantly nuclear PTP could regulate cytoplasmic RTK pathways.

    Evidence Substrate-trapping TC45-D182A overexpression with pharmacological inhibitors and signaling readouts in mammalian cells

    PMID:10488121

    Open questions at the time
    • Mechanism of nuclear exit not yet defined
    • Whether TC45 directly or indirectly targets PI3K not resolved
  2. 2001 High

    Demonstrating that hyperosmotic stress and AMPK activation trigger CRM1-independent nuclear exit of TC45 defined the upstream signal controlling TCPTP subcellular redistribution, while TC45 action on the oncogenic truncated EGFR (Δ-EGFR) in glioblastoma extended its tumor-suppressor role beyond wild-type EGFR.

    Evidence GFP-TC45 live imaging with leptomycin B and AMPK activators; substrate-trapping plus intracranial xenograft model

    PMID:11479308 PMID:11514572

    Open questions at the time
    • Precise AMPK phosphorylation site on TC45 or interacting partner not identified
    • Whether TC45 nuclear exit is purely passive diffusion in all cell types not confirmed
  3. 2003 High

    Identification of the insulin receptor as a direct TCPTP substrate, with both TC45 and TC48 isoforms forming stable complexes with IR-β and TCPTP-/- MEFs showing enhanced insulin signaling rescuable by either isoform, established TCPTP as a physiological brake on insulin signaling.

    Evidence Substrate-trapping D182A Co-IP, TCPTP-/- MEF rescue, phospho-Western blot

    PMID:12612081

    Open questions at the time
    • Tissue-specific in vivo roles of TC45 vs TC48 in insulin signaling not dissected
    • Site-specific IR dephosphorylation not fully mapped
  4. 2004 High

    Two concurrent discoveries revealed complementary regulatory axes: insulin-induced ROS transiently oxidizes and inactivates TC45 to permit signaling, and integrin-α1 binding directly activates TCPTP upon cell adhesion—establishing that TCPTP activity is bidirectionally regulated by redox state and integrin engagement.

    Evidence In-gel PTP activity assay with ROS manipulation; Co-IP of integrin-α1 tail with TCPTP plus phosphatase activity assay

    PMID:15192089 PMID:15592458

    Open questions at the time
    • Whether ROS-mediated inhibition and integrin-mediated activation operate simultaneously or sequentially not tested
    • Structural basis of integrin-α1-mediated activation not yet resolved
  5. 2005 High

    Demonstrating that PTP1B and TCPTP dephosphorylate overlapping but distinct IR phosphosites and control distinct downstream pathways (ERK1/2 vs sustained pY1162/1163) resolved the non-redundancy between these two closely related PTPs in insulin signaling.

    Evidence PTP1B-/- and TCPTP-/- MEFs, double knockdown, phosphosite-specific antibodies

    PMID:15632081

    Open questions at the time
    • Basis for substrate-site selectivity between PTP1B and TCPTP not structurally explained
  6. 2006 High

    Identification of CSF-1R as a TCPTP substrate in macrophages and TC48 localization to the ER via interaction with p25 expanded the substrate repertoire to hematopoietic receptors and provided the first mechanism for TC48 subcellular targeting.

    Evidence Substrate-trapping in TCPTP-/- macrophages with colony assays; yeast two-hybrid and Co-IP for p25-TC48 with ER localization microscopy

    PMID:16595549 PMID:16705167

    Open questions at the time
    • Whether p25 regulates TC48 catalytic activity or only localization not determined
    • Reciprocal IP for p25-TC48 lacking
  7. 2008 High

    Establishing VEGFR2 as a direct TCPTP substrate whose dephosphorylation inhibits receptor internalization and endothelial cell function, and demonstrating cell-cycle-dependent regulation of SFK/JAK1/STAT3 by TCPTP, broadened TCPTP's role to angiogenesis and proliferative control.

    Evidence Substrate-trapping Co-IP with VEGFR2, endothelial functional assays; TCPTP-/- MEFs with cell cycle analysis and pharmacological kinase inhibitors

    PMID:18840653 PMID:18948751

    Open questions at the time
    • Which VEGFR2 phosphosites are dephosphorylated and how this prevents internalization not fully mapped
    • Whether SFK is a direct or indirect substrate in cell cycle context not resolved
  8. 2011 Medium

    Multiple studies converged to show that TCPTP functions as a tumor suppressor in T-ALL (via JAK1/CSF-1R dephosphorylation), dephosphorylates c-Fos to enable ER-associated phospholipid synthesis, and dephosphorylates Golgi-localized C3G via the TC48 isoform, expanding the compartmentalized substrate repertoire.

    Evidence T-ALL patient samples with JAK kinase assays; in vitro c-Fos dephosphorylation with ER functional assays; TC48 substrate-trapping at Golgi with neurite outgrowth readout

    PMID:21551237 PMID:21876762 PMID:22105363

    Open questions at the time
    • Clinical significance of PTPN2 deletion frequency in T-ALL requires larger cohorts
    • Physiological regulation of TC48 activity at the Golgi unknown
    • c-Fos as in vivo substrate not confirmed by genetic approaches
  9. 2012 High

    Demonstrating that phospho-Ser727 on STAT3 promotes TC45-mediated pY705 dephosphorylation provided a substrate-recognition mechanism, while TCPTP loss in triple-negative breast cancer elevated SFK/STAT3 signaling and promoted tumorigenesis, establishing TCPTP as a breast cancer tumor suppressor.

    Evidence STAT3 S727A/S727D mutants in HepG2 cells with TC45 KD/OE; TCPTP-/- mammary fat pad, RNAi in breast cancer lines, xenograft

    PMID:22233524 PMID:23166300

    Open questions at the time
    • Structural basis of Ser727-dependent recognition by TC45 not resolved
    • Whether PTPN2 loss is a driver or passenger in human breast cancer not established
  10. 2014 High

    Showing that PTPN2 deficiency in CD8+ T cells causes rapid lymphopenia-induced proliferation via elevated TCR (but not IL-7) signaling established PTPN2 as a selective restraint on TCR-driven T cell homeostatic responses and a potential autoimmunity checkpoint.

    Evidence T-cell-specific PTPN2-KO mice, adoptive transfer into lymphopenic hosts, TCR signaling readouts

    PMID:24445916

    Open questions at the time
    • Direct TCR-proximal substrate(s) of PTPN2 in CD8+ T cells not conclusively identified
    • Whether LCK is the primary direct substrate not formally tested
  11. 2017 High

    An in vivo CRISPR screen identified PTPN2 deletion in tumor cells as a sensitizer to PD-1 immunotherapy via enhanced IFN-γ/JAK-STAT-driven antigen presentation, while PTPN2's role in thymic lineage commitment via LCK/STAT5 further defined its importance in T cell development.

    Evidence In vivo CRISPR-Cas9 screen in melanoma with anti-PD-1, IFN-γ signaling validation; T-cell-specific PTPN2-KO mice with thymic subset and signaling analysis

    PMID:28723893 PMID:28798028

    Open questions at the time
    • Whether PTPN2 loss in human tumors similarly sensitizes to checkpoint therapy not confirmed clinically
    • Relative contribution of STAT5 vs LCK dephosphorylation to lineage commitment not quantified
  12. 2018 High

    Cell-type-specific knockouts revealed that myeloid PTPN2 directly controls inflammasome assembly via ASC dephosphorylation and that nuclear STAT3 can be shielded from TC45 by the oncoprotein TRIM59 in glioblastoma, defining both a new innate immune substrate and a competition-based regulatory mechanism.

    Evidence PTPN2-LysMCre mice with ASC phosphorylation and IL-1β assays; TRIM59-STAT3-TC45 Co-IP and orthotopic xenograft

    PMID:29386185 PMID:29444435

    Open questions at the time
    • Which ASC tyrosine residue(s) PTPN2 dephosphorylates not identified
    • Whether TRIM59-TC45 competition is stoichiometric or catalytic not resolved
  13. 2019 High

    Multiple 2019 studies established that PTPN2 deletion in CD8+ T cells enhances anti-tumor immunity (including CAR T efficacy) through LCK/STAT5 amplification and CXCL9/10-directed homing, while also increasing terminal T cell exhaustion via type I IFN signaling; concurrently, PTPN2 was shown to maintain Treg stability by dephosphorylating STAT3 to prevent IL-6-driven FoxP3 loss.

    Evidence Conditional PTPN2 KO in CD8+ T cells with CAR T adoptive transfer and LCMV/tumor models; Treg-specific PTPN2 deletion in SKG arthritis model with STAT3 pY readout

    PMID:30620725 PMID:31527834 PMID:31803974

    Open questions at the time
    • How PTPN2 differentially regulates type I vs type II IFN signaling mechanistically not resolved
    • Whether enhanced exhaustion-driven cytotoxicity is durable long-term not tested
  14. 2020 High

    Macrophage-specific PTPN2 loss was shown to promote intestinal inflammation through IL-6-mediated epithelial barrier disruption and impaired clearance of adherent-invasive E. coli (via increased CEACAM expression and reduced autophagy/lysosomal function), linking PTPN2 to IBD pathogenesis at the mechanistic level.

    Evidence PTPN2-LysMCre mice, IBD-patient macrophages, bacterial survival assays, TEER/permeability with anti-IL-6 rescue

    PMID:32652144 PMID:33563644

    Open questions at the time
    • Whether PTPN2 directly dephosphorylates autophagy or lysosomal substrates not determined
    • Contribution of PTPN2 loss in macrophages vs epithelial cells to human IBD not separated
  15. 2021 High

    Structural studies using NMR/SAXS and X-ray crystallography resolved the autoinhibitory mechanism: the C-terminal disordered tail occludes the active site and is competitively displaced by integrin-α1, while helix α7 allosterically enhances catalytic efficiency ~4-fold, providing a unified structural framework for TCPTP activation.

    Evidence Solution NMR, SAXS, XL-MS, biochemical assays; 1.7–1.9 Å crystal structures with α7 truncation mutagenesis

    PMID:34910875 PMID:35013194

    Open questions at the time
    • Full-length TCPTP structure including the disordered tail not captured crystallographically
    • Whether other activators (e.g. mitoxantrone, endogenous ligands) use the same displacement mechanism not confirmed structurally
  16. 2023 High

    Development of AC484 (ABBV-CLS-484), a first-in-class dual PTPN2/PTP1B active-site inhibitor, demonstrated that pharmacological PTPN2 inhibition amplifies IFN-γ/JAK-STAT signaling and promotes NK and CD8+ T cell-mediated anti-tumor immunity even in PD-1-resistant settings, validating PTPN2 as a druggable immuno-oncology target.

    Evidence Active-site inhibitor biochemical characterization, cytokine signaling assays, multiple syngeneic mouse tumor models

    PMID:37794185

    Open questions at the time
    • Selectivity over other PTPs in vivo not fully characterized
    • Clinical efficacy and toxicity in humans not yet established
    • Whether combined PTPN2/PTP1B inhibition causes autoimmune adverse effects not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full structural basis of isoform-specific substrate selection (TC45 vs TC48), the direct substrates mediating PTPN2's effects on autophagy and lysosomal function, and whether therapeutic PTPN2 inhibition can achieve immune activation without autoimmune toxicity in humans.
  • No full-length structure of either isoform
  • Autophagy/lysosomal substrates not identified
  • Human clinical safety/efficacy data not available

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 21 GO:0098772 molecular function regulator activity 4
Localization
GO:0005634 nucleus 6 GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 13 R-HSA-168256 Immune System 9 R-HSA-1643685 Disease 6 R-HSA-1640170 Cell Cycle 2 R-HSA-1266738 Developmental Biology 1
Partners
CSF1REGFRINSRITGA1KDRSTAT1STAT3STAT5

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TCPTP (PTPN2) directly dephosphorylates the insulin receptor (IR) beta-subunit. Both TC48 and TC45 isoforms form stable complexes with the tyrosine-phosphorylated IR beta-subunit (shown by substrate-trapping mutant D182A), and TCPTP-/- MEFs exhibit enhanced insulin-induced IR phosphorylation and PKB/Akt activation that is rescued by physiological re-expression of either isoform. Substrate-trapping mutant (D182A) co-immunoprecipitation, TCPTP-/- MEF rescue experiments, phosphorylation-specific Western blot Molecular and cellular biology High 12612081
2004 Insulin stimulation induces rapid, transient oxidation and inhibition of TC45 (the 45-kDa TCPTP isoform) via reactive oxygen species, establishing reversible oxidation as a physiological mechanism to transiently relieve TC45-mediated suppression of insulin receptor signaling. In-gel PTP activity assay, RNAi knockdown, substrate-trapping mutants The Journal of biological chemistry High 15192089
2004 The cytoplasmic tail of integrin alpha-1 directly interacts with TCPTP and activates its phosphatase activity upon cell adhesion to collagen, resulting in reduced EGFR phosphorylation after EGF stimulation. Co-immunoprecipitation of alpha-1 integrin tail with TCPTP, cell-permeable peptide competition assay, phosphatase activity assay Nature cell biology High 15592458
2005 PTP1B and TCPTP act coordinately but non-redundantly to regulate IR phosphorylation: PTP1B controls IR Y1162/Y1163 and Y972 phosphorylation and ERK1/2 signaling, whereas TCPTP controls Y972 phosphorylation and sustains Y1162/Y1163 dephosphorylation, with both contributing to PI3K/Akt signaling. PTP1B-/- and TCPTP-/- MEFs, RNAi suppression of TCPTP in PTP1B-/- background, phosphorylation-site-specific antibodies Molecular and cellular biology High 15632081
1999 TC45 exits the nucleus upon EGF receptor activation, dephosphorylates the EGFR, inhibits EGF-dependent PI3K/PKB-Akt and JNK (but not ERK2) activation, and suppresses integrin-mediated Akt activation by acting upstream of PI3K to prevent p85 recruitment. TC45 and TC45-D182A substrate-trapping overexpression, pharmacological PI3K/EGFR inhibitors, signaling readouts The Journal of biological chemistry High 10488121
2001 TC45 dephosphorylates Delta-EGFR (a truncated, constitutively active EGFR mutant) in glioblastoma cells, inhibiting ERK2 and PI3K signaling and suppressing tumor growth in vivo. TC45-D182A substrate-trapping, signaling Western blots, anchorage-independent growth assay, intracranial xenograft mouse model The Journal of biological chemistry High 11514572
2001 Hyperosmotic and other specific cellular stresses (those that activate AMP-activated protein kinase, AMPK) cause reversible cytoplasmic redistribution of TC45, which then dephosphorylates EGFR and attenuates JNK signaling; nuclear exit occurs by passive diffusion independent of CRM-1 exportin. GFP-TC45 live imaging, leptomycin B treatment, pharmacological AMPK activators, subcellular fractionation, signaling assays The Journal of biological chemistry High 11479308
2006 TCPTP is a negative regulator of CSF-1 receptor (CSF-1R) signaling and macrophage differentiation; the CSF-1R is identified as a physiological substrate of TCPTP via substrate-trapping, and TCPTP-/- macrophages show hyperphosphorylation of CSF-1R and enhanced Grb2/Gab2/Shp2 recruitment and ERK activation. Substrate-trapping experiments, TCPTP-/- mice, colony-forming unit assays, Western blot phosphorylation analysis Molecular and cellular biology High 16705167
2008 TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization; TCPTP activity is induced by integrin alpha-1-mediated adhesion to collagen, inhibiting VEGF-triggered endothelial cell proliferation, sprouting, and migration. TCPTP substrate-trapping mutant co-immunoprecipitation with VEGFR2, kinase activity assay, VEGFR2 internalization assay, endothelial cell functional assays Journal of cell science High 18840653
2008 TCPTP negatively regulates Src family kinase (SFK), JAK1, and STAT3 signaling in a cell-cycle-dependent manner; enhanced SFK and PI3K (but not JAK1/STAT3) signaling drives the accelerated G1/S transition in TCPTP-deficient cells. TCPTP-/- MEFs, RNAi in HeLa cells, pharmacological kinase inhibitors, cell cycle analysis Cell cycle (Georgetown, Tex.) Medium 18948751
2009 PTPN2 knockdown in pancreatic beta-cells amplifies IFN-gamma-induced STAT1 phosphorylation and exacerbates cytokine-induced apoptosis; double knockdown of both PTPN2 and STAT1 protects against cytokine death, placing PTPN2 upstream of STAT1 in IFN-gamma signaling in beta-cells. siRNA knockdown in rat beta-cells and human islets, STAT1 phosphorylation Western blot, cell death assays, epistasis by double KD Diabetes High 19336676
2011 TCPTP negatively regulates CSF-1 receptor and oncogenic JAK1 (as well as NUP214-ABL1) in T-ALL; PTPN2 deletion sensitizes lymphoid cells to JAK1-mediated transformation and reduces sensitivity to JAK inhibition. PTPN2 deletion in T-ALL patient samples and functional assays, JAK1 kinase assays, JAK inhibitor sensitivity testing Blood Medium 21551237
2011 Hypothalamic TCPTP is elevated in obesity and attenuates leptin signaling; neuronal-specific TCPTP deletion enhances leptin sensitivity and protects against diet-induced obesity; combined deletion of TCPTP and PTP1B in neurons has additive anti-obesity effects. Neuron-specific conditional KO mice, intracerebroventricular TCPTP inhibitor, leptin signaling (JAK2/STAT3 phosphorylation), metabolic phenotyping Cell metabolism High 22000926
2012 TCPTP dephosphorylates SFK and regulates STAT3 signaling in breast cancer; TCPTP protein is lost in triple-negative breast cancers, and TCPTP deficiency in murine mammary fat pads or human breast cancer cell lines elevates SFK and STAT3 signaling; TCPTP reconstitution impairs cell proliferation and suppresses tumor growth in vivo. TCPTP-/- murine mammary fat pad, RNAi in human breast cancer lines, TCPTP reconstitution, xenograft mouse model Molecular and cellular biology High 23166300
2012 Phospho-Ser727 on STAT3 promotes TC45-mediated dephosphorylation of STAT3 pY705 to shorten the duration of STAT3 activity; TC45 knockdown causes prolonged pY705 in STAT3-WT but not STAT3-S727A, and TC45 overexpression causes rapid pY705 dephosphorylation only in STAT3-WT, demonstrating a phospho-Ser727-dependent substrate recognition mechanism. STAT3 mutants (S727A, S727D) in STAT3-knockdown HepG2 cells, TC45 KD and overexpression, phospho-specific Western blot Genes to cells High 22233524
2006 TC48 isoform of TCPTP is localized to the ER via interaction with transmembrane protein p25; p25 coimmunoprecipitates with TC48 and its coexpression enhances ER localization, while a p25 mutant lacking the KKxx ER-retrieval signal causes TC48 Golgi trapping. Yeast two-hybrid screen, coimmunoprecipitation, colocalization microscopy, domain deletion mutants Journal of cell science Medium 16595549
2011 TC48 directly dephosphorylates C3G (RapGEF1) at the Golgi; TC48 substrate-trapping mutant forms stable complex with phospho-C3G at the Golgi, and TC48 expression abrogates Src/IGF-induced C3G phosphorylation and inhibits neurite outgrowth in neuroblastoma cells. In vivo and in vitro binding assays, substrate-trapping mutant, co-localization microscopy, C3G phosphorylation assay, neurite outgrowth functional assay PloS one Medium 21876762
2001 TC-PTP-/- MEFs exhibit delayed G1 progression with reduced cyclin D1 induction, sustained p27(KIP1), and decreased IKKβ activity and NF-κB activation following PDGF stimulation; re-introduction of wild-type TC-PTP rescues these defects, identifying TCPTP as a positive regulator of G1 progression via the NF-κB pathway. TC-PTP-/- MEFs, TC-PTP reconstitution, cell cycle analysis, NF-κB reporter assay, IKKβ kinase assay Oncogene Medium 11498795
2014 PTPN2 attenuates T-cell receptor (TCR)-dependent lymphopenia-induced proliferation (LIP) in CD8+ T cells; PTPN2-deficient CD8+ T cells undergo rapid LIP and acquire effector characteristics when transferred into lymphopenic hosts, leading to autoimmunity via elevated TCR signaling (but not IL-7-dependent responses). T-cell-specific PTPN2-deficient mice, adoptive transfer into lymphopenic hosts, TCR signaling readouts, flow cytometry Nature communications High 24445916
2015 PTPN2 is induced by TCR activation in iTreg cells to restrain IL-2-mediated STAT5 phosphorylation, thereby promoting FOXP3 depletion; PTPN2 knockdown restores FOXP3 expression despite TCR signaling, placing PTPN2 as a negative regulator of STAT5 that limits FOXP3 stability in iTregs. PTPN2 KD in iTreg cells, STAT5 phosphorylation assay, FOXP3 expression analysis, epistasis with STAT5 and FOXO1 mutants Nature communications Medium 26815406
2017 PTPN2 deletion in melanoma tumor cells increases the efficacy of PD-1 checkpoint immunotherapy by enhancing IFN-gamma-mediated effects on antigen presentation (MHC-I upregulation) and growth suppression via the JAK-STAT pathway. In vivo CRISPR-Cas9 pooled screen in transplantable melanoma + PD-1 blockade, validation with individual gene deletion, IFN-gamma signaling assays Nature High 28723893
2017 PTPN2 regulates αβ vs. γδ T cell lineage commitment by attenuating STAT5 signaling (for T-cell lineage commitment) and LCK/STAT5 signaling (for αβ vs γδ specification) in the thymus. T-cell-specific PTPN2-deficient mice, thymic subset analysis by flow cytometry, LCK and STAT5 phosphorylation assays The Journal of experimental medicine Medium 28798028
2018 TRIM59 promotes glioblastoma by physically interacting with nuclear STAT3 and preventing TC45-mediated dephosphorylation of STAT3 pY705, thereby sustaining STAT3 transcriptional activation downstream of EGFR signaling. Co-immunoprecipitation of TRIM59-STAT3, TC45 dephosphorylation assay, TRIM59/PTPN2 KD, orthotopic xenograft Cancer research Medium 29386185
2018 Myeloid cell-specific PTPN2 deletion promotes inflammasome activation and elevated IL-1β production by increasing phosphorylation of the inflammasome adaptor ASC, identifying PTPN2 as a direct regulator of inflammasome assembly in macrophages. PTPN2-LysMCre mice, inflammasome assays, ASC phosphorylation Western blot, IL-1β ELISA, IL-1β blocking antibody rescue Cell reports High 29444435
2019 PTPN2 deletion in CD8+ T cells increases JAK-STAT signaling (LCK activation and STAT5 phosphorylation) and CXCL9/10-directed homing, enhancing CAR T-cell activation and anti-tumor efficacy against HER-2+ solid tumors in vivo. T-cell-specific PTPN2-deficient mice, CAR T-cell adoptive transfer, LCK phosphorylation and STAT5 signaling assays, tumor homing experiments The EMBO journal High 31803974
2019 PTPN2 deletion in CD8+ T cells increases generation of Tim-3+ terminally exhausted T cells and their cytotoxicity by attenuating type I interferon signaling; this is mechanistically distinct from effects on Slamf6+ progenitor exhausted cells. Ptpn2-conditional KO in CD8+ T cells, LCMV clone 13 infection model, tumor models, flow cytometry, IFN signaling assays Nature immunology High 31527834
2019 PTPN2 dephosphorylates STAT3 in Tregs to inhibit IL-6-driven loss of FoxP3; reduced PTPN2 expression promotes pathogenic conversion of RORγt+ Tregs into IL-17-producing exTregs, thereby exacerbating autoimmune arthritis. SKG mouse arthritis model with Ptpn2 haploinsufficiency, Treg-specific PTPN2 deletion, STAT3 phosphorylation assays, FoxP3 stability assays The Journal of clinical investigation High 30620725
2020 PTPN2 loss in macrophages increases CEACAM1/CEACAM6 expression (promoting bacterial uptake), impairs autophagy, and reduces lysosomal acidification, thereby compromising clearance of adherent-invasive E. coli; in vivo, macrophage-specific PTPN2 KO mice are more susceptible to AIEC infection. PTPN2-LysMCre mice, IBD-patient macrophages, bacterial invasion/survival assays, CEACAM expression analysis, autophagy flux, lysosomal pH assay Gut High 33563644
2020 PTPN2 loss in macrophages promotes an inflammatory macrophage phenotype and elevated IL-6 secretion that disrupts intestinal epithelial barrier function; anti-IL-6 antibody reverses this effect in both co-culture and in vivo Ptpn2-LysMCre mice. Macrophage-IEC co-culture, PTPN2 siRNA/shRNA KD, Ptpn2-LysMCre mice, TEER/permeability assays, anti-IL-6 antibody rescue, IBD-patient macrophages Gastroenterology High 32652144
2020 PTPN2 negatively regulates KRAS plasma membrane localization and activation by dephosphorylating tyrosine-phosphorylated KRAS; PTPN2 knockdown reduces KRAS membrane association, impairs KRAS downstream signaling, reduces proliferation, and promotes apoptosis specifically in KRAS-dependent cancer cells. High-content imaging screen, PTPN2 KD/KO, KRAS membrane localization assay, KRAS tyrosine phosphorylation Western blot, proliferation and apoptosis assays The Journal of biological chemistry Medium 33122197
2011 TC45 dephosphorylates tyrosine residues of c-Fos (Y10 and Y30), enabling c-Fos association with the endoplasmic reticulum membranes and activation of phospholipid synthesis; induction of cell growth promotes TC45 nuclear-to-cytoplasmic translocation coincident with its activation. In vivo and in vitro dephosphorylation assays, TC45 translocation microscopy, ER-association and phospholipid synthesis functional assays Oncogene Medium 22105363
2021 The C-terminal intrinsically disordered tail of TCPTP acts as an intramolecular autoinhibitory element that suppresses catalytic activity; integrin-alpha-1 cytosolic tail displaces this autoinhibitory tail via competitive binding to activate TCPTP. Solution NMR, small-angle X-ray scattering (SAXS), chemical cross-linking/mass spectrometry, biochemical phosphatase activity assays Nature communications High 35013194
2021 Crystal structures of TCPTP at 1.7 Å and 1.9 Å resolution reveal that helix α7 at the C-terminus functions as an allosteric regulator of catalytic efficiency; truncation or deletion of helix α7 reduces TCPTP catalytic efficiency ~4-fold. X-ray crystallography, mutagenesis (α7 truncation/deletion), in vitro phosphatase activity assays Biochemistry High 34910875
2013 miR-210, induced by ROS/hypoxia via PDGFR-β/Akt/ERK and NF-κB/Elk1 pathways, directly targets the PTPN2 3'UTR (validated by luciferase assay) to downregulate PTPN2 protein and thereby promote proliferation and migration of adipose-derived stem cells. Luciferase 3'UTR reporter assay, miR-210 mimic/inhibitor, PTPN2 siRNA, proliferation/migration assays Cell death & disease Medium 23579275
2019 Benzene metabolite 1,4-benzoquinone irreversibly inhibits PTPN2 by forming a covalent adduct at the catalytic cysteine residue (kinact = 645 M-1·s-1), leading to increased STAT1 tyrosine phosphorylation and STAT1-regulated gene expression in cells. In vitro kinetic assay with purified human PTPN2, mass spectrometry identification of covalent adduct, cell-based STAT1 phosphorylation assay The Journal of biological chemistry High 31248982
2013 Mitoxantrone directly binds the catalytic domain of TCPTP at a hydrophobic groove near the active site and activates its phosphatase activity; this binding site is also used by the integrin alpha-1 cytoplasmic peptide. Molecular modeling, biochemical binding assays, in vitro phosphatase activity assays, identification of binding site residues Biochimica et biophysica acta Medium 23856547
2016 PASD1 competes with TC45 to associate with nuclear STAT3, thereby preventing TC45-mediated dephosphorylation of STAT3 pY705 and sustaining STAT3 transcriptional activation and tumor growth. Endogenous co-immunoprecipitation of PASD1-STAT3 and PASD1-TC45, PASD1/TC45 competition assay, STAT3 pY705 Western blot, tumor xenograft Journal of molecular cell biology Medium 26892021
2022 TRIM32 physically associates with nuclear STAT3 and suppresses TC45-induced dephosphorylation of STAT3, promoting STAT3 transcriptional activation and radioresistance in triple-negative breast cancer. Co-immunoprecipitation, TC45-STAT3 dephosphorylation assay, TRIM32 KD, radioresistance functional assays in vitro and in vivo Oncogene Medium 35091679
2021 lncRNA TINCR directly binds the phosphatase domain of TCPTP and inhibits its tyrosine phosphatase activity, thereby preventing STAT3 dephosphorylation and maintaining STAT3 activation to promote HCC proliferation and invasion. RNA pulldown, LC-MS/MS, RNA immunoprecipitation, STAT3 phosphatase activity assay with domain-deletion TINCR constructs, functional cell assays Bioengineered Medium 34057016
2023 ABBV-CLS-484 (AC484) is a first-in-class, orally bioavailable active-site inhibitor of both PTPN2 and PTP1B; it amplifies interferon JAK-STAT signaling, promotes NK cell and CD8+ T cell function, and generates potent anti-tumor immunity in PD-1-resistant mouse tumor models. Active-site inhibitor characterization, in vitro cytokine signaling assays (JAK-STAT), in vivo mouse tumor models with immune cell analysis Nature High 37794185
2018 TC-PTP directly interacts with and dephosphorylates Flk-1 (VEGFR2/KDR) in keratinocytes after UVB exposure (demonstrated by substrate-trapping TC-PTP-D182A co-immunoprecipitation), suppressing Flk-1/JNK survival signaling and promoting UVB-induced apoptosis. Substrate-trapping mutant (D182A) immunoprecipitation, Flk-1 phosphorylation Western blot, epidermal-specific TC-PTP KO mice, Flk-1 siRNA/inhibitor rescue Cell death & disease Medium 29955047

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 897 28723893
2004 Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B. The Journal of biological chemistry 227 15192089
2019 PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity. Nature immunology 203 31527834
2005 Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP. Molecular and cellular biology 170 15632081
2004 Negative regulation of EGFR signalling through integrin-alpha1beta1-mediated activation of protein tyrosine phosphatase TCPTP. Nature cell biology 162 15592458
2010 Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nature genetics 158 20473312
2011 Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell metabolism 153 22000926
2012 PTP1B and TCPTP--nonredundant phosphatases in insulin signaling and glucose homeostasis. The FEBS journal 149 22404968
2009 PTPN2, a candidate gene for type 1 diabetes, modulates interferon-gamma-induced pancreatic beta-cell apoptosis. Diabetes 144 19336676
2003 Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP. Molecular and cellular biology 143 12612081
2023 The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. Nature 132 37794185
2013 Reactive oxygen species-responsive miR-210 regulates proliferation and migration of adipose-derived stem cells via PTPN2. Cell death & disease 132 23579275
2010 An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4(+) T cells. Genes and immunity 125 21179116
2020 PTPN2 Regulates Interactions Between Macrophages and Intestinal Epithelial Cells to Promote Intestinal Barrier Function. Gastroenterology 120 32652144
2019 PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. The EMBO journal 117 31803974
2008 PTP1B and TC-PTP: regulators of transformation and tumorigenesis. Cancer metastasis reviews 106 18236007
2014 PTPN2 controls differentiation of CD4⁺ T cells and limits intestinal inflammation and intestinal dysbiosis. Mucosal immunology 93 25492475
2018 PTPN2 Regulates Inflammasome Activation and Controls Onset of Intestinal Inflammation and Colon Cancer. Cell reports 90 29444435
1999 The protein-tyrosine phosphatase TCPTP regulates epidermal growth factor receptor-mediated and phosphatidylinositol 3-kinase-dependent signaling. The Journal of biological chemistry 87 10488121
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2012 TCPTP regulates SFK and STAT3 signaling and is lost in triple-negative breast cancers. Molecular and cellular biology 83 23166300
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2011 Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy. Inflammatory bowel diseases 71 22021207
2019 Intranasal Targeting of Hypothalamic PTP1B and TCPTP Reinstates Leptin and Insulin Sensitivity and Promotes Weight Loss in Obesity. Cell reports 70 31509751
2023 A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity. Nature communications 65 37500611
2016 PTPN2-deficiency exacerbates T follicular helper cell and B cell responses and promotes the development of autoimmunity. Journal of autoimmunity 65 27658548
2008 The protein tyrosine phosphatase TCPTP controls VEGFR2 signalling. Journal of cell science 64 18840653
2001 The protein tyrosine phosphatase TCPTP suppresses the tumorigenicity of glioblastoma cells expressing a mutant epidermal growth factor receptor. The Journal of biological chemistry 64 11514572
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
2014 PTPN2 attenuates T-cell lymphopenia-induced proliferation. Nature communications 60 24445916
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2001 Cellular stress regulates the nucleocytoplasmic distribution of the protein-tyrosine phosphatase TCPTP. The Journal of biological chemistry 59 11479308
2019 Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity. The Journal of clinical investigation 58 30620725
2011 A polymorphism in PTPN2 gene is associated with an earlier onset of type 1 diabetes. Immunogenetics 58 21246196
2018 Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus. Journal of medicinal chemistry 55 30525586
2016 The design strategy of selective PTP1B inhibitors over TCPTP. Bioorganic & medicinal chemistry 54 27353889
2006 T-cell protein tyrosine phosphatase (Tcptp) is a negative regulator of colony-stimulating factor 1 signaling and macrophage differentiation. Molecular and cellular biology 53 16705167
2021 Synergistic photothermal cancer immunotherapy by Cas9 ribonucleoprotein-based copper sulfide nanotherapeutic platform targeting PTPN2. Biomaterials 52 34749073
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2020 PTPN2 Deficiency Enhances Programmed T Cell Expansion and Survival Capacity of Activated T Cells. Cell reports 48 32726622
1985 Role of the Arg158 residue of the outer membrane PhoE pore protein of Escherichia coli K 12 in bacteriophage TC45 recognition and in channel characteristics. European journal of biochemistry 48 2414105
2014 PTPN2 restrains CD8⁺ T cell responses after antigen cross-presentation for the maintenance of peripheral tolerance in mice. Journal of autoimmunity 46 24997008
2022 Matrine suppresses NLRP3 inflammasome activation via regulating PTPN2/JNK/SREBP2 pathway in sepsis. Phytomedicine : international journal of phytotherapy and phytopharmacology 45 36610161
2006 PTP1B and TC-PTP: novel roles in immune-cell signaling. Canadian journal of physiology and pharmacology 43 16998530
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2022 PTPN2 elicits cell autonomous and non-cell autonomous effects on antitumor immunity in triple-negative breast cancer. Science advances 41 35196085
2019 T-Cell-Specific PTPN2 Deficiency in NOD Mice Accelerates the Development of Type 1 Diabetes and Autoimmune Comorbidities. Diabetes 41 30936146
2022 The catalytic activity of TCPTP is auto-regulated by its intrinsically disordered tail and activated by Integrin alpha-1. Nature communications 40 35013194
2012 Regulation of epithelial barrier function by the inflammatory bowel disease candidate gene, PTPN2. Annals of the New York Academy of Sciences 37 22671596
2010 Phosphatome profiling reveals PTPN2, PTPRJ and PTEN as potent negative regulators of PKB/Akt activation in Ras-mutated cancer cells. The Biochemical journal 37 19922411
2018 The presence of genetic risk variants within PTPN2 and PTPN22 is associated with intestinal microbiota alterations in Swiss IBD cohort patients. PloS one 36 29965986
2017 PTPN2 regulates T cell lineage commitment and αβ versus γδ specification. The Journal of experimental medicine 36 28798028
2018 25-Hydroxyvitamin D3 -enhanced PTPN2 positively regulates periodontal inflammation through the JAK/STAT pathway in human oral keratinocytes and a mouse model of type 2 diabetes mellitus. Journal of periodontal research 35 29516520
2017 MicroRNA-448 promotes multiple sclerosis development through induction of Th17 response through targeting protein tyrosine phosphatase non-receptor type 2 (PTPN2). Biochemical and biophysical research communications 35 28342869
2021 Gene Polymorphisms of NOD2, IL23R, PTPN2 and ATG16L1 in Patients with Crohn's Disease: On the Way to Personalized Medicine? Genes 34 34198814
2018 T cells are influenced by a long non-coding RNA in the autoimmune associated PTPN2 locus. Journal of autoimmunity 33 29398253
2022 PTPN2 in the Immunity and Tumor Immunotherapy: A Concise Review. International journal of molecular sciences 32 36077422
2012 Strain-dependent differences in bone development, myeloid hyperplasia, morbidity and mortality in ptpn2-deficient mice. PloS one 32 22590589
2019 PTPN2 improved renal injury and fibrosis by suppressing STAT-induced inflammation in early diabetic nephropathy. Journal of cellular and molecular medicine 28 30955247
2017 Downregulation of PTP1B and TC-PTP phosphatases potentiate dendritic cell-based immunotherapy through IL-12/IFNγ signaling. Oncoimmunology 28 28680757
2021 Crystal Structure of TCPTP Unravels an Allosteric Regulatory Role of Helix α7 in Phosphatase Activity. Biochemistry 27 34910875
2015 Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1. Nature communications 26 26815406
2020 PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis. JCI insight 25 33055428
2006 Evidence for a role of transmembrane protein p25 in localization of protein tyrosine phosphatase TC48 to the ER. Journal of cell science 25 16595549
2022 PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes. Diabetes 24 35044456
2019 Upregulated PTPN2 induced by inflammatory response or oxidative stress stimulates the progression of thyroid cancer. Biochemical and biophysical research communications 24 31735335
2014 The discovery of a novel and selective inhibitor of PTP1B over TCPTP: 3D QSAR pharmacophore modeling, virtual screening, synthesis, and biological evaluation. Chemical biology & drug design 24 24418013
2021 Autoimmune susceptibility gene PTPN2 is required for clearance of adherent-invasive Escherichia coli by integrating bacterial uptake and lysosomal defence. Gut 22 33563644
2019 PTPN2 induced by inflammatory response and oxidative stress contributed to glioma progression. Journal of cellular biochemistry 22 31241223
2008 Cell cycle-dependent regulation of SFK, JAK1 and STAT3 signalling by the protein tyrosine phosphatase TCPTP. Cell cycle (Georgetown, Tex.) 22 18948751
2020 PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells. The Journal of biological chemistry 21 33122197
2013 Emerging role of tyrosine phosphatase, TCPTP, in the organelles of the early secretory pathway. Biochimica et biophysica acta 21 23328081
2011 TC-PTP dephosphorylates the guanine nucleotide exchange factor C3G (RapGEF1) and negatively regulates differentiation of human neuroblastoma cells. PloS one 21 21876762
2014 Epistasis amongst PTPN2 and genes of the vitamin D pathway contributes to risk of juvenile idiopathic arthritis. The Journal of steroid biochemistry and molecular biology 20 25460303
2013 Characterization of PTPN2 and its use as a biomarker. Methods (San Diego, Calif.) 20 23994241
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2021 Long non-coding RNA TINCR promotes hepatocellular carcinoma proliferation and invasion via STAT3 signaling by direct interacting with T-cell protein tyrosine phosphatase (TCPTP). Bioengineered 19 34057016
2019 The effects of PTPN2 loss on cell signalling and clinical outcome in relation to breast cancer subtype. Journal of cancer research and clinical oncology 19 31025094
2021 Ptpn2 and KLRG1 regulate the generation and function of tissue-resident memory CD8+ T cells in skin. The Journal of experimental medicine 18 33914023
2020 The autoimmune susceptibility gene, PTPN2, restricts expansion of a novel mouse adherent-invasive E. coli. Gut microbes 18 32586195
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2013 Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone. Biochimica et biophysica acta 18 23856547
2021 Modulation of PTPN2/22 Function by Spermidine in CRISPR-Cas9-Edited T-Cells Associated with Crohn's Disease and Rheumatoid Arthritis. International journal of molecular sciences 17 34445589
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2017 Discovery of novel high potent and cellular active ADC type PTP1B inhibitors with selectivity over TC-PTP via modification interacting with C site. European journal of medicinal chemistry 17 29289892
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2018 Epidermal-specific deletion of TC-PTP promotes UVB-induced epidermal cell survival through the regulation of Flk-1/JNK signaling. Cell death & disease 16 29955047
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2019 Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling. The Journal of biological chemistry 15 31248982
2018 Overexpression of PTPN2 in Visceral Adipose Tissue Ameliorated Atherosclerosis via T Cells Polarization Shift in Diabetic Apoe-/- Mice. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 15 29587266
2011 The kinase c-Src and the phosphatase TC45 coordinately regulate c-Fos tyrosine phosphorylation and c-Fos phospholipid synthesis activation capacity. Oncogene 15 22105363
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2017 Genetic variants of PTPN2 are associated with lung cancer risk: a re-analysis of eight GWASs in the TRICL-ILCCO consortium. Scientific reports 13 28400551
2016 PASD1 promotes STAT3 activity and tumor growth by inhibiting TC45-mediated dephosphorylation of STAT3 in the nucleus. Journal of molecular cell biology 13 26892021