Affinage

Showing PTPN2 — TCPTP is a alias.

PTPN2

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

Length
415 aa
Mass
48.5 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTPN2 (TCPTP) is a non-receptor protein tyrosine phosphatase that acts as a broad negative regulator of growth factor, cytokine, and antigen receptor signaling by dephosphorylating activated tyrosine kinases and their downstream transcription factors (PMID:12612081, PMID:12359225, PMID:16705167). It exists as two isoforms with distinct localization-determined substrate access: the nuclear/cytoplasmic TC45, which dephosphorylates the insulin receptor β-subunit, EGFR (including the constitutively active ΔEGFRvIII), CSF-1R, VEGFR2, STAT1, STAT3, SFKs, JAK2, and c-Fos (PMID:12612081, PMID:10488121, PMID:11514572, PMID:16705167, PMID:18840653, PMID:22000926, PMID:23166300, PMID:22105363), and the ER/Golgi-targeted TC48, which is recruited to the ER through interaction with the COPI cargo receptor p25 and dephosphorylates the insulin receptor and C3G/RapGEF1 (PMID:16595549, PMID:21876762). Through receptor-proximal dephosphorylation, TC45 restrains PI3K/Akt and JAK-STAT outputs; it specifically sustains insulin receptor Y1162/Y1163 phosphorylation to control PI3K/Akt non-redundantly with PTP1B (PMID:15632081, PMID:10488121), and dephosphorylates STAT3 in a manner dependent on prior Ser727 phosphorylation (PMID:22233524). Phosphatase activity is controlled by an intramolecular autoinhibitory C-terminal intrinsically disordered tail, displaced upon binding of the integrin-α1 cytoplasmic domain to a hydrophobic groove on the catalytic domain, and by an allosteric helix α7 (PMID:15592458, PMID:35013194, PMID:34910875, PMID:23856547); catalytic activity is reversibly inactivated by insulin-stimulated ROS to permit signal amplification, and irreversibly abolished by covalent benzoquinone adduction of the catalytic cysteine (PMID:15192089, PMID:31248982). Physiologically, PTPN2 sets thresholds for insulin and leptin signaling in a tissue-specific manner in hypothalamic and AgRP neurons (PMID:22000926, PMID:29712668, PMID:22124607), governs T cell development, lymphopenia-induced proliferation, exhaustion, and Treg stability (PMID:28798028, PMID:31527834, PMID:24445916, PMID:26815406), and restrains macrophage inflammasome activation and inflammatory polarization (PMID:29444435, PMID:32652144). Its loss in tumor cells amplifies IFN-γ signaling and antigen presentation, making PTPN2 a validated immunotherapy target whose pharmacological inhibition enhances anti-tumor T and NK cell function (PMID:28723893, PMID:37794185).

Mechanistic history

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

    Established that TC45 is a regulated EGFR phosphatase that selectively shapes downstream pathway choice, answering whether a nuclear phosphatase could act on a receptor kinase and which arm of its signaling it controls.

    Evidence Substrate-trapping (D182A) overexpression, kinase assays, and immunofluorescence localization upon EGF stimulation

    PMID:10488121

    Open questions at the time
    • Did not resolve endogenous stoichiometry of nuclear export
    • Mechanism of pathway selectivity (PI3K/Akt vs ERK2) left unexplained
  2. 2002 High

    Identified STAT3 as a direct nuclear substrate of TC45, linking the phosphatase to cytokine-driven transcription and growth arrest.

    Evidence Substrate-trapping Co-IP, retroviral overexpression, endogenous nuclear Co-IP, and M1 cell viability assays

    PMID:12359225

    Open questions at the time
    • Did not define the recruitment determinant later shown to depend on STAT3 Ser727
    • Single cell-line context
  3. 2003 High

    Demonstrated genetically that both TC45 and TC48 isoforms regulate the insulin receptor in vivo, establishing IR as a bona fide TCPTP substrate.

    Evidence Substrate-trapping Co-IP plus reconstitution of TCPTP-/- fibroblasts with each isoform

    PMID:12612081

    Open questions at the time
    • Did not address tissue-specific relevance of IR regulation
    • Isoform compartment-specific substrate access not yet resolved
  4. 2004 High

    Resolved how TCPTP catalytic activity is switched on at the cell surface and showed redox provides a transient off-switch, addressing the missing activation logic for a constitutively expressed phosphatase.

    Evidence Integrin-α1 cytoplasmic peptide activation, in vitro phosphatase assay, and in-gel PTP activity assay with insulin-induced ROS

    PMID:15192089 PMID:15592458

    Open questions at the time
    • Structural basis of integrin-mediated activation not yet defined
    • Source and spatial confinement of activating ROS unclear
  5. 2006 Medium

    Extended the substrate repertoire to CSF-1R and the cargo-receptor basis of TC48 ER targeting, connecting TCPTP to myeloid development and isoform-specific localization.

    Evidence Substrate-trapping plus Tcptp-/- colony assays (CSF-1R) and yeast two-hybrid/Co-IP with p25 cargo receptor (TC48 localization)

    PMID:16595549 PMID:16705167

    Open questions at the time
    • p25 interaction rests largely on overexpression imaging
    • Endogenous TC48 ER substrate spectrum incompletely mapped
  6. 2009 High

    Defined PTPN2 as a non-redundant negative regulator of IFN-γ/STAT1 signaling, with double-knockout lethality demonstrating its essential physiological dampening of inflammatory cytokine output.

    Evidence tcptp-/-ptp1b-/- compound mice, macrophage IFN-γ stimulation, and PTPN2/STAT1 double knockdown epistasis in beta-cells

    PMID:19336676 PMID:19474293

    Open questions at the time
    • Direct STAT1 dephosphorylation in vitro not shown in these studies
    • Relative contribution to JAK vs STAT1 dephosphorylation unresolved
  7. 2011 Medium

    Connected PTPN2 to oncogenic JAK/ABL kinase restraint and expanded ER-isoform substrate biology, showing the phosphatase suppresses leukemogenic kinase activity and Golgi C3G signaling.

    Evidence PTPN2 knockdown with kinase/proliferation assays in T-ALL models; substrate-trapping TC48-D182A Co-IP with phospho-C3G at Golgi

    PMID:21551237 PMID:21876762

    Open questions at the time
    • Direct dephosphorylation of NUP214-ABL1/JAK1 not biochemically reconstituted
    • C3G dephosphorylation tested largely by overexpression
  8. 2012 Medium

    Established PTPN2 as a tumor suppressor acting on SFK and STAT3 in breast cancer and clarified the phospho-Ser727 requirement governing TC45-STAT3 engagement.

    Evidence TCPTP-/- mammary models with reconstitution and xenografts; STAT3 S727A/S727D mutagenesis with TC45 knockdown

    PMID:22233524 PMID:23166300

    Open questions at the time
    • Molecular basis linking Ser727 phosphorylation to TC45 recruitment not structurally defined
    • SFK substrate identity within the family not fully resolved
  9. 2012 High

    Defined PTPN2 as the dominant negative regulator of hypothalamic leptin signaling via JAK2 dephosphorylation, revealing a central metabolic control function.

    Evidence Neuron-specific knockout, ICV TCPTP inhibitor, clamps, and additive epistasis with PTP1B deletion

    PMID:22000926

    Open questions at the time
    • Direct JAK2 dephosphorylation kinetics not measured
    • Neuronal subtype contributions not yet dissected
  10. 2018 High

    Resolved tissue-specific and substrate-specific control of metabolism, showing AgRP-neuron PTPN2 gates insulin receptor signaling and hepatic glucose output while muscle PTPN2 is dispensable for insulin signaling.

    Evidence AgRP- and muscle-specific knockouts with clamps and Insr-heterozygosity genetic rescue

    PMID:22124607 PMID:29712668

    Open questions at the time
    • Determinants of tissue-specific substrate access not defined
    • Why muscle IR is refractory to TCPTP loss is unexplained
  11. 2018 Medium

    Expanded the substrate spectrum to non-receptor inflammatory signaling, identifying the inflammasome adaptor ASC as a direct PTPN2 substrate in myeloid cells.

    Evidence Myeloid-specific knockout, pASC Western blot, inflammasome assembly assay, and IL-1β antibody rescue

    PMID:29444435

    Open questions at the time
    • Direct ASC dephosphorylation not biochemically reconstituted
    • Specific ASC tyrosine site(s) not mapped
  12. 2017 High

    Identified PTPN2 as an immunotherapy target whose loss amplifies IFN-γ sensitivity and antigen presentation in tumor cells, motivating therapeutic inhibition.

    Evidence In vivo CRISPR-Cas9 pooled screen in transplantable melanoma with IFN-γ and antigen-presentation validation

    PMID:28723893

    Open questions at the time
    • Tumor-cell-intrinsic vs immune-cell-intrinsic contributions not separated in this study
    • Direct phosphatase substrate(s) in the screen-relevant pathway not assigned
  13. 2019 Medium

    Mapped PTPN2's cell-intrinsic roles across T cell development, exhaustion, Treg stability, CAR T function, and macrophage-epithelial crosstalk, defining the immune signaling axes (LCK/STAT5, type I IFN, STAT3, IL-6) it restrains.

    Evidence Multiple T cell- and myeloid-specific knockouts with pLCK/pSTAT5/pSTAT3 readouts, LCMV chronic infection, adoptive CAR T transfer, and cytokine-blocking rescues

    PMID:24445916 PMID:26815406 PMID:28798028 PMID:30620725 PMID:31527834 PMID:31803974 PMID:32652144

    Open questions at the time
    • Direct vs indirect dephosphorylation of LCK/STAT5/STAT3 not uniformly reconstituted in each context
    • How a single phosphatase achieves context-specific outputs unresolved
  14. 2018 Medium

    Revealed that oncogenic STAT3 signaling is driven by competitive shielding of nuclear STAT3 from TC45, defining a regulatory layer where adaptor proteins block TCPTP access to its substrate.

    Evidence Co-IP and competitive binding assays with TRIM59, PASD1, and TRIM32 against TC45, with pSTAT3 readouts and tumor models

    PMID:26892021 PMID:29386185 PMID:35091679

    Open questions at the time
    • Structural basis of competitive occlusion not resolved
    • Generality across STAT3-dependent tumors uncertain
  15. 2022 High

    Provided the structural mechanism of TCPTP autoinhibition and allosteric control, explaining how the disordered C-terminal tail and helix α7 set basal activity and how activators relieve inhibition.

    Evidence Solution NMR, SAXS, XL-MS, and crystal structures (1.7/1.9 Å) with tail- and α7-truncation mutants and in vitro phosphatase assays; NMR mapping of the activator-binding groove

    PMID:23856547 PMID:34910875 PMID:35013194

    Open questions at the time
    • Structure of the activated, tail-displaced state not captured
    • How redox and structural regulation integrate in cells unclear
  16. 2023 High

    Validated direct active-site pharmacology of PTPN2 and confirmed covalent inactivation chemistry, translating the phosphatase into a druggable immunotherapy and chemical-biology target.

    Evidence Active-site inhibitor ABBV-CLS-484 with JAK-STAT and immune-cell assays in tumor models; in vitro kinetics and MS of benzoquinone covalent catalytic-cysteine adduct with cellular pSTAT1

    PMID:31248982 PMID:37794185

    Open questions at the time
    • PTPN2 vs PTPN1 selectivity of pharmacological effects not fully separated
    • In vivo durability and on-target toxicity profile not addressed here

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single broadly-acting phosphatase achieves substrate-, isoform-, and tissue-specific selectivity in vivo, and how its activation switches (integrin, redox, allostery) are integrated within native cells, remains unresolved.
  • No structure of the fully activated, substrate-engaged enzyme
  • Mechanism coupling localization to substrate choice undefined
  • Quantitative substrate hierarchy across cell types unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0098772 molecular function regulator activity 5 GO:0016787 hydrolase activity 3
Localization
GO:0005634 nucleus 6 GO:0005829 cytosol 4 GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3
Partners
CSF1REGFRINSRITGA1JAK2KDRSTAT1STAT3

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 TC45 (the 45-kDa nuclear isoform of PTPN2/TCPTP) is reversibly oxidized and inhibited by insulin-stimulated reactive oxygen species production in cells; substrate-trapping mutants and RNAi confirmed that TC45 dephosphorylates the beta-subunit of the insulin receptor, identifying it as a direct substrate. In-gel PTP activity assay, RNA interference, substrate-trapping mutant (TC45-D182A) co-immunoprecipitation The Journal of biological chemistry High 15192089
2003 Both TC45 and TC48 isoforms of TCPTP form stable complexes with the tyrosine-phosphorylated insulin receptor (IR) beta-subunit via substrate-trapping mutants; expression of either isoform at physiological levels suppresses enhanced insulin-induced IR phosphorylation and PKB/Akt activation in TCPTP-/- fibroblasts, establishing the IR as a direct substrate of TCPTP in vivo. Substrate-trapping mutant (D182A) co-immunoprecipitation, TCPTP-/- mouse embryo fibroblasts, reconstitution with TC45/TC48 Molecular and cellular biology High 12612081
2005 PTP1B and TCPTP act in a coordinated but temporally distinct and non-redundant manner to regulate IR phosphorylation: PTP1B controls both IR Y1162/Y1163 and Y972 phosphorylation and ERK1/2 signaling, whereas TCPTP specifically sustains Y1162/Y1163 phosphorylation and PI3K/Akt signaling; double RNAi in PTP1B-null cells confirmed non-redundancy. TCPTP-/- and PTP1B-/- MEFs, phosphorylation-site-specific antibodies, RNAi knockdown Molecular and cellular biology High 15632081
2002 The nuclear 45-kDa isoform of TC-PTP (TC45) directly dephosphorylates STAT3; substrate-trapping mutant TC-PTP forms a stable complex with tyrosine-phosphorylated STAT3, overexpression suppresses IL-6-induced STAT3 activation and M1 cell growth arrest, and endogenous TC-PTP co-immunoprecipitates with STAT3 in the nucleus. Substrate-trapping mutant co-immunoprecipitation, retroviral overexpression, endogenous co-IP, cell viability assay Biochemical and biophysical research communications High 12359225
1999 TC45 exits the nucleus upon EGF receptor activation, recognizes the EGFR as a cellular substrate, and inhibits EGF-dependent PI3K and PKB/Akt activation (but not ERK2) by acting upstream of PI3K recruitment; TC45-D182A substrate-trapping mutant mimics this inhibition of PI3K/Akt but not ERK2. Overexpression of wild-type and substrate-trapping (D182A) TC45, kinase assays, immunofluorescence localization The Journal of biological chemistry High 10488121
2004 The cytoplasmic tail of integrin α1 selectively binds TCPTP and activates its phosphatase activity upon cell adhesion to collagen, resulting in reduced EGFR phosphorylation after EGF stimulation and inhibition of EGF-induced proliferation and anchorage-independent growth. Co-immunoprecipitation, cell-permeable α1 cytoplasmic domain peptide, in vitro phosphatase activation assay, proliferation assays Nature cell biology High 15592458
2001 TC45 dephosphorylates the constitutively active truncated EGFR mutant (ΔEGFRvIII) in glioblastoma cells, inhibiting ERK2 and PI3K signaling and suppressing tumor growth in vivo; the substrate-trapping D182A mutant forms stable complexes with ΔEGFRvIII. Substrate-trapping mutant co-immunoprecipitation, kinase assays, in vivo xenograft tumor model The Journal of biological chemistry High 11514572
2001 Hyperosmotic stress causes reversible cytoplasmic accumulation of TC45 (otherwise nuclear) via a mechanism dependent on AMP-activated protein kinase (AMPK) signaling and passive nuclear pore diffusion rather than CRM-1-mediated export; cytoplasmic TC45 then dephosphorylates EGFR and attenuates hyperosmotic stress-induced JNK activation. Fluorescence microscopy, leptomycin B inhibition, GFP-TC45 fusion (nuclear pore size control), pharmacological AMPK activator, JNK kinase assay The Journal of biological chemistry High 11479308
2006 TC-PTP directly dephosphorylates the CSF-1 receptor (CSF-1R) as identified by substrate-trapping; loss of TC-PTP leads to CSF-1R hyperphosphorylation, increased Grb2/Gab2/Shp2 recruitment to CSF-1R, enhanced ERK activation, and increased macrophage colony formation, establishing TC-PTP as a negative regulator of CSF-1 signaling and macrophage development. Substrate-trapping experiments, co-immunoprecipitation, Tcptp-/- mice, bone marrow colony assay, Western blot for signaling Molecular and cellular biology High 16705167
2008 TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner using substrate-trapping mutant interaction; TCPTP activity is induced by integrin-mediated binding to collagen matrix and inhibits VEGF-triggered endothelial proliferation, sprouting, and chemotaxis. Substrate-trapping mutant co-immunoprecipitation, in vitro kinase/phosphatase assay, integrin α1 cytoplasmic peptide activation, endothelial cell functional assays Journal of cell science High 18840653
2009 PTPN2 modulates interferon-γ-induced STAT1 phosphorylation in pancreatic beta-cells; siRNA knockdown of PTPN2 amplified IFN-γ-induced STAT1 phosphorylation and exacerbated cytokine-induced beta-cell apoptosis; double knockdown of PTPN2 and STAT1 protected cells, placing STAT1 hyperactivation downstream of PTPN2 loss. siRNA knockdown, Western blot for pSTAT1, cell death assay (Hoechst/PI), epistasis via double knockdown Diabetes Medium 19336676
2011 PTPN2 is a negative regulator of NUP214-ABL1 kinase activity in T-ALL; knockdown of PTPN2 sensitizes lymphoid cells to JAK1-mutation-driven transformation and reduces sensitivity to JAK inhibition, placing PTPN2 as a phosphatase that restrains oncogenic JAK1 and the JAK/STAT pathway. siRNA knockdown, proliferation assays, cytokine sensitivity assays, kinase activity measurements Blood Medium 21551237
2011 Elevated hypothalamic TCPTP attenuates leptin signaling by dephosphorylating JAK2; neuronal-specific TCPTP deletion enhances leptin sensitivity, protects against high-fat-diet obesity, and combined deletion of TCPTP and PTP1B in neurons has additive effects, establishing TCPTP as a critical negative regulator of hypothalamic leptin signaling. Neuron-specific Cre/lox knockout mice, intracerebroventricular TCPTP inhibitor administration, hyperinsulinemic-euglycemic clamps, Western blot for JAK2/STAT3 phosphorylation Cell metabolism High 22000926
2012 TC-PTP (TCPTP) dephosphorylates Src family kinases (SFKs) and STAT3 in breast cancer cells; TCPTP deficiency in triple-negative breast cancer enhances SFK and STAT3 signaling, and TCPTP reconstitution suppresses anchorage-independent growth and xenograft growth. TCPTP-/- mammary fat pad mice, siRNA knockdown in human cell lines, TCPTP reconstitution, Western blot for pSFK/pSTAT3, in vitro/in vivo tumor assays Molecular and cellular biology High 23166300
2012 Phosphorylation of STAT3 at Ser727 promotes rapid dephosphorylation of pTyr705 specifically through nuclear TC45 (PTPN2); TC45 knockdown prolonged pY705 in STAT3-WT but not STAT3-S727A mutant, and overexpressed TC45 caused rapid pY705 dephosphorylation only in STAT3-WT, establishing a phospho-Ser727-dependent interaction mechanism between STAT3 and TC45. STAT3 mutagenesis (S727A, S727D), TC45 knockdown via siRNA, reconstitution with STAT3 mutants in STAT3-knockdown cells, Western blot Genes to cells Medium 22233524
2009 Both PTP-1B and TC-PTP are non-redundant negative regulators of IFN-γ signaling (STAT1 phosphorylation); double knockout of both genes causes embryonic lethality at E9.5–10.5 with constitutive STAT1 phosphorylation; macrophages heterozygous for TC-PTP on a PTP1B-null background show markedly increased STAT1 phosphorylation and nitric oxide in response to IFN-γ. Double knockout mice (tcptp-/-ptp1b-/-), compound heterozygote analysis, macrophage IFN-γ stimulation, Western blot for pSTAT1, nitric oxide assay Proceedings of the National Academy of Sciences of the United States of America High 19474293
2006 TC48 (ER-localized isoform of TCPTP) is targeted to the ER through interaction with the transmembrane protein p25 (a COPI vesicle cargo receptor); p25 co-immunoprecipitates with TC48, and coexpression with p25 enhances ER localization of TC48, whereas coexpression with a p25 mutant lacking the KKxx ER-localization signal causes enhanced Golgi localization of TC48. Yeast two-hybrid screen, co-immunoprecipitation in Cos-1 cells, confocal colocalization, deletion construct analysis Journal of cell science Medium 16595549
2010 TC-PTP (TC45, SHP1, and SHP2 together) dephosphorylates STAT3 in keratinocytes following UVB irradiation; individual knockdown of each phosphatase by RNAi significantly elevated pSTAT3 after UVB, and TC45 translocated from cytoplasm to nucleus upon UVB irradiation, linking nuclear translocation to STAT3 dephosphorylation. siRNA knockdown of TC-PTP/SHP1/SHP2, Western blot for pSTAT3, immunofluorescence for TC45 localization PloS one Medium 20421975
2011 TC48 (ER isoform of TCPTP) directly dephosphorylates C3G (RapGEF1) at the Golgi; substrate-trapping TC48-D182A formed stable complexes with phospho-C3G at the Golgi, TC48 expression abrogated pervanadate- and c-Src-induced C3G phosphorylation, and TC48-mediated dephosphorylation of C3G inhibited neurite outgrowth in neuroblastoma cells. Substrate-trapping mutant co-immunoprecipitation, in vitro binding assay, immunofluorescence colocalization, overexpression studies, neurite outgrowth assay PloS one Medium 21876762
2011 TC45 directly dephosphorylates tyrosine residues #10 and #30 of c-Fos, enabling c-Fos to associate with ER membranes and activate phospholipid synthesis; growth stimulation promotes nuclear-to-cytoplasmic translocation and activation of TC45, which then dephosphorylates c-Src-phosphorylated c-Fos. In vivo and in vitro phosphorylation/dephosphorylation assays, immunofluorescence localization, co-immunoprecipitation Oncogene Medium 22105363
2017 PTPN2 deletion in tumor cells enhances interferon-γ-mediated antigen presentation and growth suppression, sensitizing tumors to immunotherapy; identified through in vivo CRISPR-Cas9 pooled screen and validated in melanoma models. In vivo CRISPR-Cas9 pooled genetic screen in transplantable tumors, IFN-γ signaling assays, antigen presentation assays Nature High 28723893
2017 PTPN2 attenuates STAT5 signaling to regulate T cell lineage commitment in the thymus, and attenuates LCK (Src family kinase) and STAT5 signaling to regulate αβ versus γδ TCR T cell specification; T cell-specific PTPN2 deletion skews development toward γδ T cells. T cell-specific Cre/lox knockout mice, Western blot for pSTAT5 and pLCK, flow cytometry of thymic subsets The Journal of experimental medicine Medium 28798028
2018 PTPN2 in myeloid cells directly regulates inflammasome activation by dephosphorylating the inflammasome adaptor ASC; myeloid-specific PTPN2 deletion increased ASC phosphorylation, promoted inflammasome assembly, and elevated mature IL-1β production in an IL-1β-dependent manner. Myeloid-specific LysMCre knockout mice, Western blot for pASC, inflammasome assembly assay, ELISA for IL-1β, IL-1β-blocking antibody rescue Cell reports Medium 29444435
2019 PTPN2 dephosphorylates STAT3 in regulatory T cells (Tregs) to inhibit IL-6-driven pathogenic conversion; reduced PTPN2 expression enhanced Treg-to-exTreg conversion associated with RORγt expression and increased chromatin accessibility for STAT3-targeted IL-17 transcription factors in a Treg-intrinsic manner. SKG mouse arthritis model, Treg-specific Cre/lox PTPN2 deletion, Western blot for pSTAT3, chromatin accessibility assay (ATAC-seq), flow cytometry for Treg subsets The Journal of clinical investigation Medium 30620725
2018 TRIM59 promotes glioblastoma tumor growth by interacting with nuclear STAT3 and preventing TC45-mediated dephosphorylation of STAT3; EGFR signaling upregulates TRIM59, which binds STAT3 and shields it from TC45 phosphatase activity in the nucleus. Co-immunoprecipitation, knockdown/overexpression of TRIM59 and TC45, Western blot for pSTAT3, orthotopic xenograft Cancer research Medium 29386185
2016 PASD1 (cancer/testis antigen) competes with TC45 (nuclear PTPN2) to associate with STAT3 in the nucleus, thereby inhibiting TC45-mediated dephosphorylation of STAT3 at Y705 and promoting oncogenic STAT3 signaling. Endogenous co-immunoprecipitation, overexpression/knockdown of PASD1, Western blot for pSTAT3, competitive binding assay with TC45 Journal of molecular cell biology Medium 26892021
2022 TRIM32 interacts with nuclear STAT3 and suppresses TC45-mediated dephosphorylation of STAT3, thereby increasing STAT3 transcriptional activation and promoting radioresistance in triple-negative breast cancer. Co-immunoprecipitation of TRIM32 with STAT3, Western blot for pSTAT3, siRNA knockdown of TRIM32, in vitro and in vivo radioresistance assays Oncogene Medium 35091679
2022 The C-terminal intrinsically disordered tail of TCPTP functions as an intramolecular autoinhibitory element that suppresses catalytic activity under basal conditions; activation by Integrin-α1 occurs because the cytosolic tail of Integrin-α1 displaces the autoinhibitory TCPTP tail, allowing full phosphatase activation. Solution NMR spectroscopy, small-angle X-ray scattering (SAXS), chemical cross-linking coupled with mass spectrometry, in vitro phosphatase assay with tail-truncation mutants Nature communications High 35013194
2021 Crystal structures of TCPTP at 1.7 and 1.9 Å reveal that helix α7 at the C-terminus plays an allosteric role in regulating TCPTP's catalytic activity; truncation or deletion of helix α7 reduced the catalytic efficiency of TCPTP by ~4-fold. X-ray crystallography (1.7 Å and 1.9 Å crystal structures), helix α7 truncation/deletion mutagenesis, in vitro phosphatase activity assay Biochemistry High 34910875
2013 The α1-integrin cytoplasmic peptide and mitoxantrone both activate TCPTP by directly binding to a hydrophobic groove surrounded by negatively charged residues on the surface of TCPTP's catalytic domain; spermidine does not interact with the catalytic domain yet activates TCPTP by a different mechanism. Molecular modeling, NMR-based binding mapping, in vitro phosphatase activation assays, surface competition experiments Biochimica et biophysica acta Medium 23856547
2019 PTPN2 deletion in T cells increases LCK kinase activity and cytokine-induced STAT5 signaling, enhancing CAR T-cell activation, cytokine production, and homing to CXCL9/10-expressing tumors to eradicate HER-2+ mammary tumors in vivo. T cell-specific Cre/lox PTPN2 knockout, Western blot for pLCK and pSTAT5, adoptive CAR T-cell transfer into tumor-bearing mice, flow cytometry The EMBO journal Medium 31803974
2019 PTPN2 regulates the differentiation of terminally exhausted Tim-3+ CD8+ T cells from progenitor exhausted Slamf6+ cells by attenuating type 1 interferon signaling; Ptpn2 deletion in CD8+ T cells increases Tim-3+ cell generation, proliferative capacity, and cytotoxicity without altering Slamf6+ progenitor numbers. T cell-specific Ptpn2 knockout, LCMV clone 13 chronic infection model, flow cytometry for T cell subsets, interferon signaling assays Nature immunology High 31527834
2019 PTPN2 deficiency in TCPTP-/- macrophages (via LysMCre) promotes inflammatory macrophage polarization and increases IL-6 secretion, which disrupts intestinal epithelial barrier function; anti-IL-6 antibody reverses the barrier defect, placing IL-6 downstream of PTPN2 in macrophage–epithelial crosstalk. Myeloid-specific LysMCre knockout mice, macrophage-IEC coculture system, TEER and dextran permeability assays, anti-IL-6 antibody rescue, Nanostring gene expression analysis Gastroenterology Medium 32652144
2018 TCPTP deletion in AgRP neurons enhances insulin receptor (IR) signaling in AgRP neurons, reducing hepatic glucose production (HGP) and increasing brown adipose tissue glucose uptake; IR heterozygosity in AgRP-PTPN2-null mice corrects the metabolic phenotype, causally linking effects to IR signaling. AgRP neuron-specific Cre/lox PTPN2 knockout, hyperinsulinemic-euglycemic clamps, [14C]-2-deoxy-glucose uptake, compound genetic rescue (Insr heterozygosity) Diabetes High 29712668
2019 1,4-benzoquinone (a benzene metabolite) irreversibly inhibits PTPN2 by forming a covalent adduct at the catalytic cysteine residue (kinact = 645 M⁻¹·s⁻¹), leading to increased cellular STAT1 tyrosine phosphorylation and upregulation of STAT1-regulated genes. In vitro kinetic assays with purified human PTPN2, mass spectrometry identification of covalent adduct, cell-based pSTAT1 Western blot The Journal of biological chemistry High 31248982
2021 Loss of PTPN2 in macrophages promotes bacterial uptake via enhanced expression of CEACAM1 and CEACAM6, while simultaneously impairing bacterial clearance through defects in autophagy and compromised lysosomal acidification, resulting in increased adherent-invasive E. coli survival intracellularly. Myeloid-specific LysMCre knockout mice, macrophage infection assays, flow cytometry for CEACAM expression, autophagy flux assays, lysosomal acidification assay Gut Medium 33563644
2023 The dual PTPN2/PTPN1 active-site inhibitor ABBV-CLS-484 (AC484) amplifies interferon responses in vitro and promotes NK cell and CD8+ T cell function by enhancing JAK-STAT signaling and reducing T cell dysfunction in mouse tumor models; it is the first active-site phosphatase inhibitor to enter clinical evaluation for immunotherapy. In vitro JAK-STAT signaling assays (pSTAT readouts), immune cell activation assays, mouse tumor model pharmacology, tumor microenvironment profiling Nature High 37794185
2014 PTPN2 is elevated in naïve T cells exiting the thymus and restrains lymphopenia-induced proliferation (LIP) by attenuating TCR-dependent (but not IL-7-dependent) signaling; PTPN2-deficient CD8+ T cells undergo rapid LIP, acquire effector phenotype, and cause autoimmunity when transferred into lymphopenic hosts. T cell-specific Cre/lox PTPN2 knockout, lymphopenic adoptive transfer, flow cytometry for proliferation/effector markers, cytokine receptor blocking experiments Nature communications Medium 24445916
2011 PTPN2 deficiency in muscle has no effect on insulin receptor signaling or glucose homeostasis under chow or high-fat diet conditions; muscle-specific Mck-Cre;Ptpn2(lox/lox) mice showed no differences in IR phosphorylation, PI3K/Akt signaling, or metabolic parameters, demonstrating that TCPTP differentially regulates IR in a tissue-specific manner. Muscle-specific Cre/lox PTPN2 knockout, hyperinsulinemic-euglycemic clamps, Western blot for pIR/pAkt Diabetologia Medium 22124607
2015 TCR activation induces PTPN2 expression to restrain IL-2/STAT5 phosphorylation in induced regulatory T cells (iTregs), contributing to FOXP3 loss; knockdown of PTPN2 or expression of phosphorylation-independent active STAT5 restores FOXP3 expression despite TCR signaling and absence of TGFβ. Western blot for pSTAT5, PTPN2 knockdown via siRNA, overexpression of constitutively active STAT5, FOXP3 expression assay Nature communications Medium 26815406

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 917 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 206 31527834
2002 The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. Biochemical and biophysical research communications 196 12359225
2005 Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP. Current opinion in cell biology 193 15780598
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 164 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 151 22404968
2009 PTPN2, a candidate gene for type 1 diabetes, modulates interferon-gamma-induced pancreatic beta-cell apoptosis. Diabetes 145 19336676
2023 The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. Nature 143 37794185
2003 Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP. Molecular and cellular biology 143 12612081
2020 PTPN2 Regulates Interactions Between Macrophages and Intestinal Epithelial Cells to Promote Intestinal Barrier Function. Gastroenterology 126 32652144
2010 An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4(+) T cells. Genes and immunity 126 21179116
2019 PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. The EMBO journal 119 31803974
2005 Involvement of the small protein tyrosine phosphatases TC-PTP and PTP1B in signal transduction and diseases: from diabetes, obesity to cell cycle, and cancer. Biochimica et biophysica acta 115 16198645
2008 PTP1B and TC-PTP: regulators of transformation and tumorigenesis. Cancer metastasis reviews 107 18236007
2014 PTPN2 controls differentiation of CD4⁺ T cells and limits intestinal inflammation and intestinal dysbiosis. Mucosal immunology 95 25492475
2018 PTPN2 Regulates Inflammasome Activation and Controls Onset of Intestinal Inflammation and Colon Cancer. Cell reports 94 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
2012 Phospho-Ser727 of STAT3 regulates STAT3 activity by enhancing dephosphorylation of phospho-Tyr705 largely through TC45. Genes to cells : devoted to molecular & cellular mechanisms 83 22233524
2012 TCPTP regulates SFK and STAT3 signaling and is lost in triple-negative breast cancers. Molecular and cellular biology 83 23166300
2010 MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta-cell responses to the viral by-product double-stranded RNA. Human molecular genetics 82 19825843
2011 PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia. Blood 77 21551237
2009 Protein tyrosine phosphatases PTP-1B and TC-PTP play nonredundant roles in macrophage development and IFN-gamma signaling. Proceedings of the National Academy of Sciences of the United States of America 75 19474293
2016 TC-PTP and PTP1B: Regulating JAK-STAT signaling, controlling lymphoid malignancies. Cytokine 71 26817397
2019 Intranasal Targeting of Hypothalamic PTP1B and TCPTP Reinstates Leptin and Insulin Sensitivity and Promotes Weight Loss in Obesity. Cell reports 70 31509751
2010 Protein tyrosine phosphatases, TC-PTP, SHP1, and SHP2, cooperate in rapid dephosphorylation of Stat3 in keratinocytes following UVB irradiation. PloS one 70 20421975
2023 A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity. Nature communications 69 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
2012 PTPN2 gene variants are associated with susceptibility to both Crohn's disease and ulcerative colitis supporting a common genetic disease background. PloS one 60 22457781
2019 Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity. The Journal of clinical investigation 59 30620725
2001 Cellular stress regulates the nucleocytoplasmic distribution of the protein-tyrosine phosphatase TCPTP. The Journal of biological chemistry 59 11479308
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
2011 Mutation analysis of the tyrosine phosphatase PTPN2 in Hodgkin's lymphoma and T-cell non-Hodgkin's lymphoma. Haematologica 53 21791476
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
2020 PTPN2 Deficiency Enhances Programmed T Cell Expansion and Survival Capacity of Activated T Cells. Cell reports 51 32726622
2018 TRIM59 Promotes Gliomagenesis by Inhibiting TC45 Dephosphorylation of STAT3. Cancer research 50 29386185
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
2022 Matrine suppresses NLRP3 inflammasome activation via regulating PTPN2/JNK/SREBP2 pathway in sepsis. Phytomedicine : international journal of phytotherapy and phytopharmacology 47 36610161
2006 PTP1B and TC-PTP: novel roles in immune-cell signaling. Canadian journal of physiology and pharmacology 43 16998530
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
2017 Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development. Scientific reports 39 28322331
2018 TCPTP Regulates Insulin Signaling in AgRP Neurons to Coordinate Glucose Metabolism With Feeding. Diabetes 38 29712668
2012 Investigation of the vitamin D receptor gene (VDR) and its interaction with protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2) on risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY). The Journal of steroid biochemistry and molecular biology 38 22960018
2017 PTPN2 regulates T cell lineage commitment and αβ versus γδ specification. The Journal of experimental medicine 36 28798028
2022 PTPN2 in the Immunity and Tumor Immunotherapy: A Concise Review. International journal of molecular sciences 35 36077422
2018 T cells are influenced by a long non-coding RNA in the autoimmune associated PTPN2 locus. Journal of autoimmunity 33 29398253
2012 Strain-dependent differences in bone development, myeloid hyperplasia, morbidity and mortality in ptpn2-deficient mice. PloS one 32 22590589
2000 Tc45, a dimorphic Trypanosoma cruzi immunogen with variable chromosomal localization, is calreticulin. The American journal of tropical medicine and hygiene 32 11421383
2018 Polymorphisms in Protein Tyrosine Phosphatase Non-receptor Type 2 and 22 (PTPN2/22) Are Linked to Hyper-Proliferative T-Cells and Susceptibility to Mycobacteria in Rheumatoid Arthritis. Frontiers in cellular and infection microbiology 31 29423382
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
2023 Inhibition of the type 1 diabetes candidate gene PTPN2 aggravates TNF-α-induced human beta cell dysfunction and death. Diabetologia 27 36988639
2021 Crystal Structure of TCPTP Unravels an Allosteric Regulatory Role of Helix α7 in Phosphatase Activity. Biochemistry 27 34910875
2020 PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis. JCI insight 26 33055428
2015 Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1. Nature communications 26 26815406
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 25 24418013
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
2021 Autoimmune susceptibility gene PTPN2 is required for clearance of adherent-invasive Escherichia coli by integrating bacterial uptake and lysosomal defence. Gut 24 33563644
2019 Upregulated PTPN2 induced by inflammatory response or oxidative stress stimulates the progression of thyroid cancer. Biochemical and biophysical research communications 24 31735335
2019 PTPN2 induced by inflammatory response and oxidative stress contributed to glioma progression. Journal of cellular biochemistry 22 31241223
2011 T cell protein tyrosine phosphatase (TCPTP) deficiency in muscle does not alter insulin signalling and glucose homeostasis in mice. Diabetologia 22 22124607
2008 Cell cycle-dependent regulation of SFK, JAK1 and STAT3 signalling by the protein tyrosine phosphatase TCPTP. Cell cycle (Georgetown, Tex.) 22 18948751
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
2021 Ptpn2 and KLRG1 regulate the generation and function of tissue-resident memory CD8+ T cells in skin. The Journal of experimental medicine 20 33914023
2018 Molecular and clinical characterization of PTPN2 expression from RNA-seq data of 996 brain gliomas. Journal of neuroinflammation 20 29764444
2013 Characterization of PTPN2 and its use as a biomarker. Methods (San Diego, Calif.) 20 23994241
2022 TRIM32 promotes radioresistance by disrupting TC45-STAT3 interaction in triple-negative breast cancer. Oncogene 19 35091679
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
2020 The autoimmune susceptibility gene, PTPN2, restricts expansion of a novel mouse adherent-invasive E. coli. Gut microbes 18 32586195
2016 Discovery of novel, high potent, ABC type PTP1B inhibitors with TCPTP selectivity and cellular activity. European journal of medicinal chemistry 18 27123900
2013 Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone. Biochimica et biophysica acta 18 23856547
2013 Associations between PTPN2 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: a meta-analysis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 18 24127071
2011 Potent and selective inhibition of T-cell protein tyrosine phosphatase (TCPTP) by a dinuclear copper(II) complex. Chemical communications (Cambridge, England) 18 22159501
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
2019 Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling. The Journal of biological chemistry 17 31248982
2018 Role of PTPN2/22 polymorphisms in pathophysiology of Crohn's disease. World journal of gastroenterology 17 29456405
2013 Association between the PTPN2 gene and Crohn's disease: dissection of potential causal variants. Inflammatory bowel diseases 17 23518806
2012 Protein tyrosine phosphatases and type 1 diabetes: genetic and functional implications of PTPN2 and PTPN22. The review of diabetic studies : RDS 17 23804260
2009 TC-PTP is required for the maintenance of MYC-driven B-cell lymphomas. Blood 17 19755676
2020 Inflammatory response or oxidative stress induces upregulation of PTPN2 and thus promotes the progression of laryngocarcinoma. European review for medical and pharmacological sciences 16 32373968
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
2012 PTPN2 is associated with Crohn's disease and its expression is regulated by NKX2-3. Disease markers 16 22377701
2019 Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia. Blood advances 15 31270080
2018 PTPN2 deficiency along with activation of nuclear Akt predict endocrine resistance in breast cancer. Journal of cancer research and clinical oncology 15 30515568
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
2016 PASD1 promotes STAT3 activity and tumor growth by inhibiting TC45-mediated dephosphorylation of STAT3 in the nucleus. Journal of molecular cell biology 14 26892021

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