Affinage

PTPN1

Tyrosine-protein phosphatase non-receptor type 1 · UniProt P18031

Length
435 aa
Mass
50.0 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 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

PTPN1 (PTP1B) is an endoplasmic-reticulum-anchored protein tyrosine phosphatase that acts as a spatially partitioned terminator of tyrosine-kinase signaling, dephosphorylating receptor tyrosine kinases (EGFR, PDGFR, EphA3, insulin receptor) at defined cytoplasmic sites only after receptor endocytosis brings them into contact with the ER surface, thereby establishing a steady-state enzyme-substrate gradient that permits signaling in the cytoplasm while ensuring eventual signal extinction (PMID:11872838, PMID:17204654, PMID:21135139, PMID:21707536). Its substrate repertoire extends beyond RTKs to transcriptional effectors and structural regulators: it deactivates prolactin-activated STAT5a/b to block β-casein transcription (PMID:10993888), terminates JAK-STAT signaling in lymphoma where somatic loss-of-function mutations drive oncogenesis (PMID:24531327), and dephosphorylates MITA/STING at Y245 to promote its 20S-proteasomal degradation and attenuate the innate antiviral response (PMID:31527250). At cell-matrix adhesions, ER-bound PTP1B is delivered along microtubules to nascent focal complexes where it dephosphorylates the Src negative-regulatory site (pY529), paxillin, and p130Cas, thereby tuning RhoA/Rac1 balance and supporting focal-complex lifetime, lamellar protrusion, and directional migration (PMID:16522684, PMID:23444382), and a parallel ER-extension mechanism positions it in axonal growth cones to support Src activity and axon elongation (PMID:19158394). In neurons it dephosphorylates β-catenin at Tyr654 within N-cadherin complexes to control dendritic spine morphology and learning, with conditional knockout improving memory (PMID:22844492). PTP1B catalysis is governed by coordinated dynamics of its WPD, Q, E, and substrate-binding loops linked through a conserved CH/π allosteric switch (PMID:28212750, PMID:32737198), and its activity is reversibly tuned by oxidation of the catalytic cysteine—reactivated by thioredoxin-1 through direct thiol-disulfide exchange (PMID:24976139), promoted by bicarbonate-derived peroxymonocarbonate (PMID:31197039), stabilized in the inactive oxidized state by 14-3-3ζ (PMID:31873221), and modulated by O-GlcNAcylation (PMID:26402673). Loss-of-function mutations in PTPN1 occur in Hodgkin lymphoma and primary mediastinal B-cell lymphoma, where reduced phosphatase activity hyperactivates JAK-STAT signaling (PMID:24531327).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 2000 High

    Established that PTP1B is not solely an RTK phosphatase but directly inactivates downstream transcription factors, dephosphorylating prolactin-activated STAT5a/b and blocking their nuclear function.

    Evidence Substrate-trapping co-precipitation, in vitro dephosphorylation, and overexpression with β-casein promoter readout in mammary epithelial cells

    PMID:10993888

    Open questions at the time
    • Did not resolve where in the cell STAT5 dephosphorylation occurs
    • Physiological stoichiometry versus other STAT phosphatases not established
  2. 2002 High

    Resolved the central spatial paradox of how an ER-tethered phosphatase reaches plasma-membrane RTKs, showing dephosphorylation of EGFR and PDGFR requires receptor endocytosis and occurs at defined ER-surface sites.

    Evidence FRET live-cell imaging of PTP1B–RTK interactions across two RTK types

    PMID:11872838

    Open questions at the time
    • Did not quantify the global activity distribution across the cell
    • Trafficking machinery delivering receptors to the ER contact site unspecified
  3. 2006 High

    Defined the delivery mechanism for ER-bound PTP1B to peripheral structures, showing dynamic ER extensions along microtubules target it to immature FAK/paxillin focal complexes.

    Evidence GFP substrate-trapping mutant live imaging, ER-targeting deletion mutants, focal-adhesion marker co-localization, nocodazole

    PMID:16522684

    Open questions at the time
    • Direct adhesion-site substrates not yet identified in this study
    • Selectivity for immature versus mature adhesions mechanistically unexplained
  4. 2007 High

    Generalized the spatial model into a quantitative principle: PTP1B sets a robust steady-state enzyme-substrate gradient permitting cytoplasmic signaling while ensuring termination, independent of cell-to-cell variability.

    Evidence FRET imaging of enzyme-substrate intermediates with quantitative gradient measurement

    PMID:17204654

    Open questions at the time
    • Molecular basis maintaining the gradient not fully resolved
    • Does not address redox or post-translational tuning of the gradient
  5. 2009 Medium

    Extended the ER-extension targeting paradigm to neurons, showing microtubule-dependent positioning of PTP1B in growth cones supports Src activity and axon elongation.

    Evidence Live imaging of GFP-PTP1B, nocodazole, ER marker co-localization, functional impairment

    PMID:19158394

    Open questions at the time
    • Direct growth-cone substrate not biochemically pinned down
    • Single-lab functional impairment without genetic confirmation
  6. 2010 High

    Showed PTP1B regulates Eph receptor signaling amplitude and trafficking, directly dephosphorylating EphA3 at both the plasma membrane and endosomes.

    Evidence FLIM showing direct interaction, substrate-trapping mutant, EphA3 phosphorylation time-course

    PMID:21135139

    Open questions at the time
    • How PTP1B accesses EphA3 at cell-cell contacts pre-internalization unresolved
    • Endocytic adaptor requirement not defined
  7. 2011 High

    Identified the adaptor-based recruitment mechanism for substrate selection, showing the Nck/Dock SH3-SH2 adaptor forms a stable complex with PTP1B and recruits it to the insulin receptor.

    Evidence Reciprocal Co-IP, in vitro IR dephosphorylation, in vivo Drosophila eye-overgrowth rescue, mammalian inducible IR association

    PMID:21707536

    Open questions at the time
    • Whether Nck recruitment generalizes to other RTK substrates not tested
    • Structural basis of the PTP1B–Nck interaction unresolved
  8. 2012 High

    Connected PTP1B to synaptic structure and cognition, identifying β-catenin pY654 in N-cadherin complexes as a neuronal substrate controlling spine morphology and memory.

    Evidence Global and Emx1-Cre conditional KO mice, western blotting, immunofluorescence, Barnes maze behavior

    PMID:22844492

    Open questions at the time
    • Site of β-catenin dephosphorylation within the neuron not localized
    • Link between spine remodeling and improved memory only correlative
  9. 2013 High

    Defined the adhesion-site substrate set and migratory consequence, showing PTP1B targets Src pY529, paxillin, and p130Cas to extend focal-complex lifetime and bias RhoA/Rac1 toward directional migration.

    Evidence FRET, kymography, pull-down, substrate-trapping and active-site mutants, FAK/Src inhibitors

    PMID:23444382

    Open questions at the time
    • Order and interdependence of the three substrate dephosphorylations unresolved
    • Coupling to RhoA/Rac1 GEFs/GAPs not delineated
  10. 2014 High

    Established PTP1B as a tumor suppressor in lymphoid malignancy, showing somatic loss-of-function mutations and silencing hyperactivate JAK-STAT signaling.

    Evidence Genome/transcriptome sequencing, phosphatase activity assays on mutants, RNAi in Hodgkin lymphoma cells, phospho-westerns

    PMID:24531327

    Open questions at the time
    • Which JAK-STAT members are direct substrates versus indirect not fully resolved
    • Tumor-suppressive role context-dependent across cancer types
  11. 2014 High

    Demonstrated direct thioredoxin-1-mediated reactivation of oxidized PTP1B, defining how cells reset phosphatase activity after oxidative inactivation.

    Evidence Mechanism-based thioredoxin-PTP1B trapping, Co-IP, TRX1 inducible depletion in live cells

    PMID:24976139

    Open questions at the time
    • Kinetics relative to ongoing signaling not quantified
    • Competition with other reductants in vivo not addressed
  12. 2015 High

    Linked PTP1B redox/activity control to disease neurobiology, showing MECP2 normally represses PTPN1 and its loss in Rett syndrome elevates PTP1B to impair BDNF/TRKB signaling, reversible by inhibition.

    Evidence MECP2-deficient mice, ChIP of MECP2 at PTPN1, pharmacological inhibition, TRKB phospho-westerns, behavior

    PMID:26214522

    Open questions at the time
    • Whether TRKB is a direct PTP1B substrate not biochemically isolated here
    • Site of TRKB dephosphorylation not mapped
  13. 2015 Medium

    Identified an ER-retention mechanism, showing UBC9-dependent SUMOylation of calnexin modulates calnexin–PTP1B complex formation to hold PTP1B at the ER membrane.

    Evidence Co-IP, SUMOylation assays, UBC9 interaction, ER localization analysis

    PMID:25586181

    Open questions at the time
    • Functional consequence for substrate access not directly tested
    • Single-lab Co-IP without structural mapping of the interface
  14. 2015 Medium

    Added O-GlcNAcylation as a metabolic post-translational input, showing modification at Ser104/201/386 tunes phosphatase activity and downstream insulin signaling.

    Evidence Site-directed mutagenesis, phosphatase activity assays, Akt/GSK3β westerns in HepG2

    PMID:26402673

    Open questions at the time
    • In vivo occupancy of these sites not established
    • Mechanism by which O-GlcNAc alters catalytic activity unresolved
  15. 2015 Medium

    Extended PTP1B function to innate immunity, showing myeloid-specific loss impairs dendritic-cell maturation, CCR7-driven chemotaxis, and Src/podosome organization.

    Evidence LysM-Cre deletion, BMDC functional assays, immunofluorescence, in vivo migration, T-cell co-culture

    PMID:26063615

    Open questions at the time
    • Direct substrate(s) underlying the DC phenotypes not isolated
    • Single-lab study with phenotypic rather than biochemical resolution
  16. 2017 High

    Defined the structural-dynamic logic of catalysis, identifying a conserved CH/π allosteric switch governing WPD-loop positioning through conformational and dynamic allostery.

    Evidence NMR, X-ray crystallography, and MD on WT and ≥10 PTP1B variants

    PMID:28212750

    Open questions at the time
    • Connection of the switch to physiological substrate selectivity not tested
    • Druggability of the allosteric path defined only in vitro
  17. 2017 Medium

    Showed protein stabilization as a regulatory layer in cancer, with HDAC6 binding and stabilizing PTP1B to drive an HDAC6/PTPN1/ERK1/2/MMP9 melanoma progression axis.

    Evidence Co-IP/LC-MS-MS, westerns, proliferation/migration assays, shRNA

    PMID:29278704

    Open questions at the time
    • Whether ERK1/2 activation is via direct or indirect PTP1B action unresolved
    • Mechanism of HDAC6-mediated stabilization not defined
  18. 2017 Medium

    Placed PTPN1 in a synaptic regulatory circuit, showing it is a direct miR-124 target required for GluR2 membrane insertion, plasticity, and memory.

    Evidence AAV/lentiviral overexpression and knockdown, LTP, Golgi staining, Morris water maze, luciferase reporter

    PMID:28965984

    Open questions at the time
    • Substrate linking PTP1B to GluR2 trafficking not identified
    • Single-lab in vivo manipulations
  19. 2018 Medium

    Provided proof-of-concept for trapping oxidized PTP1B therapeutically, showing scFv45 and a mimicking small molecule lock the oxidized inactive conformation to enhance insulin and leptin signaling.

    Evidence Structural analysis of scFv45–oxidized PTP1B, small-molecule screening, signaling assays

    PMID:29348454

    Open questions at the time
    • In vivo efficacy and selectivity of the small molecule not established
    • Single-lab structural and functional validation
  20. 2019 High

    Identified an antiviral-attenuation substrate, showing PTP1B (with PTPN2) dephosphorylates MITA/STING at Y245 to drive its ubiquitin-independent 20S degradation.

    Evidence Co-IP, Y245 mutagenesis, proteasome inhibitors, PTPN1/2 KO with antiviral gene readout

    PMID:31527250

    Open questions at the time
    • How dephosphorylation routes STING to the 20S proteasome mechanistically unclear
    • Relative contributions of PTPN1 versus PTPN2 not separated
  21. 2019 Medium

    Identified 14-3-3ζ as a binding partner that stabilizes oxidized inactive PTP1B, required for full ROS-mediated inactivation in cells.

    Evidence Co-IP/pulldown, mass spectrometry, phospho-EGFR readout after complex disruption

    PMID:31873221

    Open questions at the time
    • Structural basis of 14-3-3ζ recognition of oxidized PTP1B unresolved
    • Single-lab interaction study
  22. 2019 High

    Linked acid-base chemistry to redox regulation, showing bicarbonate forms peroxymonocarbonate to facilitate H2O2-mediated PTP1B oxidation, with cellular oxidation bicarbonate-dependent.

    Evidence In vitro assays with recombinant PTP1B, cellular bicarbonate manipulation, EGF-stimulated A431 oxidation measurement

    PMID:31197039

    Open questions at the time
    • Spatial coupling of bicarbonate flux to local PTP1B inactivation not mapped
    • Generality across other PTPs not addressed
  23. 2019 Medium

    Connected PTP1B to metabolic-oncogenic signaling, showing PKM2 Tyr105 is a substrate whose dephosphorylation modulates AMPK/mTORC1 and pancreatic cancer growth.

    Evidence shRNA, small-molecule inhibitor, phospho-westerns, in vitro and in vivo tumor assays

    PMID:31745071

    Open questions at the time
    • Direct versus indirect dephosphorylation of PKM2 not fully resolved
    • Single-lab study
  24. 2020 High

    Established a coordinated multi-loop dynamic model of catalysis, showing WPD, Q, E, and substrate-binding loops plus the N-terminal helix move as a dynamically unified system across timescales.

    Evidence 13C-methyl ILV NMR relaxation and CPMG relaxation dispersion

    PMID:32737198

    Open questions at the time
    • Direct linkage of these dynamics to turnover rate not quantified
    • Effect of substrate binding on the coordinated motion not fully mapped
  25. 2020 Medium

    Identified PTP1B protein turnover by calpain and a tumor-suppressive substrate set, showing CAPN1 degrades PTP1B and PTP1B dephosphorylates c-Met and PIK3R2 to suppress lung adenocarcinoma growth and erlotinib resistance.

    Evidence Co-IP, cycloheximide chase, phospho-westerns, proliferation/colony/transwell assays, shRNA and overexpression

    PMID:32395869

    Open questions at the time
    • Whether c-Met and PIK3R2 are direct substrates not biochemically confirmed
    • Single-lab study
  26. 2022 Medium

    Linked PTP1B inhibition to neutrophil immunomodulation, showing inhibition suppresses NET formation and migration via reduced CXCR4–PI3Kγ/AKT/mTOR signaling in TRALI and sepsis models.

    Evidence PTP1B inhibitor in TRALI and LPS/CLP models, pathway phospho-analysis, neutrophil functional assays

    PMID:35866483

    Open questions at the time
    • Direct PTP1B substrate in the CXCR4 pathway not identified
    • Pharmacological inhibition rather than genetic deletion
  27. 2023 High

    Revealed temperature-dependent conformational landscapes relevant to drug discovery, showing room-temperature crystallography exposes binding modes and allosteric sites missed by cryogenic structures.

    Evidence Room-temperature X-ray fragment screens versus cryogenic comparison

    PMID:36881464

    Open questions at the time
    • Functional/cellular consequence of the newly revealed sites untested
    • Translation to in vivo inhibitor efficacy not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse regulatory inputs—redox oxidation/reactivation, 14-3-3ζ binding, O-GlcNAcylation, ER retention, adaptor recruitment, and proteolytic turnover—are integrated in real time to set substrate-specific PTP1B activity across the gradient remains unresolved.
  • No unified model coupling redox state to substrate-specific spatial activity
  • Quantitative hierarchy among the post-translational regulators unknown
  • Whether distinct substrate pools require distinct recruitment/retention mechanisms untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016787 hydrolase activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005783 endoplasmic reticulum 5 GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
CANXCAPN1HDAC6NCK1STING1TXNUBE2IYWHAZ

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 PTP1B-catalyzed dephosphorylation of receptor tyrosine kinases (EGFR and PDGFR) requires endocytosis of the receptors and occurs at specific sites on the cytoplasmic surface of the endoplasmic reticulum, demonstrating that RTK activation and inactivation are spatially and temporally partitioned within cells. Fluorescence resonance energy transfer (FRET) live-cell imaging of PTP1B–RTK interactions Science High 11872838
2000 PTP1B specifically dephosphorylates and deactivates prolactin-activated STAT5a and STAT5b, inhibiting their nuclear translocation and downstream transcriptional activation of the beta-casein gene promoter; substrate-trapping mutants of PTP1B co-precipitated tyrosine-phosphorylated STAT5 proteins. Substrate-trapping co-precipitation, overexpression in COS7 cells, in vitro dephosphorylation assay, retrovirus-mediated overexpression in mammary epithelial cells The Journal of Biological Chemistry High 10993888
2007 PTP1B activity is spatially regulated across the cell, establishing a steady-state enzyme-substrate gradient; this gradient is robust to cell-to-cell variability, growth factor activation, and RTK localization, and the ER-localized enzyme allows RTK signaling in the cytoplasm while mediating eventual signal termination. FRET-based live-cell imaging of enzyme-substrate intermediates Science High 17204654
2010 PTP1B directly interacts with and dephosphorylates EphA3 receptor, governing its signaling amplitude and duration; PTP1B interacts with EphA3 at the plasma membrane at cell-cell contacts before ligand-stimulated internalization and on endosomes after internalization, and overexpression of wild-type or substrate-trapping PTP1B decelerates EphA3 trafficking and controls its cell-surface concentration. Confocal fluorescence lifetime imaging microscopy (FLIM), overexpression of wild-type and D-A substrate-trapping mutant, EphA3 phosphorylation time-course assay The Journal of Cell Biology High 21135139
2006 ER-bound PTP1B is targeted to newly forming cell-matrix adhesion sites via dynamic ER extensions along microtubules; deletion of the ER-targeting sequence relocalizes PTP1B to the cytosol and alters its distribution at cell-matrix foci; PTP1B preferentially associates with FAK- and paxillin-containing immature focal complexes rather than zyxin-containing mature foci. GFP-PTP1B substrate-trapping mutant (D181A) live imaging, deletion mutants, co-localization with focal adhesion markers, nocodazole treatment Journal of Cell Science High 16522684
2013 PTP1B enhances focal complex lifetime, facilitates α-actinin incorporation, and contributes to lamellar protrusion persistence and directional migration; PTP1B targets the negative regulatory site of Src (pY529), paxillin, and p130Cas at peripheral cell-matrix adhesions; PTP1B is required for integrin-dependent downregulation of RhoA and upregulation of Rac1 during spreading. Kymograph analysis, pull-down, FRET, substrate-trapping mutant (D181A), FAK/Src inhibitors, active-site mutant Journal of Cell Science High 23444382
2009 In hippocampal axonal growth cones, PTP1B localizes to the central domain and peripheral region via ER extensions along microtubules; microtubule disruption by nocodazole redistributes PTP1B to the growth cone base; functional impairment of PTP1B reduces axon elongation, decreases filopodia lifetime, and diminishes Src activity in growth cones. Live imaging of GFP-PTP1B, nocodazole treatment, ER marker co-localization, functional impairment of PTP1B Molecular Biology of the Cell Medium 19158394
2012 PTP1B dephosphorylates β-catenin at Tyr-654 in N-cadherin complexes in hippocampal neurons; PTP1B deficiency leads to ~5-fold increased β-catenin pY654 and reduced N-cadherin association with β-catenin, increased filopodia-like dendritic spines, reduced mushroom spines, and disorganized pre- and post-synaptic markers; hippocampus/cortex-specific PTP1B knockout mice show improved learning and memory in the Barnes maze. PTP1B(-/-) mouse model, hippocampus/cortex-specific conditional knockout (Emx1-Cre), western blotting, immunofluorescence, Barnes maze behavioral testing PloS One High 22844492
2019 PTPN1 (PTP1B) and PTPN2 associate with MITA/STING following viral infection and dephosphorylate MITA/STING at Y245; this dephosphorylation promotes MITA/STING degradation via the ubiquitin-independent 20S proteasomal pathway in an intrinsically disordered region (IDR)-dependent manner, thereby attenuating innate antiviral response. Co-immunoprecipitation, site-directed mutagenesis (Y245), proteasome inhibitor assays, PTPN1/2 deficiency with antiviral gene expression readout Proceedings of the National Academy of Sciences of the United States of America High 31527250
2014 Oxidized (inactive) PTP1B is preferentially reactivated by thioredoxin 1 (TRX1) via direct thiol-disulfide exchange between the active sites; inducible depletion of TRX1 slows PTP1B reactivation in intact living cells; demonstrated by mechanism-based thioredoxin trapping mutants that directly co-immunoprecipitate with PTP1B. Mechanism-based trapping of thioredoxin–PTP1B complexes, anti-tag co-immunoprecipitation, TRX1 inducible depletion in live cells The FEBS Journal High 24976139
2019 14-3-3ζ interacts with the reversibly oxidized (inactive) form of PTP1B; destabilizing this interaction prevents PTP1B inactivation by reactive oxygen species and decreases EGFR phosphorylation, establishing that the 14-3-3ζ–oxidized PTP1B complex is required for full ROS-mediated PTP1B inactivation in cells. Molecular interaction studies (co-immunoprecipitation/pulldown), phospho-EGFR readout after complex disruption, mass spectrometry Nature Chemical Biology Medium 31873221
2019 Bicarbonate facilitates H2O2-mediated PTP1B inactivation by forming the more reactive peroxymonocarbonate; EGF-induced cellular oxidation of PTP1B and total protein phosphotyrosine levels are completely dependent on intracellular bicarbonate concentration, linking cellular acid-base balance to PTP1B redox regulation. In vitro biochemical assays with purified recombinant PTP1B, cellular bicarbonate manipulation, EGF-stimulated A431 cells, PTP1B oxidation measurement The Journal of Biological Chemistry High 31197039
2018 A recombinant antibody (scFv45) that specifically recognizes oxidized, inactive PTP1B stabilizes it in an inactive conformation, providing proof-of-concept that small molecules mimicking scFv45 can promote insulin and leptin signaling by locking PTP1B in an oxidized state; a small molecule mimicking scFv45 was identified that reproduces this effect. Structural analysis of scFv45–oxidized PTP1B complex, small molecule screening, insulin and leptin signaling assays Nature Communications Medium 29348454
2017 PTP1B uses a CH/π switch (evolutionarily conserved) critical for positioning the catalytically important WPD loop, and employs both conformational and dynamic allostery to regulate its activity; these mechanisms were defined by combining NMR, crystallography, and computational data on wild-type and ≥10 PTP1B variants. NMR spectroscopy, X-ray crystallography, molecular dynamics simulations on WT and multiple PTP1B variants Molecular Cell High 28212750
2020 All four catalytically important loops of PTP1B (WPD, Q, E, and substrate-binding loops) work in dynamic unity throughout the catalytic cycle; slow N-terminal helix dynamics, fast side-chain dynamics, and μs–ms conformational exchange of all key loops are dynamically coordinated, not independent. 13C-methyl ILV NMR relaxation studies, constant-time CPMG relaxation dispersion measurements The Journal of Biological Chemistry High 32737198
2015 PTP1B is a negative regulator of tyrosine phosphorylation of TRKB (the BDNF receptor); elevated PTP1B in Rett syndrome models (due to MECP2 disruption, which removes MECP2-mediated repression of the PTPN1 gene) impairs BDNF/TRKB signaling; pharmacological PTP1B inhibition increases TRKB tyrosine phosphorylation in brain and improves Rett syndrome phenotypes in mice. MECP2-deficient mouse models, pharmacological PTP1B inhibition, TRKB phosphorylation western blotting, behavioral assays, ChIP/promoter analysis for MECP2 at PTPN1 locus The Journal of Clinical Investigation High 26214522
2014 Somatic loss-of-function mutations in PTPN1 in Hodgkin lymphoma and PMBCL lead to reduced PTP1B phosphatase activity and increased phosphorylation of JAK-STAT pathway members; RNAi silencing of PTPN1 in Hodgkin lymphoma cells causes hyperphosphorylation of downstream oncogenic targets, establishing PTP1B as a negative regulator of JAK-STAT signaling in these lymphomas. Whole-genome and whole-transcriptome sequencing, phosphatase activity assays on mutant proteins, RNA interference in Hodgkin lymphoma cell lines, phospho-western blotting Nature Genetics High 24531327
2011 The Drosophila PTP1B orthologue PTP61F dephosphorylates the insulin receptor (IR) in S2 cells and attenuates IR-induced eye overgrowth in vivo; the SH3/SH2 adaptor protein Dock (Drosophila) / Nck (mammalian) forms a stable complex with PTP61F/PTP1B and recruits PTP1B to the IR in response to insulin, which is required for efficient IR dephosphorylation and inactivation. Co-immunoprecipitation, in vitro IR dephosphorylation assay in S2 cells, in vivo Drosophila eye overgrowth assay, mammalian cell-based inducible IR association assay The Biochemical Journal High 21707536
2002 Sprouty 2 (hSPRY2) mediates anti-migratory (but not anti-mitogenic) effects by increasing soluble PTP1B amount and activity; overexpression of catalytically active but not inactive (C215S) PTP1B mimics the anti-migratory action of hSPRY2; the C215S catalytically inactive mutant attenuated the anti-migratory effects of hSPRY2. Subcellular fractionation, PTP activity assay, wild-type vs. C215S mutant overexpression, cell migration assay in HeLa cells The Journal of Biological Chemistry Medium 12414790
2015 Calnexin and PTP1B form UBC9-dependent complexes at the endoplasmic reticulum; SUMOylation of the calnexin cytoplasmic domain by UBC9 modulates calnexin's interaction with PTP1B, revealing a role of the SUMOylation machinery in retaining PTP1B at the ER membrane. Co-immunoprecipitation, SUMOylation assays, UBC9 interaction studies, ER localization analysis The Journal of Biological Chemistry Medium 25586181
2015 PTP1B deficiency in dendritic cells leads to increased phospho-STAT3, decreased CCR7 expression, impaired chemotaxis to CCL19, fewer podosomes, increased phosphorylation of Src at Y527, loss of Src localization to podosome puncta, fewer and shorter DC-T cell contacts, and impaired antigen presentation to T cells; establishing PTP1B as a regulator of dendritic cell maturation, migration, and T cell activation. Myeloid-specific genetic deletion (LysM-Cre), bone marrow-derived DC functional assays, immunofluorescence, in vivo migration assay, T cell co-culture antigen presentation assay Journal of Molecular Cell Biology Medium 26063615
2015 O-GlcNAcylation of PTP1B at Ser104, Ser201, and Ser386 modulates its phosphatase activity; site-directed mutation of these O-GlcNAc sites reduces PTP1B phosphatase activity, resulting in higher Akt and GSK3β phosphorylation and improved insulin sensitivity in HepG2 cells. Site-directed mutagenesis of O-GlcNAc sites, PTP1B phosphatase activity assay, western blotting for downstream signaling in HepG2 cells International Journal of Molecular Sciences Medium 26402673
2019 PTP1B directly increases PKM2 Tyr-105 phosphorylation when inhibited (i.e., PKM2 pY105 is a PTP1B substrate); PTP1B inhibition activates AMPK and decreases mTORC1 activity through PKM2/AMPK signaling, linking PTP1B's dephosphorylation of PKM2 to the control of pancreatic cancer cell growth. shRNA knockdown, small-molecule PTP1B inhibitor, phospho-western blotting, in vitro and in vivo tumor growth assays Cell Death & Disease Medium 31745071
2017 PTPN1 is a direct target of miR-124; overexpression of miR-124 or knockdown of PTPN1 impairs glutamate receptor 2 (GluR2) membrane insertion, causing synaptic transmission and plasticity deficits and memory loss in mice; restoration of PTPN1 or suppression of miR-124 rescues these phenotypes. Adeno-associated virus / lentivirus-mediated overexpression and knockdown, LTP measurements, Golgi staining, Morris water maze, luciferase reporter for miR-124/PTPN1 interaction Biological Psychiatry Medium 28965984
2014 Curcumin physically interacts with PTPN1/PTP1B to increase its phosphatase activity, leading to dephosphorylation of cortactin at pTyr421; PTPN1 inhibition eliminates curcumin's effects on pTyr421-cortactin and cell migration in colon cancer cells. Surface biotinylation, mass spectrometry, western blotting, PTP1B activity assay, siRNA knockdown, cell migration assay PloS One Medium 24465712
2017 HDAC6 directly interacts with PTPN1 (PTP1B), stabilizing its protein level independently of HDAC6's histone-modifying activity; PTPN1 promotes melanoma cell proliferation, colony formation, migration, and ERK1/2 activation; HDAC6 enhances aggressive melanoma progression via the HDAC6/PTPN1/ERK1/2/MMP9 axis. Co-immunoprecipitation combined with LC-MS/MS, western blotting, cell proliferation/migration assays, shRNA knockdown Biochemical and Biophysical Research Communications Medium 29278704
2020 CAPN1 (calpain 1) promotes degradation of PTPN1 protein; PTPN1 mediates dephosphorylation of c-Met and PIK3R2 by direct binding, thereby suppressing cell proliferation, metastasis, and erlotinib resistance in lung adenocarcinoma cells; CAPN1-mediated PTPN1 degradation relieves this suppression. Co-IP, cycloheximide chase (protein synthesis block), phospho-western blotting, CCK-8/colony/transwell assays, shRNA and overexpression Thoracic Cancer Medium 32395869
2019 Inhibition of PTP1B in the TRALI mouse model attenuates aberrant neutrophil function, releases myeloperoxidase, suppresses NET formation, and inhibits neutrophil migration; mechanistically, reduced CXCR4 signaling—particularly via PI3Kγ/AKT/mTOR—is essential for these effects, linking PTP1B inhibition to promotion of an aged-neutrophil phenotype. PTP1B inhibitor treatment in TRALI and LPS/CLP sepsis mouse models, PI3Kγ/AKT/mTOR phosphorylation analysis, neutrophil functional assays (NET, migration, myeloperoxidase) JCI Insight Medium 35866483
2023 Room-temperature (RT) X-ray crystallography of PTP1B reveals distinct protein-ligand conformational states compared to cryogenic structures: at RT, fewer ligands bind and often more weakly, with different binding poses, altered solvation, new binding sites, and distinct allosteric conformational responses, indicating that cryo-structures provide an incomplete picture of PTP1B-ligand interactions. Room-temperature X-ray crystallographic screens of PTP1B with diverse small-molecule fragment libraries; comparison to cryogenic structures eLife High 36881464

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 PTP1B as a drug target: recent developments in PTP1B inhibitor discovery. Drug discovery today 450 17467573
2002 PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proceedings of the National Academy of Sciences of the United States of America 354 12169659
2002 Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science (New York, N.Y.) 347 11872838
2003 PTP1B: from the sidelines to the front lines! FEBS letters 295 12829250
2010 PTP1B: a double agent in metabolism and oncogenesis. Trends in biochemical sciences 228 20381358
2017 A Novel MicroRNA-124/PTPN1 Signal Pathway Mediates Synaptic and Memory Deficits in Alzheimer's Disease. Biological psychiatry 173 28965984
2009 The two faces of PTP1B in cancer. Biochimica et biophysica acta 163 19782770
2014 Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nature genetics 152 24531327
2012 PTP1B and TCPTP--nonredundant phosphatases in insulin signaling and glucose homeostasis. The FEBS journal 151 22404968
2013 PTP1B: a simple enzyme for a complex world. Critical reviews in biochemistry and molecular biology 148 23879520
2023 The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. Nature 143 37794185
2000 A cytosolic protein-tyrosine phosphatase PTP1B specifically dephosphorylates and deactivates prolactin-activated STAT5a and STAT5b. The Journal of biological chemistry 139 10993888
2001 Protein-tyrosine phosphatase 1B (PTP1B): a novel therapeutic target for type 2 diabetes mellitus, obesity and related states of insulin resistance. Current drug targets. Immune, endocrine and metabolic disorders 119 12477292
2017 Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery. Molecular cell 115 28212750
2007 Live-cell imaging of enzyme-substrate interaction reveals spatial regulation of PTP1B. Science (New York, N.Y.) 113 17204654
2008 PTP1B and TC-PTP: regulators of transformation and tumorigenesis. Cancer metastasis reviews 107 18236007
2022 Human Protein Tyrosine Phosphatase 1B (PTP1B): From Structure to Clinical Inhibitor Perspectives. International journal of molecular sciences 106 35806030
2020 Recent advance on PTP1B inhibitors and their biomedical applications. European journal of medicinal chemistry 103 32416458
2014 PTP1B inhibitors for type 2 diabetes treatment: a patent review (2011 - 2014). Expert opinion on therapeutic patents 98 25120222
2013 Protein tyrosine phosphatase 1B (PTP1B) and obesity. Vitamins and hormones 97 23374726
2015 PTP1B inhibition suggests a therapeutic strategy for Rett syndrome. The Journal of clinical investigation 92 26214522
2013 MiRNA-362-3p induces cell cycle arrest through targeting of E2F1, USF2 and PTPN1 and is associated with recurrence of colorectal cancer. International journal of cancer 88 23280316
2014 Reactivation of oxidized PTP1B and PTEN by thioredoxin 1. The FEBS journal 86 24976139
2022 The role of protein tyrosine phosphatase 1B (PTP1B) in the pathogenesis of type 2 diabetes mellitus and its complications. Journal of physiology and biochemistry 76 34988903
2019 PTPN1/2-mediated dephosphorylation of MITA/STING promotes its 20S proteasomal degradation and attenuates innate antiviral response. Proceedings of the National Academy of Sciences of the United States of America 74 31527250
2010 In control at the ER: PTP1B and the down-regulation of RTKs by dephosphorylation and endocytosis. Trends in cell biology 73 20864346
2016 TC-PTP and PTP1B: Regulating JAK-STAT signaling, controlling lymphoid malignancies. Cytokine 71 26817397
2019 Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway. Cell death & disease 69 31745071
2023 Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B. eLife 64 36881464
2010 PTP1B regulates Eph receptor function and trafficking. The Journal of cell biology 57 21135139
2019 PTP1b Inhibition, A Promising Approach for the Treatment of Diabetes Type II. Current topics in medicinal chemistry 56 30714526
2006 ER-bound PTP1B is targeted to newly forming cell-matrix adhesions. Journal of cell science 55 16522684
2018 PTP1B markedly promotes breast cancer progression and is regulated by miR-193a-3p. The FEBS journal 54 30548198
2016 The design strategy of selective PTP1B inhibitors over TCPTP. Bioorganic & medicinal chemistry 54 27353889
2019 Bicarbonate is essential for protein-tyrosine phosphatase 1B (PTP1B) oxidation and cellular signaling through EGF-triggered phosphorylation cascades. The Journal of biological chemistry 53 31197039
2021 Recent advances in PTP1B signaling in metabolism and cancer. Bioscience reports 52 34726241
2020 Correcting abnormalities in miR-124/PTPN1 signaling rescues tau pathology in Alzheimer's disease. Journal of neurochemistry 52 31951013
2019 Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential anti-diabetes agents: patent review (2015-2018). Expert opinion on therapeutic patents 52 31402706
2012 Protein tyrosine phosphatase PTP1B is involved in hippocampal synapse formation and learning. PloS one 51 22844492
2022 Protein tyrosine phosphatase 1B (PTP1B) as a potential therapeutic target for neurological disorders. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 50 36126456
2018 Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development. Nature communications 50 29348454
2017 Inhibition of protein tyrosine phosphatase (PTP1B) and α-glucosidase by geranylated flavonoids from Paulownia tomentosa. Journal of enzyme inhibition and medicinal chemistry 46 28933230
2002 Protein-tyrosine phosphatase-1B (PTP1B) mediates the anti-migratory actions of Sprouty. The Journal of biological chemistry 46 12414790
2006 PTP1B and TC-PTP: novel roles in immune-cell signaling. Canadian journal of physiology and pharmacology 43 16998530
2006 Analysis of common PTPN1 gene variants in type 2 diabetes, obesity and associated phenotypes in the French population. BMC medical genetics 42 16677372
2022 circMAP3K4 regulates insulin resistance in trophoblast cells during gestational diabetes mellitus by modulating the miR-6795-5p/PTPN1 axis. Journal of translational medicine 41 35449053
2015 Protein tyrosine phosphatase 1B (PTP1B): A key regulator and therapeutic target in liver diseases. Toxicology 41 26299811
2005 Association testing of the protein tyrosine phosphatase 1B gene (PTPN1) with type 2 diabetes in 7,883 people. Diabetes 41 15919813
2012 Endoplasmic reticulum stress and the on site function of resident PTP1B. Biochemical and biophysical research communications 39 22609202
2019 PTP1B promotes macrophage activation by regulating the NF-κB pathway in alcoholic liver injury. Toxicology letters 37 31711802
2024 Protein tyrosine phosphatase 1B (PTP1B) function, structure, and inhibition strategies to develop antidiabetic drugs. FEBS letters 36 38724486
2015 Protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and glucosidase inhibitory activity of compounds isolated from Agrimonia pilosa. Pharmaceutical biology 36 26084800
2019 Curcumin and Cinnamaldehyde as PTP1B Inhibitors With Antidiabetic and Anticancer Potential. Anticancer research 34 30711953
2014 Ventromedial hypothalamus-specific Ptpn1 deletion exacerbates diet-induced obesity in female mice. The Journal of clinical investigation 34 25083988
2012 The Genetics of PTPN1 and Obesity: Insights from Mouse Models of Tissue-Specific PTP1B Deficiency. Journal of obesity 34 22811891
2019 PTPN1 promotes the progression of glioma by activating the MAPK/ERK and PI3K/AKT pathways and is associated with poor patient survival. Oncology reports 32 31173266
2019 Inhibitors of Protein Tyrosine Phosphatase PTP1B With Anticancer Potential. Anticancer research 32 31262859
2019 Regulation of PTP1B activation through disruption of redox-complex formation. Nature chemical biology 32 31873221
2015 Novel PTP1B inhibitors identified by DNA display of fragment pairs. Bioorganic & medicinal chemistry letters 32 26691757
2011 Protein Tyrosine Phosphatase 1B (PTP1B) deficiency accelerates hepatic regeneration in mice. The American journal of pathology 32 21406170
2020 Cooperative dynamics across distinct structural elements regulate PTP1B activity. The Journal of biological chemistry 31 32737198
2022 PTP1B inhibitors protect against acute lung injury and regulate CXCR4 signaling in neutrophils. JCI insight 30 35866483
2014 Walnut leaf extract inhibits PTP1B and enhances glucose-uptake in vitro. Journal of ethnopharmacology 30 24548753
2021 Diarylheptanoid-chalcone hybrids with PTP1B and α-glucosidase dual inhibition from Alpinia katsumadai. Bioorganic chemistry 29 33545534
2015 The Role of PTP1B O-GlcNAcylation in Hepatic Insulin Resistance. International journal of molecular sciences 29 26402673
2014 pTyr421 cortactin is overexpressed in colon cancer and is dephosphorylated by curcumin: involvement of non-receptor type 1 protein tyrosine phosphatase (PTPN1). PloS one 29 24465712
2011 PTP1B expression contributes to gastric cancer progression. Medical oncology (Northwood, London, England) 29 21442314
2020 Protein Tyrosine Phosphatase (PTP1B): A promising Drug Target Against Life-threatening Ailments. Current molecular pharmacology 28 31339082
2020 Potential Inhibitors of Protein Tyrosine Phosphatase (PTP1B) Enzyme: Promising Target for Type-II Diabetes Mellitus. Current topics in medicinal chemistry 28 32888269
2011 Dock/Nck facilitates PTP61F/PTP1B regulation of insulin signalling. The Biochemical journal 28 21707536
2019 Inhibition of PTP1B Promotes M2 Polarization via MicroRNA-26a/MKP1 Signaling Pathway in Murine Macrophages. Frontiers in immunology 27 31474996
2017 A novel PTPN1 splice variant upregulates JAK/STAT activity in classical Hodgkin lymphoma cells. Blood 27 28082443
2015 A key role for PTP1B in dendritic cell maturation, migration, and T cell activation. Journal of molecular cell biology 27 26063615
2022 Small extracellular vesicles from Ptpn1-deficient macrophages alleviate intestinal inflammation by reprogramming macrophage polarization via lactadherin enrichment. Redox biology 26 36462232
2013 PTP1B promotes focal complex maturation, lamellar persistence and directional migration. Journal of cell science 26 23444382
2020 Protein tyrosine phosphatase 1B (PTP1B) inhibitorsfrom the deep-sea fungus Penicillium chrysogenum SCSIO 07007. Bioorganic chemistry 25 32036160
2017 HDAC6 interacts with PTPN1 to enhance melanoma cells progression. Biochemical and biophysical research communications 25 29278704
2024 Protein Tyrosine Phosphatase 1B (PTP1B): A Comprehensive Review of Its Role in Pathogenesis of Human Diseases. International journal of molecular sciences 24 39000142
2015 PTP1B confers liver fibrosis by regulating the activation of hepatic stellate cells. Toxicology and applied pharmacology 24 26739621
2024 Native dynamics and allosteric responses in PTP1B probed by high-resolution HDX-MS. Protein science : a publication of the Protein Society 23 38801229
2019 Pristimerin inhibits glioma progression by targeting AGO2 and PTPN1 expression via miR-542-5p. Bioscience reports 23 31015365
2014 Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction. Biochemical pharmacology 23 25451690
2021 Pyrazoles as novel protein tyrosine phosphatase 1B (PTP1B) inhibitors: An in vitro and in silico study. International journal of biological macromolecules 22 33857515
2020 Identification of natural products as selective PTP1B inhibitors via virtual screening. Bioorganic chemistry 22 32199302
2020 CAPN1 promotes malignant behavior and erlotinib resistance mediated by phosphorylation of c-Met and PIK3R2 via degrading PTPN1 in lung adenocarcinoma. Thoracic cancer 22 32395869
2017 Inhibition of PTP1B disrupts cell-cell adhesion and induces anoikis in breast epithelial cells. Cell death & disease 22 28492548
2023 A comprehensive review on the research progress of PTP1B inhibitors as antidiabetics. Chemical biology & drug design 21 37232059
2015 UBC9-dependent association between calnexin and protein tyrosine phosphatase 1B (PTP1B) at the endoplasmic reticulum. The Journal of biological chemistry 20 25586181
2009 Microtubule and cell contact dependency of ER-bound PTP1B localization in growth cones. Molecular biology of the cell 20 19158394
2010 3D nuclear organization of telomeres in the Hodgkin cell lines U-HO1 and U-HO1-PTPN1: PTPN1 expression prevents the formation of very short telomeres including "t-stumps". BMC cell biology 19 21144060
2016 PTP1B inhibitor promotes endothelial cell motility by activating the DOCK180/Rac1 pathway. Scientific reports 18 27052191
2013 Protein tyrosine phosphatase PTP1B in cell adhesion and migration. Cell adhesion & migration 18 24104540
2022 Allosteric Inhibition of PTP1B by a Nonpolar Terpenoid. The journal of physical chemistry. B 17 36223525
2012 Protein tyrosine phosphatase 1B (PTP1B) modulates palmitate-induced cytokine production in macrophage cells. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 17 23229720
2021 Ketamine's schizophrenia-like effects are prevented by targeting PTP1B. Neurobiology of disease 16 34015491
2019 Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes. Science translational medicine 16 31217339
2018 PTP1B promotes the malignancy of ovarian cancer cells in a JNK-dependent mechanism. Biochemical and biophysical research communications 16 29928877
2020 The antidiabetic drug lobeglitazone has the potential to inhibit PTP1B activity. Bioorganic chemistry 15 32422389
2019 Honey extracts inhibit PTP1B, upregulate insulin receptor expression, and enhance glucose uptake in human HepG2 cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 15 30927676
2021 Licoricidin Abrogates T-Cell Activation by Modulating PTPN1 Activity and Attenuates Atopic Dermatitis In Vivo. The Journal of investigative dermatology 14 33857487

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