Tyrosine-protein phosphatase non-receptor type 7 · UniProt P35236
PTPN7 (HePTP/LC-PTP) is a hematopoietic cytoplasmic protein-tyrosine phosphatase that functions as a dedicated negative regulator of MAP kinase signaling (PMID:1510684, PMID:10702794). It docks onto ERK1/2 and p38 (but not JNK) through a noncatalytic N-terminal kinase-interaction motif (KIM), and through this engagement dephosphorylates ERK2 at its activation-loop tyrosine, identifying ERK2 as its specific direct substrate (PMID:10206983, PMID:10702794). By retaining dephosphorylated ERK2 in the cytosol, PTPN7 limits ERK2 nuclear translocation and the downstream transcriptional output (NFAT/AP-1), thereby dampening T-cell activation and shaping megakaryocytic differentiation (PMID:9624114, PMID:12592337). The phosphatase activity is dynamically gated: PKA phosphorylates the KIM at Ser-23 to drive MAPK dissociation, and PP1 reverses this mark, so that the writer/eraser pair continuously toggles PTPN7–MAPK association in response to cAMP-elevating signals such as prostaglandin E2 (PMID:14613483). PTPN7 also assembles into a cholesterol-sensitive ~440 kDa complex with PP2A that confers dual-specificity (pTyr and pThr) ERK phosphatase activity, an arrangement disrupted by cholesterol depletion (PMID:12773382). Structural studies define a classical PTP1B-like catalytic fold whose cycle depends on coordinated WPD- and E-loop dynamics, with the ERK2:HePTP complex reorganizing from an extended, dynamic resting state to a compact active conformation upon ERK2 phosphorylation (PMID:16226275, PMID:21094165, PMID:21985012). Physiologically, PTPN7 restrains GPCR-driven ERK1/2 signaling and thromboxane A2 generation in platelets (PMID:31266805), and a distinct role in dephosphorylating GSK3β to activate Wnt/β-catenin signaling has been described in triple-negative breast cancer cells (PMID:31545274).
Established the molecular identity of PTPN7 as a hematopoietic-restricted cytoplasmic phosphatase, defining the protein class before any function was known.
Evidence cDNA cloning, Northern blot, and sequence analysis
Linked PTPN7 to immune-receptor signaling by showing it occupies discrete cytoplasmic compartments and becomes tyrosine-phosphorylated in a Ca2+-dependent manner after IgE receptor aggregation.
Evidence Immunofluorescence and 2D electrophoresis in stimulated rat mast cells
Identified the MAPK arm targeted by PTPN7, showing it selectively suppresses ERK2 and downstream NFAT/AP-1 transcription in TCR signaling, dependent on catalytic activity.
Evidence Reporter assays and phospho-ERK blots with WT vs catalytically dead C270S in T cells
Mapped the docking determinant, showing the noncatalytic N-terminus mediates association with ERK1/2 and p38 but not JNK.
Evidence Co-IP, deletion mutants, and kinase assays in intact T cells
Proved ERK2 is the specific direct substrate via phosphorylation-dependent substrate trapping and in vitro activation-loop tyrosine dephosphorylation, with the N-terminal region required for interaction.
Evidence Substrate-trapping C/S and D/A mutants, Co-IP, and in vitro phosphatase assay
Revealed that PTPN7 acts beyond a solo tyrosine phosphatase by forming a cholesterol-dependent ~440 kDa PP2A complex with combined pTyr/pThr ERK phosphatase activity.
Evidence Complex isolation, dual-substrate phosphatase assays, and cholesterol depletion
Defined the sequence determinants and redox sensitivity of MAPK selectivity, showing kinase-specificity sequences adjacent to the KIM bias ERK1/2 vs p38α binding.
Evidence Co-IP under oxidizing/reducing conditions with chimeric constructs and nuclear translocation assays
Connected PTPN7 to a differentiation program by showing it controls ERK2 nuclear translocation and megakaryocytic markers in K562 cells.
Evidence Overexpression, antisense knockdown, fractionation, and flow cytometry
Established the regulatory switch governing PTPN7–MAPK engagement, identifying PKA as the Ser-23 writer that drives ERK2 dissociation and PP1 as the eraser.
Evidence Phospho-specific blots, kinase/phosphatase inhibitors, PP1 transfection, and in vitro assays in T cells
Resolved the catalytic and conformational mechanism, defining the PTP1B-like fold, coordinated WPD/E-loop dynamics, and the extended-to-compact transition of the ERK2:HePTP complex.
Evidence Multiple crystal structures of open/closed states with kinetic mutagenesis, plus SAXS/EROS ensemble modeling and inhibitor discovery
PMID:16226275 PMID:16441242 PMID:21094165 PMID:21985012
Extended PTPN7 function to platelet hemostasis and cancer, placing it in a GPCR-ERK-thromboxane axis in vivo and linking it to GSK3β/Wnt-driven invasion.
Evidence PTPN7 knockout mice with platelet aggregometry, TXA2 ELISA, and thromboembolism model; siRNA, migration/invasion, and Wnt reporter assays in TNBC cells
| Year | Finding | Method | Journal | Conf | PMIDs |
|---|---|---|---|---|---|
| 1992 | PTPN7 (LC-PTP/HePTP) encodes a ~40 kDa non-transmembrane protein-tyrosine phosphatase preferentially expressed in hematopoietic cells, establishing it as a cytoplasmic PTP. | cDNA cloning, Northern blot, sequence analysis | Biochemical and biophysical research communications | Medium | 1510684 |
| 1995 | In rat mast cells (basophilic leukemia 2H3 cells), HePTP localizes to discrete cytoplasmic compartments (not nucleus or plasma membrane) and is tyrosine-phosphorylated upon IgE receptor aggregation in a Ca2+-dependent manner. | Immunofluorescence microscopy, two-dimensional electrophoresis, cell stimulation assays in Ca2+-free media | The Journal of biological chemistry | Medium | 7545170 |
| 1998 | HePTP negatively regulates TCR signaling by dephosphorylating ERK2 (but not JNK); phosphatase-dead mutant C270S abolishes suppression of NFAT/AP-1 transcription and ERK activation. | Reporter gene assay (NFAT/AP-1 luciferase), overexpression of WT and C270S mutant HePTP, immunoblot for phospho-ERK | The Journal of biological chemistry | Medium | 9624114 |
| 1999 | HePTP physically associates via its noncatalytic N-terminus with ERK1/2 and p38 (but not JNK), and overexpression reduces ERK catalytic activation in T cells; HePTP acts specifically on MAP kinases in the cytosol. | Co-immunoprecipitation, deletion mutant analysis, kinase activity assays in intact T cells | The Journal of biological chemistry | Medium | 10206983 |
| 2000 | ERK2 (but not ERK1, p38, or JNK1) is a specific direct substrate of HePTP; substrate-trapping mutants (C/S and D/A) bind tyrosine-phosphorylated ERK2 in a phosphorylation-dependent manner; HePTP dephosphorylates ERK2 at the activation-loop tyrosine in vitro; the N-terminal region outside the catalytic domain is required for interaction. | Substrate-trapping mutants (C/S and D/A), co-immunoprecipitation, in vitro phosphatase assay, deletion mutagenesis | Oncogene | High | 10702794 |
| 2003 | HePTP and PP2A form a ~440 kDa complex that displays dual specificity pERK phosphatase activity (dephosphorylating both phosphotyrosine and phosphothreonine on ERK activation loop); acute cholesterol depletion disassembles this complex and abolishes dual-specificity pERK phosphatase activity. | Biochemical fractionation/isolation of high MW complex, phosphatase activity assays (pTyr and pThr substrates), cholesterol depletion experiments | The EMBO journal | High | 12773382 |
| 2003 | The binding specificity of HePTP, STEP, and PTP-SL to ERK1/2 vs. p38α is determined by kinase-specificity sequences (KSS) adjacent to the KIM; under control conditions HePTP binds preferentially to p38α, but under reducing conditions p38α association is impaired while ERK1/2 association increases, indicating redox modulation of MAPK binding. | Co-immunoprecipitation under control and reducing conditions, deletion/chimeric constructs, intact-cell assays of MAPK nuclear translocation | The Biochemical journal | Medium | 12583813 |
| 2003 | HePTP regulates nuclear translocation of ERK2 in K562 cells; overexpression retains ERK2 in cytosol and impairs megakaryocytic differentiation markers (CD41, IL-6), while antisense knockdown enhances ERK2 nuclear translocation and those markers. | Overexpression and antisense knockdown, subcellular fractionation/nuclear translocation assays, flow cytometry for CD41 | Leukemia | Medium | 12592337 |
| 2004 | PKA phosphorylates HePTP at Ser-23 within the KIM, causing dissociation from ERK2; this phosphorylation is basally present in resting T cells, increased by cAMP-elevating agents (e.g., prostaglandin E2), and reversed by PP1 (not PP2A or calcineurin); PKA/PP1 thus continuously toggle HePTP–MAPK association. | Phospho-specific immunoblot in intact T cells, PKA/PP1/PP2A inhibitors, ceramide treatment, transfection of PP1 catalytic subunit, in vitro phosphatase assay | The Biochemical journal | High | 14613483 |
| 2005 | Crystal structure of HePTP catalytic domain (residues 44–339) reveals classical PTP1B fold with WPD loop in closed conformation and phosphate bound at active site; structure shows that ERK2-mediated phosphorylation of HePTP at Thr45 and Ser72, and HePTP dephosphorylation of ERK2 at pTyr185, both require significant conformational changes in both proteins. | X-ray crystallography of HePTP catalytic domain | Journal of molecular biology | High | 16226275 |
| 2006 | Crystal structures of all three human KIM-PTP family members (PTPN5, PTPRR, PTPN7) were determined; PTPN7 structure shows WPD loop in closed conformation with the KIM Thr66 phosphorylation site accessible; two classes of small-molecule inhibitors (cyclopenta[c]quinolinecarboxylic acids and 2,5-dimethylpyrrolyl benzoic acids) were identified for the family. | X-ray crystallography, compound library screening (24,000 compounds), docking | The Biochemical journal | High | 16441242 |
| 2010 | Crystal structures of HePTP in open (WPD loop open, 'atypically open' conformation) and closed states reveal that WPD loop opening involves coordinated movement of the E loop; E-loop residue Lys182 enhances catalytic activity through interaction with WPD-loop Asp236; a secondary oxyanion-binding site coordinates PTP, WPD, and E loops. | X-ray crystallography (novel crystal form enabling open/closed transition), kinetic assays of E-loop mutants | Journal of molecular biology | High | 21094165 |
| 2011 | SAXS combined with EROS ensemble refinement shows that the resting-state ERK2:HePTP complex adopts a highly extended, dynamic conformation, whereas the active-state complex (with phosphorylated ERK2) is compact and ordered, demonstrating significant dynamic structural reorganization upon activation. | Small-angle X-ray scattering (SAXS), EROS ensemble refinement | Journal of the American Chemical Society | High | 21985012 |
| 2019 | In platelets, PTPN7 negatively regulates ERK1/2 phosphorylation and thromboxane A2 generation downstream of GPCR agonists (but not GPVI agonists); PTPN7 KO mice show elevated platelet aggregation, dense granule secretion, TXA2 generation, and faster thromboembolism death, all attributable to elevated ERK activity. | PTPN7 knockout mouse model, platelet aggregometry, dense granule secretion assay, TXA2 ELISA, phospho-ERK immunoblot, pulmonary thromboembolism model | The Journal of biological chemistry | High | 31266805 |
| 2019 | In triple-negative breast cancer cells, HePTP promotes migration and invasion by dephosphorylating GSK3β, thereby activating Wnt/β-catenin signaling; knockdown of HePTP suppresses metastatic capacity. | siRNA knockdown, wound healing assay, transwell invasion assay, luciferase reporter for Wnt/β-catenin, nuclear fractionation for β-catenin, western blot for pGSK3β | Biomedicine & pharmacotherapy | Medium | 31545274 |
| Year | Title | Journal | Citations | PMID |
|---|---|---|---|---|
| 1999 | Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP). | The Journal of biological chemistry | 120 | 10206983 |
| 2003 | Differential interaction of the tyrosine phosphatases PTP-SL, STEP and HePTP with the mitogen-activated protein kinases ERK1/2 and p38alpha is determined by a kinase specificity sequence and influenced by reducing agents. | The Biochemical journal | 103 | 12583813 |
| 2003 | A cholesterol-regulated PP2A/HePTP complex with dual specificity ERK1/2 phosphatase activity. | The EMBO journal | 70 | 12773382 |
| 1998 | Negative regulation of T cell antigen receptor signal transduction by hematopoietic tyrosine phosphatase (HePTP). | The Journal of biological chemistry | 68 | 9624114 |
| 1994 | A hematopoietic protein tyrosine phosphatase (HePTP) gene that is amplified and overexpressed in myeloid malignancies maps to chromosome 1q32.1. | Leukemia | 62 | 8309248 |
| 2006 | Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases. | The Biochemical journal | 58 | 16441242 |
| 1992 | Molecular cloning and chromosomal mapping of a human protein-tyrosine phosphatase LC-PTP. | Biochemical and biophysical research communications | 55 | 1510684 |
| 2004 | Haematopoietic protein tyrosine phosphatase (HePTP) phosphorylation by cAMP-dependent protein kinase in T-cells: dynamics and subcellular location. | The Biochemical journal | 38 | 14613483 |
| 2000 | The MAP-kinase ERK2 is a specific substrate of the protein tyrosine phosphatase HePTP. | Oncogene | 37 | 10702794 |
| 2005 | Structure of the hematopoietic tyrosine phosphatase (HePTP) catalytic domain: structure of a KIM phosphatase with phosphate bound at the active site. | Journal of molecular biology | 34 | 16226275 |
| 2010 | Visualizing active-site dynamics in single crystals of HePTP: opening of the WPD loop involves coordinated movement of the E loop. | Journal of molecular biology | 31 | 21094165 |
| 2022 | Extracellular vesicles microRNA-592 of melanoma stem cells promotes metastasis through activation of MAPK/ERK signaling pathway by targeting PTPN7 in non-stemness melanoma cells. | Cell death discovery | 30 | 36302748 |
| 2011 | Resting and active states of the ERK2:HePTP complex. | Journal of the American Chemical Society | 28 | 21985012 |
| 1995 | Aggregation of IgE receptors in rat basophilic leukemia 2H3 cells induces tyrosine phosphorylation of the cytosolic protein-tyrosine phosphatase HePTP. | The Journal of biological chemistry | 26 | 7545170 |
| 2003 | The protein tyrosine phosphatase HePTP regulates nuclear translocation of ERK2 and can modulate megakaryocytic differentiation of K562 cells. | Leukemia | 25 | 12592337 |
| 2021 | LncRNA CDKN2B-AS1 hinders the proliferation and facilitates apoptosis of ox-LDL-induced vascular smooth muscle cells via the ceRNA network of CDKN2B-AS1/miR-126-5p/PTPN7. | International journal of cardiology | 23 | 34384839 |
| 2019 | The protein tyrosine phosphatase PTPN7 is a negative regulator of ERK activation and thromboxane generation in platelets. | The Journal of biological chemistry | 21 | 31266805 |
| 1994 | Induction of protein-tyrosine phosphatase LC-PTP by IL-2 in human T cells. LC-PTP is an early response gene. | FEBS letters | 21 | 8307155 |
| 2022 | Comprehensive analysis of PTPN gene family revealing PTPN7 as a novel biomarker for immuno-hot tumors in breast cancer. | Frontiers in genetics | 13 | 36226189 |
| 2008 | Immunohistochemical analyses of phosphatases in childhood B-cell lymphoma: lower expression of PTEN and HePTP and higher number of positive cells for nuclear SHP2 in B-cell lymphoma cases compared to controls. | Pediatric hematology and oncology | 12 | 18728972 |
| 2019 | HePTP promotes migration and invasion in triple-negative breast cancer cells via activation of Wnt/β-catenin signaling. | Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie | 11 | 31545274 |
| 2008 | Sequence-specific 1H, 13C and 15N backbone resonance assignments of the 34 kDa catalytic domain of human PTPN7. | Biomolecular NMR assignments | 9 | 19636879 |
| 2022 | piR-121380 Is Involved in Cryo-Capacitation and Regulates Post-Thawed Boar Sperm Quality Through Phosphorylation of ERK2 via Targeting PTPN7. | Frontiers in cell and developmental biology | 8 | 35155446 |
| 1994 | Structure of the human LC-PTP (HePTP) gene: similarity in genomic organization within protein-tyrosine phosphatase genes. | Oncogene | 8 | 8084610 |
| 2024 | PTPN7 mediates macrophage-polarization and determines immunotherapy in gliomas: A single-cell sequencing analysis. | Environmental toxicology | 4 | 38581214 |
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