Affinage

PTPRE

Receptor-type tyrosine-protein phosphatase epsilon · UniProt P23469

Round 2 corrected
Length
700 aa
Mass
80.6 kDa
Annotated
2026-04-28
40 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTPRE encodes a receptor-type protein tyrosine phosphatase that exists as both a transmembrane isoform with a minimal extracellular domain and a cytoplasmic isoform generated from an alternative PKC-regulated promoter, each with distinct tissue expression and signaling functions (PMID:2170109, PMID:8618876). The cytoplasmic isoform dephosphorylates Jak1, Tyk2, and Stat3 to suppress IL-6/LIF-driven differentiation (PMID:10859312), while both isoforms oppose Src/Fyn-mediated tyrosine phosphorylation of voltage-gated K+ channels (Kv2.1 at Y124, Kv1.5), a function required for normal Schwann-cell myelination as demonstrated in PTPRE-knockout mice (PMID:10921884, PMID:12615930). PTPRE also associates with and differentially inhibits wild-type versus oncogenic KIT receptor mutants (PMID:33732906), and in multiple cancer contexts it promotes proliferation, migration, and EMT through SRC–MYC, AKT, ERK1/2, and JNK/p38 MAPK signaling axes (PMID:38458013, PMID:36654463, PMID:38674157).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1990 High

    Cloning of PTPRE established it as a novel receptor-like PTP with a minimal extracellular domain and tandem intracellular catalytic domains possessing intrinsic tyrosine phosphatase activity, defining its molecular identity.

    Evidence cDNA cloning and recombinant enzymatic activity assay in E. coli

    PMID:2170109

    Open questions at the time
    • Endogenous substrates unknown
    • Physiological function not addressed
    • No structural data for the catalytic domains
  2. 1995 High

    Discovery of a cytoplasmic isoform from an alternative PKC-regulated promoter revealed that PTPRE is not exclusively a transmembrane receptor but also a cytosolic phosphatase with distinct expression patterns, expanding the functional repertoire of the gene.

    Evidence cDNA cloning, Northern blot, subcellular fractionation, PKC inhibitor studies in NIH 3T3 and HL-60 cells

    PMID:8618876

    Open questions at the time
    • Functional differences between isoforms not yet defined
    • Cytoplasmic isoform substrates unknown
  3. 2000 High

    PTPRE-knockout mice revealed hypomyelination due to unopposed Src/Fyn-driven hyperphosphorylation and hyperactivation of Kv channels in Schwann cells, identifying voltage-gated K+ channels as direct PTPRE substrates and establishing a physiological role in peripheral nerve myelination.

    Evidence PTPRE knockout mice, substrate-trapping co-IP with Kv2.1, electrophysiology in Xenopus oocytes and Schwann cells, HEK 293 reconstitution

    PMID:10921884

    Open questions at the time
    • Specific phosphorylation site on Kv2.1 not yet identified
    • Whether transmembrane or cytoplasmic isoform mediates Schwann cell function unclear
  4. 2000 High

    The cytoplasmic isoform was shown to specifically dephosphorylate Jak1, Tyk2, and Stat3, blocking IL-6/LIF-induced monocytic differentiation, while the transmembrane isoform lacked this activity — resolving isoform-specific signaling roles.

    Evidence Stable expression of wild-type and catalytically dead PTPepsilonC in M1 leukemia cells, phosphorylation blots for Jak-STAT components, differentiation/apoptosis assays

    PMID:10859312

    Open questions at the time
    • Direct dephosphorylation versus scaffolding not distinguished
    • Physiological relevance in primary immune cells not tested
  5. 2003 High

    Identification of Kv2.1 tyrosine 124 as the specific residue dephosphorylated by PTPRE (and phosphorylated by Src) completed the molecular logic of kinase–phosphatase antagonism at the channel.

    Evidence In vitro Src phosphorylation, Y124F mutagenesis, substrate-trapping co-IP with D245A PTPRE, Xenopus oocyte electrophysiology

    PMID:12615930

    Open questions at the time
    • Whether other Kv channel family members share this site unknown
    • In vivo confirmation of Y124 relevance in myelination not performed
  6. 2021 Medium

    PTPRE was found to physically associate with and inhibit the KIT receptor tyrosine kinase, with mastocytosis-type KIT mutants (D816V) largely resistant to PTPRE-mediated inhibition — revealing a new RTK substrate and a mechanism for mutant-selective escape from phosphatase control.

    Evidence Co-immunoprecipitation, dose-dependent overexpression with phospho-KIT readout across multiple KIT mutant constructs

    PMID:33732906

    Open questions at the time
    • Direct dephosphorylation site on KIT not mapped
    • Endogenous interaction in mast cells or GIST tissue not demonstrated
    • No loss-of-function validation
  7. 2020 Medium

    In hepatocellular carcinoma, PTPRE was identified as a direct miR-631 target that promotes migration, invasion, and EMT, shifting the view of PTPRE from purely tumor-suppressive to context-dependent pro-oncogenic.

    Evidence Luciferase reporter assay for miR-631 targeting, PTPRE rescue experiments, migration/invasion/EMT assays, in vivo models

    PMID:33344226

    Open questions at the time
    • Downstream effector pathway not specified
    • Single-lab finding
    • Mechanism by which a phosphatase promotes EMT unclear
  8. 2023 Medium

    Bidirectional manipulation in thyroid carcinoma cells confirmed that PTPRE promotes proliferation, migration, and EMT through activation of AKT and ERK1/2, establishing these kinases as downstream effectors of PTPRE's pro-oncogenic activity.

    Evidence siRNA knockdown and overexpression, phospho-AKT/ERK1/2 Western blot, proliferation/invasion/EMT assays in thyroid carcinoma lines

    PMID:36654463

    Open questions at the time
    • Direct substrate mediating AKT/ERK activation unknown
    • Paradox of a phosphatase activating kinase pathways not mechanistically resolved
  9. 2024 Medium

    Pharmacological inhibition of PTPRE with Cpd-63 blocked SRC activation and MYC expression in HCC, linking the phosphatase to the SRC–MYC axis and demonstrating therapeutic tractability including sorafenib sensitization.

    Evidence Small molecule inhibitor Cpd-63, HCC cell lines and organoids, phospho-SRC and MYC Western blot, drug combination assays

    PMID:38458013

    Open questions at the time
    • Cpd-63 selectivity across PTP family not fully characterized
    • Whether PTPRE directly dephosphorylates SRC inhibitory Y527 in HCC not shown
  10. 2024 Medium

    PTPRE knockdown in etoposide-resistant retinoblastoma cells re-sensitized them to chemotherapy and induced apoptosis, with SGK3 phosphorylation identified as an additional downstream readout, broadening the spectrum of PTPRE-regulated kinases in drug resistance.

    Evidence Lentiviral KD, caspase activity assays, CAM in vivo assay, phospho-SGK3/AKT/ERK1/2 blots, miR-631 overexpression rescue

    PMID:38674157

    Open questions at the time
    • SGK3 as a direct PTPRE substrate not validated
    • Mechanism of chemoresistance modulation unclear
  11. 2026 Medium

    In hypertensive mice, PTPRE drives vascular smooth muscle cell phenotypic switching from contractile to synthetic via JNK/p38 MAPK and their upstream kinases MKK3/MKK6, extending PTPRE's physiological roles to vascular remodeling.

    Evidence Bidirectional PTPRE manipulation in DOCA-salt hypertensive mice, aortic ring vasomotor assays, phospho-JNK/p38/MKK3/MKK6 Western blot

    PMID:41492999

    Open questions at the time
    • Direct PTPRE substrate in VSMCs not identified
    • Isoform responsible not defined
    • Single hypertension model

Open questions

Synthesis pass · forward-looking unresolved questions
  • A central unresolved question is how a tyrosine phosphatase activates kinase pathways (AKT, ERK1/2, SRC, JNK/p38) in cancer and vascular cells — whether through direct dephosphorylation of inhibitory phosphotyrosines (analogous to SRC Y527) or through indirect scaffolding/adaptor functions — and which isoform mediates each context-dependent outcome.
  • No systematic substrate identification (e.g., phosphoproteomics) performed
  • Isoform-specific contributions in cancer and vascular disease remain undefined
  • Full-length structural model of PTPRE is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4
Partners
JAK1KITKV1.5KV2.1SRCSTAT3TYK2

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 HPTP epsilon (PTPRE) was cloned as a novel receptor-like protein tyrosine phosphatase with a short extracellular domain (27 amino acids) and two tandemly duplicated intracellular PTPase catalytic domains. The cytoplasmic PTPase-like domains of HPTP epsilon expressed in E. coli were shown to possess tyrosine phosphatase activity. cDNA cloning, structural analysis, recombinant protein expression in E. coli with enzymatic activity assay The EMBO journal High 2170109
1995 A non-transmembrane, cytoplasmic isoform of PTP epsilon (PTPepsilon-cytoplasmic) was identified, arising from a separate transcriptional start site regulated by protein kinase C. The cytoplasmic isoform has nonoverlapping expression with the transmembrane isoform, is encoded by a delayed early response gene in NIH 3T3 fibroblasts, and is strongly upregulated during phorbol ester-induced differentiation of HL-60 cells. Cellular fractionation confirmed its cytoplasmic localization. cDNA cloning, RT-PCR, Northern blotting, phorbol ester induction assays, subcellular fractionation, PKC inhibitor experiments Proceedings of the National Academy of Sciences of the United States of America High 8618876
1995 The murine Ptpre gene was mapped to the distal part of chromosome 7, in the vicinity of imprinted regions, using interspecific backcross analysis. PTP epsilon was implicated in early molecular events during in vitro differentiation of mouse erythroleukemia (MEL) and embryonic carcinoma (F9) cells. Interspecific backcross genetic mapping, cDNA hybridization, in vitro differentiation assays Genomics Medium 8575779
2000 Mice lacking PTP epsilon (PTPRE) exhibit hypomyelination of sciatic nerve axons at early postnatal age, accompanied by increased activity of delayed-rectifier voltage-gated K+ (Kv) channels (Kv1.5 and Kv2.1) and hyperphosphorylation of Kv channel alpha-subunits in sciatic nerve tissue and primary Schwann cells. PTP epsilon was shown to associate with Kv2.1 via a substrate-trapping mutant, and to markedly reduce Kv1.5 or Kv2.1 current amplitudes in Xenopus oocytes. PTP epsilon also profoundly reduces Src- or Fyn-stimulated Kv2.1 currents and tyrosine phosphorylation in HEK 293 cells, demonstrating that PTPRE antagonizes Kv channel activation by tyrosine kinases in vivo. PTP epsilon knockout mice, electrophysiology (Xenopus oocytes, Schwann cells), substrate-trapping co-immunoprecipitation, Western blot for phosphorylation, HEK 293 transfection assays The EMBO journal High 10921884
2000 The cytosolic isoform PTPepsilonC inhibits IL-6- and LIF-induced Jak-STAT signaling in M1 leukemia cells. Forced expression of PTPepsilonC reduced tyrosine phosphorylation of Jak1, Tyk2, gp130, and Stat3, and blocked IL-6/LIF-induced monocytic differentiation and apoptosis. Expression of an inactive (catalytically dead) mutant of PTPepsilonC potentiated these signaling responses instead. The transmembrane isoform PTPepsilonM had no such effect, establishing isoform-specific regulation of Jak-STAT signaling. Stable transfection of wild-type and catalytic mutant PTPepsilonC in M1 cells, Western blot for phosphorylation of Jak1/Tyk2/gp130/Stat3, differentiation and apoptosis assays The Journal of biological chemistry High 10859312
2002 RPTP epsilon (PTPRE) D2 domain engages in intra- and intermolecular interactions with RPTP D1 domains. The membrane-distal D2 domain of RPTPepsilon can bind D1 domains of RPTPepsilon itself and of other RPTPs. The C-terminus of D2 and the 'wedge' structure in D1 are central determinants of binding specificity. These interactions are proposed to regulate RPTP catalytic activity. Co-immunoprecipitation of HA- and myc-tagged RPTP domain constructs, site-directed mutagenesis of wedge and C-terminal regions The Journal of biological chemistry Medium 12376545
2003 Tyrosine 124 (Y124) within the T1 cytosolic domain of Kv2.1 was identified as the key phosphorylation site targeted by both Src kinase and PTPRE (cyt-PTPepsilon). Y124 is phosphorylated by Src in vitro; Y124F mutant Kv2.1 is less phosphorylated by Src in whole cells and fails to bind the D245A substrate-trapping mutant of cyt-PTPepsilon. Phosphorylation of Y124 is required for Src-mediated 3-fold upregulation of Kv2.1 channel activity; Y124F channels show only marginal upregulation. Other Kv2.1 properties (expression, localization, voltage dependence) are unaffected by the mutation. In vitro Src kinase assay, substrate-trapping co-immunoprecipitation with D245A mutant PTPRE, Xenopus oocyte electrophysiology, site-directed mutagenesis, Western blot The Journal of biological chemistry High 12615930
2005 PTPepsilon (PTPRE) is listed among candidate receptor-type phosphatases (along with CD45, PTPalpha, and PTPlambda) that dephosphorylate inhibitory phosphotyrosine 527 of Src, thereby activating Src kinase activity. Literature review synthesizing biochemical and genetic data on Src regulation Biochemical and biophysical research communications Low 15845350
2009 Large-scale structural analysis of the classical human PTP family included PTPRE among 22 PTP crystal structures analyzed. The study established diversity in surface properties, catalytic loop conformations, and a potential secondary substrate-binding pocket across the family, with implications for substrate recognition and inhibitor development applicable to PTPRE. X-ray crystallography of PTP catalytic domains, enzymatic activity assays Cell Low 19167335
2021 PTPRE associates with wild-type KIT receptor tyrosine kinase and inhibits KIT activation in a dose-dependent manner. PTPRE also associates with and inhibits the oncogenic D816V KIT mutant (found in mastocytosis), but with much weaker inhibition than wild-type KIT. PTPRE almost completely blocks activation of GIST-type KIT mutants, while mastocytosis-type KIT mutants (including D816V) are substantially more resistant to PTPRE-mediated inhibition. Co-immunoprecipitation, dose-dependent overexpression assays, Western blot for KIT phosphorylation, comparison of wild-type and mutant KIT constructs Biochemistry and biophysics reports Medium 33732906
2020 PTPRE was validated as a direct downstream target of miR-631 in hepatocellular carcinoma. Overexpression of PTPRE promotes migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells, and increasing PTPRE expression reverses the inhibitory effects of miR-631 on these processes. The negative correlation between miR-631 and PTPRE expression was confirmed both in vivo and in vitro. Luciferase reporter assay (implied by miRNA target validation), rescue experiments with PTPRE overexpression, migration/invasion/EMT assays, in vivo tumor models Frontiers in oncology Medium 33344226
2023 PTPRE plays an oncogenic role in thyroid carcinoma by activating the AKT and ERK1/2 signaling pathways. PTPRE knockdown suppresses proliferation, migration, invasion, and EMT in thyroid carcinoma cells, while PTPRE overexpression promotes these behaviors. Enhanced phosphorylation of AKT and ERK1/2 was demonstrated upon PTPRE upregulation. siRNA knockdown and overexpression in thyroid carcinoma cell lines, Western blot for phospho-AKT and phospho-ERK1/2, MTT proliferation assay, wound healing, transwell invasion, immunofluorescence for EMT markers Current cancer drug targets Medium 36654463
2024 PTPRE inhibition using compound Cpd-63 suppresses tumor cell proliferation, migration, and HCC organoid growth. Mechanistically, Cpd-63 inhibits SRC activation, which in turn reduces expression of MYC and MYC target genes. PTPRE inhibition also improves sorafenib sensitivity in HCC cells. Small molecule inhibitor (Cpd-63) treatment, HCC organoid models, Western blot for SRC phosphorylation and MYC expression, cell proliferation and migration assays, drug combination assays Biomedicine & pharmacotherapy Medium 38458013
2024 PTPRE knockdown in etoposide-resistant retinoblastoma cells significantly decreases cell growth, viability, and anchorage-independent growth, increases caspase-dependent apoptosis, and re-sensitizes cells to etoposide. In vivo CAM assays show decreased tumor formation and size. PTPRE KD alters phosphorylation of SGK3 and (cell-line dependently) AKT and ERK1/2. miR-631 overexpression recapitulates PTPRE KD effects, and PTPRE expression is not regulated by promoter methylation in retinoblastoma. Lentiviral PTPRE knockdown, transient miR-631 overexpression, caspase activity assays, colony formation assay, in vivo chicken chorioallantoic membrane (CAM) assay, Western blot for SGK3/AKT/ERK1/2 phosphorylation, methylation analysis International journal of molecular sciences Medium 38674157
2026 PTPRE upregulation in vascular smooth muscle cells (VSMCs) of DOCA-salt hypertensive mice promotes phenotypic transformation from contractile to synthetic phenotype (increased OPN, decreased α-SMA and SM22α) and impairs vasoconstriction and vasodilation. PTPRE modulates JNK and p38 MAPK subfamilies and their upstream kinases MKK3 and MKK6, establishing PTPRE as a regulator of VSMC phenotypic switching via the JNK/p38 MAPK pathway. PTPRE gene knockdown and overexpression in DOCA-salt hypertensive mice, aortic ring vasomotor function assays, Western blot for phenotypic markers and MAPK pathway phosphorylation (JNK, p38, MKK3, MKK6) Cell biology international Medium 41492999

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1995 Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence. Nature 660 7566098
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2005 Src kinase regulation by phosphorylation and dephosphorylation. Biochemical and biophysical research communications 481 15845350
1990 Structural diversity and evolution of human receptor-like protein tyrosine phosphatases. The EMBO journal 450 2170109
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2009 Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell 393 19167335
2017 Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nature biotechnology 378 28319085
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2005 Substrate-trapping techniques in the identification of cellular PTP targets. Methods (San Diego, Calif.) 146 15588985
2005 A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. American journal of human genetics 137 16385451
2021 Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers. Nature genetics 116 34857952
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2007 Genome-wide association with select biomarker traits in the Framingham Heart Study. BMC medical genetics 108 17903293
2019 LncRNA PTPRE-AS1 modulates M2 macrophage activation and inflammatory diseases by epigenetic promotion of PTPRE. Science advances 94 31844669
2000 Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon. The EMBO journal 75 10921884
2010 Human variation in alcohol response is influenced by variation in neuronal signaling genes. Alcoholism, clinical and experimental research 74 20201926
2016 Phenotypic and Interaction Profiling of the Human Phosphatases Identifies Diverse Mitotic Regulators. Cell reports 72 27880917
2000 Protein-tyrosine phosphatase PTPepsilon C inhibits Jak-STAT signaling and differentiation induced by interleukin-6 and leukemia inhibitory factor in M1 leukemia cells. The Journal of biological chemistry 70 10859312
1995 Identification of a cytoplasmic, phorbol ester-inducible isoform of protein tyrosine phosphatase epsilon. Proceedings of the National Academy of Sciences of the United States of America 66 8618876
2017 Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics. Cell systems 65 28330616
2012 Genome-wide association study of d-amphetamine response in healthy volunteers identifies putative associations, including cadherin 13 (CDH13). PloS one 62 22952603
2023 Cross-linking mass spectrometry discovers, evaluates, and corroborates structures and protein-protein interactions in the human cell. Proceedings of the National Academy of Sciences of the United States of America 60 37071682
2002 Intra- and intermolecular interactions between intracellular domains of receptor protein-tyrosine phosphatases. The Journal of biological chemistry 58 12376545
2003 Phosphorylation-dependent regulation of Kv2.1 Channel activity at tyrosine 124 by Src and by protein-tyrosine phosphatase epsilon. The Journal of biological chemistry 49 12615930
2020 miR-631 Inhibits Intrahepatic Metastasis of Hepatocellular Carcinoma by Targeting PTPRE. Frontiers in oncology 17 33344226
2019 Tuning the Protein Phosphorylation by Receptor Type Protein Tyrosine Phosphatase Epsilon (PTPRE) in Normal and Cancer Cells. Journal of Cancer 15 30662530
2024 A novel diagnostic model based on lncRNA PTPRE expression, neutrophil count and red blood cell distribution width for diagnosis of seronegative rheumatoid arthritis. Clinical and experimental medicine 6 38662200
2024 Inhibition of PTPRE suppresses tumor progression and improves sorafenib response in hepatocellular carcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 5 38458013
2023 Receptor Type Protein Tyrosine Phosphatase Epsilon (PTPRE) Plays an Oncogenic Role in Thyroid Carcinoma by Activating the AKT and ERK1/2 Signaling Pathway. Current cancer drug targets 5 36654463
1995 Chromosomal location of murine protein tyrosine phosphatase (Ptprj and Ptpre) genes. Genomics 5 8575779
2021 Protein tyrosine phosphatase receptor type E (PTPRE) regulates the activation of wild-type KIT and KIT mutants differently. Biochemistry and biophysics reports 4 33732906
2024 Role of Protein Tyrosine Phosphatase Receptor Type E (PTPRE) in Chemoresistant Retinoblastoma. International journal of molecular sciences 2 38674157
2026 PTPRE Exacerbates Phenotypic Transformation of Vascular Smooth Muscle Cells and Vasomotor Dysfunction in Salt-Sensitive Hypertension. Cell biology international 0 41492999