{"gene":"PTPRE","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1990,"finding":"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.","method":"cDNA cloning, structural analysis, recombinant protein expression in E. coli with enzymatic activity assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — original biochemical characterization with direct enzymatic activity demonstration; foundational paper","pmids":["2170109"],"is_preprint":false},{"year":1995,"finding":"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.","method":"cDNA cloning, RT-PCR, Northern blotting, phorbol ester induction assays, subcellular fractionation, PKC inhibitor experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including fractionation and transcriptional regulation assays; foundational isoform discovery","pmids":["8618876"],"is_preprint":false},{"year":1995,"finding":"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.","method":"Interspecific backcross genetic mapping, cDNA hybridization, in vitro differentiation assays","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic mapping with functional implication in differentiation; single study","pmids":["8575779"],"is_preprint":false},{"year":2000,"finding":"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.","method":"PTP epsilon knockout mice, electrophysiology (Xenopus oocytes, Schwann cells), substrate-trapping co-immunoprecipitation, Western blot for phosphorylation, HEK 293 transfection assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — KO mouse with defined phenotype, substrate-trapping pulldown, electrophysiology reconstitution; multiple orthogonal methods","pmids":["10921884"],"is_preprint":false},{"year":2000,"finding":"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.","method":"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","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — overexpression with catalytic mutant control, multiple phosphorylation readouts, isoform specificity established; rigorous design","pmids":["10859312"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Co-immunoprecipitation of HA- and myc-tagged RPTP domain constructs, site-directed mutagenesis of wedge and C-terminal regions","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — co-immunoprecipitation with domain mutants; single study but multiple RPTP family members tested","pmids":["12376545"],"is_preprint":false},{"year":2003,"finding":"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.","method":"In vitro Src kinase assay, substrate-trapping co-immunoprecipitation with D245A mutant PTPRE, Xenopus oocyte electrophysiology, site-directed mutagenesis, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro phosphorylation assay, substrate-trapping mutant, electrophysiology, mutagenesis; multiple orthogonal methods in single study","pmids":["12615930"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Literature review synthesizing biochemical and genetic data on Src regulation","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 4 — review/inference; no direct experimental data in this paper for PTPRE specifically","pmids":["15845350"],"is_preprint":false},{"year":2009,"finding":"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.","method":"X-ray crystallography of PTP catalytic domains, enzymatic activity assays","journal":"Cell","confidence":"Low","confidence_rationale":"Tier 1 method but findings are family-wide; PTPRE-specific structural insights not individually described in the abstract","pmids":["19167335"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, dose-dependent overexpression assays, Western blot for KIT phosphorylation, comparison of wild-type and mutant KIT constructs","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal co-IP and dose-dependent inhibition assays; single lab but multiple KIT variants tested","pmids":["33732906"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Luciferase reporter assay (implied by miRNA target validation), rescue experiments with PTPRE overexpression, migration/invasion/EMT assays, in vivo tumor models","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — miRNA-target validation with rescue experiment; single lab, multiple functional assays","pmids":["33344226"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Current cancer drug targets","confidence":"Medium","confidence_rationale":"Tier 2-3 — bidirectional genetic manipulation with pathway-level readout; single lab","pmids":["36654463"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological inhibition with defined molecular pathway (SRC-MYC axis); single lab, multiple models including organoids","pmids":["38458013"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — lentiviral KD with in vivo validation plus multiple signaling readouts; single lab","pmids":["38674157"],"is_preprint":false},{"year":2026,"finding":"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.","method":"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)","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional genetic manipulation in vivo with functional vascular readouts and defined signaling pathway; single study","pmids":["41492999"],"is_preprint":false}],"current_model":"PTPRE is a receptor-type (and alternatively, cytoplasmic-isoform) protein tyrosine phosphatase that dephosphorylates and inactivates substrates including voltage-gated K+ channel Kv2.1 (at Y124, opposing Src/Fyn kinase activation) and components of the Jak-STAT pathway (Jak1, Tyk2, Stat3), thereby regulating Schwann cell myelination, cytokine-driven differentiation, and cancer cell proliferation/invasion through modulation of SRC, AKT, ERK1/2, JNK/p38 MAPK, and MYC signaling axes; it also directly associates with and differentially inhibits wild-type versus mutant forms of the KIT receptor tyrosine kinase."},"narrative":{"teleology":[{"year":1990,"claim":"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","pmids":["2170109"],"confidence":"High","gaps":["Endogenous substrates unknown","Physiological function not addressed","No structural data for the catalytic domains"]},{"year":1995,"claim":"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","pmids":["8618876"],"confidence":"High","gaps":["Functional differences between isoforms not yet defined","Cytoplasmic isoform substrates unknown"]},{"year":2000,"claim":"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","pmids":["10921884"],"confidence":"High","gaps":["Specific phosphorylation site on Kv2.1 not yet identified","Whether transmembrane or cytoplasmic isoform mediates Schwann cell function unclear"]},{"year":2000,"claim":"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","pmids":["10859312"],"confidence":"High","gaps":["Direct dephosphorylation versus scaffolding not distinguished","Physiological relevance in primary immune cells not tested"]},{"year":2003,"claim":"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","pmids":["12615930"],"confidence":"High","gaps":["Whether other Kv channel family members share this site unknown","In vivo confirmation of Y124 relevance in myelination not performed"]},{"year":2021,"claim":"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","pmids":["33732906"],"confidence":"Medium","gaps":["Direct dephosphorylation site on KIT not mapped","Endogenous interaction in mast cells or GIST tissue not demonstrated","No loss-of-function validation"]},{"year":2020,"claim":"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","pmids":["33344226"],"confidence":"Medium","gaps":["Downstream effector pathway not specified","Single-lab finding","Mechanism by which a phosphatase promotes EMT unclear"]},{"year":2023,"claim":"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","pmids":["36654463"],"confidence":"Medium","gaps":["Direct substrate mediating AKT/ERK activation unknown","Paradox of a phosphatase activating kinase pathways not mechanistically resolved"]},{"year":2024,"claim":"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","pmids":["38458013"],"confidence":"Medium","gaps":["Cpd-63 selectivity across PTP family not fully characterized","Whether PTPRE directly dephosphorylates SRC inhibitory Y527 in HCC not shown"]},{"year":2024,"claim":"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","pmids":["38674157"],"confidence":"Medium","gaps":["SGK3 as a direct PTPRE substrate not validated","Mechanism of chemoresistance modulation unclear"]},{"year":2026,"claim":"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","pmids":["41492999"],"confidence":"Medium","gaps":["Direct PTPRE substrate in VSMCs not identified","Isoform responsible not defined","Single hypertension model"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,4,6,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,9,11,12,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11,12,13]}],"complexes":[],"partners":["KV2.1","KV1.5","JAK1","TYK2","STAT3","KIT","SRC"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"P23469","full_name":"Receptor-type tyrosine-protein phosphatase epsilon","aliases":[],"length_aa":700,"mass_kda":80.6,"function":"Isoform 1 plays a critical role in signaling transduction pathways and phosphoprotein network topology in red blood cells. May play a role in osteoclast formation and function (By similarity) Isoform 2 acts as a negative regulator of insulin receptor (IR) signaling in skeletal muscle. Regulates insulin-induced tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate 1 (IRS-1), phosphorylation of protein kinase B and glycogen synthase kinase-3 and insulin induced stimulation of glucose uptake (By similarity) Isoform 1 and isoform 2 act as a negative regulator of FceRI-mediated signal transduction leading to cytokine production and degranulation, most likely by acting at the level of SYK to affect downstream events such as phosphorylation of SLP76 and LAT and mobilization of Ca(2+)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P23469/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRE","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTPRE","total_profiled":1310},"omim":[{"mim_id":"600926","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, EPSILON; PTPRE","url":"https://www.omim.org/entry/600926"},{"mim_id":"600925","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, J; PTPRJ","url":"https://www.omim.org/entry/600925"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":44.3}],"url":"https://www.proteinatlas.org/search/PTPRE"},"hgnc":{"alias_symbol":["PTPE"],"prev_symbol":[]},"alphafold":{"accession":"P23469","domains":[{"cath_id":"3.90.190.10","chopping":"121-398","consensus_level":"high","plddt":94.4897,"start":121,"end":398},{"cath_id":"3.90.190.10","chopping":"409-694","consensus_level":"high","plddt":92.273,"start":409,"end":694}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23469","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23469-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23469-F1-predicted_aligned_error_v6.png","plddt_mean":85.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRE","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRE"},"sequence":{"accession":"P23469","fasta_url":"https://rest.uniprot.org/uniprotkb/P23469.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23469/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23469"}},"corpus_meta":[{"pmid":"31844669","id":"PMC_31844669","title":"LncRNA 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pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/38458013","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36654463","id":"PMC_36654463","title":"Receptor Type Protein Tyrosine Phosphatase Epsilon (PTPRE) Plays an Oncogenic Role in Thyroid Carcinoma by Activating the AKT and ERK1/2 Signaling Pathway.","date":"2023","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/36654463","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33732906","id":"PMC_33732906","title":"Protein tyrosine phosphatase receptor type E (PTPRE) regulates the activation of wild-type KIT and KIT mutants differently.","date":"2021","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/33732906","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38674157","id":"PMC_38674157","title":"Role of Protein Tyrosine Phosphatase Receptor Type E (PTPRE) in Chemoresistant 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34857952","citation_count":116,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18029348","id":"PMC_18029348","title":"Toward a confocal subcellular atlas of the human proteome.","date":"2007","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/18029348","citation_count":114,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17903293","id":"PMC_17903293","title":"Genome-wide association with select biomarker traits in the Framingham Heart Study.","date":"2007","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17903293","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20379614","id":"PMC_20379614","title":"Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.","date":"2010","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/20379614","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10921884","id":"PMC_10921884","title":"Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10921884","citation_count":75,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20201926","id":"PMC_20201926","title":"Human variation in alcohol response is influenced by variation in neuronal signaling genes.","date":"2010","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/20201926","citation_count":74,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27880917","id":"PMC_27880917","title":"Phenotypic and Interaction Profiling of the Human Phosphatases Identifies Diverse Mitotic Regulators.","date":"2016","source":"Cell 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Interactions and Dynamics.","date":"2017","source":"Cell systems","url":"https://pubmed.ncbi.nlm.nih.gov/28330616","citation_count":65,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22952603","id":"PMC_22952603","title":"Genome-wide association study of d-amphetamine response in healthy volunteers identifies putative associations, including cadherin 13 (CDH13).","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22952603","citation_count":62,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"37071682","id":"PMC_37071682","title":"Cross-linking mass spectrometry discovers, evaluates, and corroborates structures and protein-protein interactions in the human cell.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37071682","citation_count":60,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12376545","id":"PMC_12376545","title":"Intra- and intermolecular interactions between intracellular domains of receptor protein-tyrosine phosphatases.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12376545","citation_count":58,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12615930","id":"PMC_12615930","title":"Phosphorylation-dependent regulation of Kv2.1 Channel activity at tyrosine 124 by Src and by protein-tyrosine phosphatase epsilon.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12615930","citation_count":49,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5922,"output_tokens":1762,"usd":0.022098},"stage2":{"model":"claude-opus-4-6","input_tokens":5029,"output_tokens":2257,"usd":0.122355},"total_usd":0.492008,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of 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\"pmids\": [\"31844669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTPRE physically associates with wild-type KIT receptor tyrosine kinase and inhibits its activation in a dose-dependent manner; PTPRE also associates with and inhibits GISTs-type KIT mutants nearly completely, whereas mastocytosis-type KIT mutants (e.g., D816V) are more resistant to PTPRE-mediated inhibition.\",\n      \"method\": \"Co-immunoprecipitation (association assay), dose-dependent expression/activation analysis, Western blot for KIT phosphorylation\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and dose-dependent functional assay, single lab, single study\",\n      \"pmids\": [\"33732906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPRE acts as a downstream target of miR-631; miR-631 directly targets PTPRE to suppress migration, invasion, and EMT of hepatocellular carcinoma cells, and re-expression of PTPRE reverses the inhibitory effects of miR-631.\",\n      \"method\": \"miRNA target validation (luciferase reporter implied by context), rescue experiments (PTPRE overexpression reversing miR-631 effects), migration/invasion/EMT assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — target validation with rescue experiment, single lab\",\n      \"pmids\": [\"33344226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Pharmacological inhibition of PTPRE with compound Cpd-63 suppresses HCC cell proliferation, migration, and organoid growth by inhibiting SRC activation and downstream MYC/MYC-target expression.\",\n      \"method\": \"Small-molecule inhibitor treatment, Western blot for SRC phosphorylation and MYC levels, cell proliferation/migration assays, HCC organoid models\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological inhibition with mechanistic readout (SRC/MYC pathway), single lab\",\n      \"pmids\": [\"38458013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTPRE promotes thyroid carcinoma cell proliferation, migration, invasion, and EMT by activating the AKT and ERK1/2 signaling pathways, as shown by increased phospho-AKT and phospho-ERK1/2 upon PTPRE overexpression and reduction upon PTPRE knockdown.\",\n      \"method\": \"PTPRE knockdown/overexpression, Western blot for p-AKT and p-ERK1/2, MTT proliferation assay, wound healing, transwell invasion, immunofluorescent EMT markers\",\n      \"journal\": \"Current cancer drug targets\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD and OE with defined signaling readouts, single lab\",\n      \"pmids\": [\"36654463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPRE knockdown in etoposide-resistant retinoblastoma cells decreases proliferation, increases caspase-dependent apoptosis, and re-sensitizes cells to etoposide; PTPRE KD alters phosphorylation of SGK3 and, cell-line dependently, AKT and ERK1/2, indicating these as downstream signaling targets.\",\n      \"method\": \"Lentiviral PTPRE knockdown, miR-631 overexpression, Western blot for p-SGK3/p-AKT/p-ERK1/2, caspase apoptosis assay, in vivo CAM tumor model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with in vivo validation and defined phospho-signaling readouts, moderate evidence\",\n      \"pmids\": [\"38674157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PTPRE regulates vascular smooth muscle cell phenotypic transformation (synthetic vs. contractile markers) and vasomotor dysfunction in salt-sensitive hypertension by modulating phosphorylation of JNK and p38 MAPK subfamilies via upstream MKK3 and MKK6.\",\n      \"method\": \"Gene knockdown and overexpression in DOCA-salt hypertensive mice, aortic ring vasomotor function assay, Western blot for MAPK pathway phosphorylation, phenotypic marker expression (OPN, α-SMA, SM22α)\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD and OE in vivo with defined pathway (MKK3/6-JNK/p38) and functional readout, single study\",\n      \"pmids\": [\"41492999\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRE is a receptor-type protein tyrosine phosphatase that dephosphorylates and inhibits receptor tyrosine kinases (including KIT) and acts upstream of multiple signaling cascades—including MAPK/ERK1/2, AKT, JNK/p38, and SRC/MYC—to regulate macrophage polarization, vascular smooth muscle cell phenotype, and cancer cell migration, invasion, and survival; its expression is itself epigenetically controlled via the lncRNA PTPRE-AS1/WDR5/H3K4me3 axis and post-transcriptionally regulated by miR-631.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEPT papers.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:31844669 — About lncRNA PTPRE-AS1, not the canonical PTPRE protein → EXCLUDE (case B: alt-locus product)\n2. PMID:33344226 — PTPRE protein as target of miR-631 in HCC; describes PTPRE protein function → KEEP\n3. PMID:30662530 — Review of PTPRE protein → KEEP\n4. PMID:38662200 — lncRNA PTPRE expression, diagnostic model → EXCLUDE (case B)\n5. PMID:8575779 — Chromosomal mapping of murine Ptpre → KEEP (foundational)\n6. PMID:38458013 — PTPRE inhibitor in HCC, mechanistic study → KEEP\n7. PMID:36654463 — PTPRE in thyroid carcinoma, AKT/ERK pathway → KEEP\n8. PMID:33732906 — PTPRE regulation of KIT → KEEP\n9. PMID:38674157 — PTPRE in retinoblastoma → KEEP\n10. PMID:41492999 — PTPRE in vascular smooth muscle, MAPK → KEEP\n\nGene2pubmed curated papers:\n- PMID:12477932, 14702039, 7566098, 21873635, 15489334, 16344560, 8889548 — genome-wide cDNA/EST projects → EXCLUDE (no mechanistic PTPRE content)\n- PMID:28514442, 33961781 — BioPlex interactome (PTPRE appears as a node) → borderline; no specific mechanistic finding about PTPRE → EXCLUDE\n- PMID:15845350 — Src kinase review, mentions PTPepsilon as candidate phosphatase → KEEP (mechanistic mention)\n- PMID:2170109 — Original cloning of HPTP epsilon (PTPRE), structural characterization → KEEP\n- PMID:19167335 — Crystal structures of PTP family including PTPRE → KEEP\n- PMID:28319085, 28611215, 34857952 — CRISPR screens, not PTPRE-specific → EXCLUDE\n- PMID:16385451, 17903293, 20379614, 20201926, 22952603 — GWAS/association studies → EXCLUDE\n- PMID:10921884 — PTP epsilon KO mice, Kv channels, myelination → KEEP\n- PMID:74 citations: PMID:20201926 — AUD GWAS → EXCLUDE\n- PMID:27880917 — Phosphatase interactome, PTPRE included → borderline; no specific mechanistic finding → EXCLUDE\n- PMID:10859312 — PTPepsilonC inhibits Jak-STAT → KEEP\n- PMID:8618876 — Cytoplasmic isoform of PTP epsilon → KEEP\n- PMID:28330616 — Phosphatase interactions, PTPRE included → borderline; no specific mechanism → EXCLUDE\n- PMID:37071682 — XL-MS, PTPRE may appear → EXCLUDE (no specific PTPRE mechanistic content)\n- PMID:12376545 — Intra/intermolecular interactions of RPTPs including RPTPepsilon → KEEP\n- PMID:12615930 — Kv2.1 Y124, Src and PTPepsilon → KEEP\n- PMID:15588985 — Substrate-trapping methods, mentions PTPepsilon → KEEP (methodological with mechanistic content)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA cloning, structural analysis, recombinant protein expression in E. coli with enzymatic activity assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original biochemical characterization with direct enzymatic activity demonstration; foundational paper\",\n      \"pmids\": [\"2170109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA cloning, RT-PCR, Northern blotting, phorbol ester induction assays, subcellular fractionation, PKC inhibitor experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including fractionation and transcriptional regulation assays; foundational isoform discovery\",\n      \"pmids\": [\"8618876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"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.\",\n      \"method\": \"Interspecific backcross genetic mapping, cDNA hybridization, in vitro differentiation assays\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic mapping with functional implication in differentiation; single study\",\n      \"pmids\": [\"8575779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"PTP epsilon knockout mice, electrophysiology (Xenopus oocytes, Schwann cells), substrate-trapping co-immunoprecipitation, Western blot for phosphorylation, HEK 293 transfection assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO mouse with defined phenotype, substrate-trapping pulldown, electrophysiology reconstitution; multiple orthogonal methods\",\n      \"pmids\": [\"10921884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — overexpression with catalytic mutant control, multiple phosphorylation readouts, isoform specificity established; rigorous design\",\n      \"pmids\": [\"10859312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of HA- and myc-tagged RPTP domain constructs, site-directed mutagenesis of wedge and C-terminal regions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-immunoprecipitation with domain mutants; single study but multiple RPTP family members tested\",\n      \"pmids\": [\"12376545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro Src kinase assay, substrate-trapping co-immunoprecipitation with D245A mutant PTPRE, Xenopus oocyte electrophysiology, site-directed mutagenesis, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation assay, substrate-trapping mutant, electrophysiology, mutagenesis; multiple orthogonal methods in single study\",\n      \"pmids\": [\"12615930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Literature review synthesizing biochemical and genetic data on Src regulation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — review/inference; no direct experimental data in this paper for PTPRE specifically\",\n      \"pmids\": [\"15845350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography of PTP catalytic domains, enzymatic activity assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 method but findings are family-wide; PTPRE-specific structural insights not individually described in the abstract\",\n      \"pmids\": [\"19167335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, dose-dependent overexpression assays, Western blot for KIT phosphorylation, comparison of wild-type and mutant KIT constructs\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal co-IP and dose-dependent inhibition assays; single lab but multiple KIT variants tested\",\n      \"pmids\": [\"33732906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay (implied by miRNA target validation), rescue experiments with PTPRE overexpression, migration/invasion/EMT assays, in vivo tumor models\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — miRNA-target validation with rescue experiment; single lab, multiple functional assays\",\n      \"pmids\": [\"33344226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Current cancer drug targets\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — bidirectional genetic manipulation with pathway-level readout; single lab\",\n      \"pmids\": [\"36654463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological inhibition with defined molecular pathway (SRC-MYC axis); single lab, multiple models including organoids\",\n      \"pmids\": [\"38458013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — lentiviral KD with in vivo validation plus multiple signaling readouts; single lab\",\n      \"pmids\": [\"38674157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"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)\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic manipulation in vivo with functional vascular readouts and defined signaling pathway; single study\",\n      \"pmids\": [\"41492999\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRE is a receptor-type (and alternatively, cytoplasmic-isoform) protein tyrosine phosphatase that dephosphorylates and inactivates substrates including voltage-gated K+ channel Kv2.1 (at Y124, opposing Src/Fyn kinase activation) and components of the Jak-STAT pathway (Jak1, Tyk2, Stat3), thereby regulating Schwann cell myelination, cytokine-driven differentiation, and cancer cell proliferation/invasion through modulation of SRC, AKT, ERK1/2, JNK/p38 MAPK, and MYC signaling axes; it also directly associates with and differentially inhibits wild-type versus mutant forms of the KIT receptor tyrosine kinase.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PTPRE is a receptor-type protein tyrosine phosphatase that functions as a signaling hub regulating cell proliferation, migration, survival, and phenotypic switching across multiple tissue contexts. It physically associates with and inhibits the receptor tyrosine kinase KIT in a dose-dependent manner, with differential efficacy against GIST-type versus mastocytosis-type KIT mutants [PMID:33732906], and activates SRC/MYC, AKT, and ERK1/2 signaling to promote cancer cell proliferation, invasion, and epithelial–mesenchymal transition in hepatocellular and thyroid carcinomas [PMID:38458013, PMID:36654463, PMID:33344226]. In vascular smooth muscle cells, PTPRE modulates JNK and p38 MAPK signaling via MKK3/MKK6 to control contractile-to-synthetic phenotypic transformation and vasomotor function in salt-sensitive hypertension [PMID:41492999]. PTPRE expression is epigenetically upregulated through a PTPRE-AS1/WDR5/H3K4me3 axis during IL-4-induced M2 macrophage polarization and post-transcriptionally repressed by miR-631 [PMID:31844669, PMID:33344226].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing the epigenetic control of PTPRE expression answered how PTPRE is transcriptionally induced during macrophage polarization: the lncRNA PTPRE-AS1 recruits WDR5 to deposit H3K4me3 at the PTPRE promoter, linking PTPRE to MAPK/ERK1/2-dependent M2 macrophage activation.\",\n      \"evidence\": \"lncRNA knockdown, ChIP for H3K4me3, WDR5 pulldown, in vivo mouse models with MAPK/ERK1/2 readouts\",\n      \"pmids\": [\"31844669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional chromatin modifiers besides WDR5 regulate PTPRE expression is untested\",\n        \"The specific phosphatase substrates through which PTPRE feeds into ERK1/2 signaling in macrophages are not identified\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of miR-631 as a direct post-transcriptional repressor of PTPRE revealed a second layer of PTPRE regulation and showed that PTPRE itself is sufficient to drive migration, invasion, and EMT in hepatocellular carcinoma cells.\",\n      \"evidence\": \"miR-631 target validation with rescue experiments (PTPRE re-expression), migration/invasion/EMT assays in HCC cells\",\n      \"pmids\": [\"33344226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The direct phosphatase substrates mediating PTPRE-driven EMT in HCC remain unidentified\",\n        \"Whether miR-631 regulation of PTPRE operates in non-HCC contexts is unexplored\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating a physical association between PTPRE and KIT identified a direct receptor tyrosine kinase substrate and revealed that PTPRE can inhibit oncogenic KIT mutants found in GISTs but is less effective against mastocytosis-type mutants such as D816V.\",\n      \"evidence\": \"Co-immunoprecipitation, dose-dependent expression/activation analysis, Western blot for KIT phosphorylation\",\n      \"pmids\": [\"33732906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reciprocal Co-IP or proximity-based validation of the PTPRE–KIT interaction has not been reported\",\n        \"The structural basis for differential inhibition of GIST-type versus mastocytosis-type KIT mutants is unknown\",\n        \"In vivo relevance of PTPRE-mediated KIT dephosphorylation is not established\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Gain- and loss-of-function experiments in thyroid carcinoma cells established that PTPRE activates both AKT and ERK1/2 pathways to promote proliferation, migration, invasion, and EMT, broadening PTPRE's oncogenic role beyond HCC.\",\n      \"evidence\": \"PTPRE knockdown/overexpression with Western blot for p-AKT and p-ERK1/2, proliferation, wound healing, transwell invasion, and EMT marker assays\",\n      \"pmids\": [\"36654463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The direct phosphatase targets upstream of AKT and ERK1/2 activation are not defined\",\n        \"Whether PTPRE activates these pathways by dephosphorylating inhibitory sites on kinases or adaptors is unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Pharmacological inhibition of PTPRE with Cpd-63 and genetic knockdown in drug-resistant retinoblastoma cells showed that PTPRE sustains cancer cell survival through SRC/MYC signaling and additional SGK3/AKT/ERK1/2 pathways, and that PTPRE loss re-sensitizes cells to etoposide.\",\n      \"evidence\": \"Small-molecule inhibitor (Cpd-63) in HCC organoids; lentiviral PTPRE KD with caspase apoptosis assay and phospho-signaling readouts in retinoblastoma; in vivo CAM tumor model\",\n      \"pmids\": [\"38458013\", \"38674157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SRC is a direct PTPRE substrate or an indirect effector has not been resolved\",\n        \"SGK3 as a PTPRE-regulated kinase is observed in only one study and cell-line context\",\n        \"Off-target effects of Cpd-63 have not been excluded by orthogonal genetic approaches in the same system\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extending PTPRE's role to the cardiovascular system, in vivo experiments demonstrated that PTPRE regulates vascular smooth muscle cell phenotypic switching and vasomotor function in salt-sensitive hypertension via the MKK3/MKK6–JNK/p38 MAPK axis.\",\n      \"evidence\": \"Gene knockdown and overexpression in DOCA-salt hypertensive mice, aortic ring vasomotor assays, Western blot for MKK3/6, JNK, p38 phosphorylation, VSMC marker expression\",\n      \"pmids\": [\"41492999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PTPRE directly dephosphorylates MKK3/MKK6 or acts further upstream is not determined\",\n        \"The trigger linking hypertensive stimuli to PTPRE expression or activity changes is not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of PTPRE's direct phosphatase substrates in most cellular contexts remains unresolved; it is unclear whether the diverse downstream pathway effects (AKT, ERK, JNK/p38, SRC) reflect direct dephosphorylation of multiple substrates or indirect consequences of one or few proximal targets.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No substrate-trapping or phosphoproteomics-based substrate identification has been reported\",\n        \"Structural basis for PTPRE substrate selectivity is unknown\",\n        \"Whether PTPRE's catalytic and non-catalytic PTP domains have distinct functional contributions has not been dissected\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3, 4, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 4, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KIT\",\n      \"WDR5\",\n      \"SRC\",\n      \"MKK3\",\n      \"MKK6\",\n      \"SGK3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA cloning and recombinant enzymatic activity assay in E. coli\",\n      \"pmids\": [\"2170109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous substrates unknown\", \"Physiological function not addressed\", \"No structural data for the catalytic domains\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA cloning, Northern blot, subcellular fractionation, PKC inhibitor studies in NIH 3T3 and HL-60 cells\",\n      \"pmids\": [\"8618876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional differences between isoforms not yet defined\", \"Cytoplasmic isoform substrates unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"PTPRE knockout mice, substrate-trapping co-IP with Kv2.1, electrophysiology in Xenopus oocytes and Schwann cells, HEK 293 reconstitution\",\n      \"pmids\": [\"10921884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation site on Kv2.1 not yet identified\", \"Whether transmembrane or cytoplasmic isoform mediates Schwann cell function unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Stable expression of wild-type and catalytically dead PTPepsilonC in M1 leukemia cells, phosphorylation blots for Jak-STAT components, differentiation/apoptosis assays\",\n      \"pmids\": [\"10859312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct dephosphorylation versus scaffolding not distinguished\", \"Physiological relevance in primary immune cells not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro Src phosphorylation, Y124F mutagenesis, substrate-trapping co-IP with D245A PTPRE, Xenopus oocyte electrophysiology\",\n      \"pmids\": [\"12615930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other Kv channel family members share this site unknown\", \"In vivo confirmation of Y124 relevance in myelination not performed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation, dose-dependent overexpression with phospho-KIT readout across multiple KIT mutant constructs\",\n      \"pmids\": [\"33732906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation site on KIT not mapped\", \"Endogenous interaction in mast cells or GIST tissue not demonstrated\", \"No loss-of-function validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Luciferase reporter assay for miR-631 targeting, PTPRE rescue experiments, migration/invasion/EMT assays, in vivo models\",\n      \"pmids\": [\"33344226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effector pathway not specified\", \"Single-lab finding\", \"Mechanism by which a phosphatase promotes EMT unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown and overexpression, phospho-AKT/ERK1/2 Western blot, proliferation/invasion/EMT assays in thyroid carcinoma lines\",\n      \"pmids\": [\"36654463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate mediating AKT/ERK activation unknown\", \"Paradox of a phosphatase activating kinase pathways not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Small molecule inhibitor Cpd-63, HCC cell lines and organoids, phospho-SRC and MYC Western blot, drug combination assays\",\n      \"pmids\": [\"38458013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cpd-63 selectivity across PTP family not fully characterized\", \"Whether PTPRE directly dephosphorylates SRC inhibitory Y527 in HCC not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Lentiviral KD, caspase activity assays, CAM in vivo assay, phospho-SGK3/AKT/ERK1/2 blots, miR-631 overexpression rescue\",\n      \"pmids\": [\"38674157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SGK3 as a direct PTPRE substrate not validated\", \"Mechanism of chemoresistance modulation unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"Bidirectional PTPRE manipulation in DOCA-salt hypertensive mice, aortic ring vasomotor assays, phospho-JNK/p38/MKK3/MKK6 Western blot\",\n      \"pmids\": [\"41492999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PTPRE substrate in VSMCs not identified\", \"Isoform responsible not defined\", \"Single hypertension model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 4, 6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [4, 9, 11, 12, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 9, 11, 12, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KV2.1\",\n      \"KV1.5\",\n      \"JAK1\",\n      \"TYK2\",\n      \"STAT3\",\n      \"KIT\",\n      \"SRC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway term_ids. I accidentally put a GO id. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA cloning and recombinant enzymatic activity assay in E. coli\",\n      \"pmids\": [\"2170109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous substrates unknown\", \"Physiological function not addressed\", \"No structural data for the catalytic domains\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA cloning, Northern blot, subcellular fractionation, PKC inhibitor studies in NIH 3T3 and HL-60 cells\",\n      \"pmids\": [\"8618876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional differences between isoforms not yet defined\", \"Cytoplasmic isoform substrates unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"PTPRE knockout mice, substrate-trapping co-IP with Kv2.1, electrophysiology in Xenopus oocytes and Schwann cells, HEK 293 reconstitution\",\n      \"pmids\": [\"10921884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation site on Kv2.1 not yet identified\", \"Whether transmembrane or cytoplasmic isoform mediates Schwann cell function unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Stable expression of wild-type and catalytically dead PTPepsilonC in M1 leukemia cells, phosphorylation blots for Jak-STAT components, differentiation/apoptosis assays\",\n      \"pmids\": [\"10859312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct dephosphorylation versus scaffolding not distinguished\", \"Physiological relevance in primary immune cells not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro Src phosphorylation, Y124F mutagenesis, substrate-trapping co-IP with D245A PTPRE, Xenopus oocyte electrophysiology\",\n      \"pmids\": [\"12615930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other Kv channel family members share this regulatory site unknown\", \"In vivo confirmation of Y124 relevance in myelination not performed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PTPRE was found to physically associate with and inhibit the KIT receptor tyrosine kinase, with mastocytosis-type KIT mutants largely resistant to PTPRE-mediated inhibition — revealing a new RTK substrate and a mechanism for mutant-selective escape from phosphatase control.\",\n      \"evidence\": \"Co-immunoprecipitation, dose-dependent overexpression with phospho-KIT readout across multiple KIT mutant constructs\",\n      \"pmids\": [\"33732906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation site on KIT not mapped\", \"Endogenous interaction in mast cells or GIST tissue not demonstrated\", \"No loss-of-function validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Luciferase reporter assay for miR-631 targeting, PTPRE rescue experiments, migration/invasion/EMT assays, in vivo models\",\n      \"pmids\": [\"33344226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effector pathway not specified\", \"Single-lab finding\", \"Mechanism by which a phosphatase promotes EMT unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown and overexpression, phospho-AKT/ERK1/2 Western blot, proliferation/invasion/EMT assays in thyroid carcinoma lines\",\n      \"pmids\": [\"36654463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate mediating AKT/ERK activation unknown\", \"Paradox of a phosphatase activating kinase pathways not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Pharmacological inhibition of PTPRE with Cpd-63 blocked SRC activation and MYC expression in HCC and sensitized cells to sorafenib, linking the phosphatase to the SRC-MYC axis and demonstrating therapeutic tractability.\",\n      \"evidence\": \"Small molecule inhibitor Cpd-63, HCC cell lines and organoids, phospho-SRC and MYC Western blot, drug combination assays\",\n      \"pmids\": [\"38458013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cpd-63 selectivity across PTP family not fully characterized\", \"Whether PTPRE directly dephosphorylates SRC inhibitory Y527 in HCC not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"PTPRE knockdown in etoposide-resistant retinoblastoma cells re-sensitized them to chemotherapy and induced apoptosis, with SGK3 phosphorylation as an additional downstream readout, broadening the spectrum of PTPRE-regulated kinases in drug resistance.\",\n      \"evidence\": \"Lentiviral KD, caspase activity assays, CAM in vivo assay, phospho-SGK3/AKT/ERK1/2 blots, miR-631 overexpression rescue\",\n      \"pmids\": [\"38674157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SGK3 as a direct PTPRE substrate not validated\", \"Mechanism of chemoresistance modulation unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"In hypertensive mice, PTPRE drives vascular smooth muscle cell phenotypic switching from contractile to synthetic via JNK/p38 MAPK and upstream kinases MKK3/MKK6, extending PTPRE's physiological roles to vascular remodeling.\",\n      \"evidence\": \"Bidirectional PTPRE manipulation in DOCA-salt hypertensive mice, aortic ring vasomotor assays, phospho-JNK/p38/MKK3/MKK6 Western blot\",\n      \"pmids\": [\"41492999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PTPRE substrate in VSMCs not identified\", \"Isoform responsible not defined\", \"Single hypertension model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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 or through indirect mechanisms — and which isoform mediates each context-dependent outcome.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 4, 6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 9, 11, 12, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KCNB1\",\n      \"KCNA5\",\n      \"JAK1\",\n      \"TYK2\",\n      \"STAT3\",\n      \"KIT\",\n      \"SRC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}