{"gene":"PTPN7","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1992,"finding":"PTPN7 (LC-PTP/HePTP) encodes a ~40 kDa non-transmembrane protein-tyrosine phosphatase preferentially expressed in hematopoietic cells, establishing it as a cytoplasmic PTP.","method":"cDNA cloning, Northern blot, sequence analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, molecular cloning with sequence analysis but no functional enzymatic assay","pmids":["1510684"],"is_preprint":false},{"year":1995,"finding":"In rat mast cells (basophilic leukemia 2H3 cells), HePTP localizes to discrete cytoplasmic compartments (not nucleus or plasma membrane) and is tyrosine-phosphorylated upon IgE receptor aggregation in a Ca2+-dependent manner.","method":"Immunofluorescence microscopy, two-dimensional electrophoresis, cell stimulation assays in Ca2+-free media","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence and functional phosphorylation assay, single lab with two orthogonal methods","pmids":["7545170"],"is_preprint":false},{"year":1998,"finding":"HePTP negatively regulates TCR signaling by dephosphorylating ERK2 (but not JNK); phosphatase-dead mutant C270S abolishes suppression of NFAT/AP-1 transcription and ERK activation.","method":"Reporter gene assay (NFAT/AP-1 luciferase), overexpression of WT and C270S mutant HePTP, immunoblot for phospho-ERK","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — active-site mutagenesis plus reporter assay and phospho-blot, single lab","pmids":["9624114"],"is_preprint":false},{"year":1999,"finding":"HePTP physically associates via its noncatalytic N-terminus with ERK1/2 and p38 (but not JNK), and overexpression reduces ERK catalytic activation in T cells; HePTP acts specifically on MAP kinases in the cytosol.","method":"Co-immunoprecipitation, deletion mutant analysis, kinase activity assays in intact T cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal association and kinase assay, single lab, two orthogonal approaches","pmids":["10206983"],"is_preprint":false},{"year":2000,"finding":"ERK2 (but not ERK1, p38, or JNK1) is a specific direct substrate of HePTP; substrate-trapping mutants (C/S and D/A) bind tyrosine-phosphorylated ERK2 in a phosphorylation-dependent manner; HePTP dephosphorylates ERK2 at the activation-loop tyrosine in vitro; the N-terminal region outside the catalytic domain is required for interaction.","method":"Substrate-trapping mutants (C/S and D/A), co-immunoprecipitation, in vitro phosphatase assay, deletion mutagenesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphatase assay with mutagenesis and substrate trapping, replicated conceptually with earlier T cell data","pmids":["10702794"],"is_preprint":false},{"year":2003,"finding":"HePTP and PP2A form a ~440 kDa complex that displays dual specificity pERK phosphatase activity (dephosphorylating both phosphotyrosine and phosphothreonine on ERK activation loop); acute cholesterol depletion disassembles this complex and abolishes dual-specificity pERK phosphatase activity.","method":"Biochemical fractionation/isolation of high MW complex, phosphatase activity assays (pTyr and pThr substrates), cholesterol depletion experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — complex isolation with in vitro dual-specificity phosphatase assay and pharmacological disassembly, single lab with multiple orthogonal methods","pmids":["12773382"],"is_preprint":false},{"year":2003,"finding":"The binding specificity of HePTP, STEP, and PTP-SL to ERK1/2 vs. p38α is determined by kinase-specificity sequences (KSS) adjacent to the KIM; under control conditions HePTP binds preferentially to p38α, but under reducing conditions p38α association is impaired while ERK1/2 association increases, indicating redox modulation of MAPK binding.","method":"Co-immunoprecipitation under control and reducing conditions, deletion/chimeric constructs, intact-cell assays of MAPK nuclear translocation","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mutants and two conditions (oxidizing/reducing), single lab","pmids":["12583813"],"is_preprint":false},{"year":2003,"finding":"HePTP regulates nuclear translocation of ERK2 in K562 cells; overexpression retains ERK2 in cytosol and impairs megakaryocytic differentiation markers (CD41, IL-6), while antisense knockdown enhances ERK2 nuclear translocation and those markers.","method":"Overexpression and antisense knockdown, subcellular fractionation/nuclear translocation assays, flow cytometry for CD41","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with nuclear translocation readout, single lab","pmids":["12592337"],"is_preprint":false},{"year":2004,"finding":"PKA phosphorylates HePTP at Ser-23 within the KIM, causing dissociation from ERK2; this phosphorylation is basally present in resting T cells, increased by cAMP-elevating agents (e.g., prostaglandin E2), and reversed by PP1 (not PP2A or calcineurin); PKA/PP1 thus continuously toggle HePTP–MAPK association.","method":"Phospho-specific immunoblot in intact T cells, PKA/PP1/PP2A inhibitors, ceramide treatment, transfection of PP1 catalytic subunit, in vitro phosphatase assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphatase assay identifying writer (PKA) and eraser (PP1) of Ser-23, corroborated by multiple pharmacological and genetic approaches in intact cells, single lab","pmids":["14613483"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of HePTP catalytic domain (residues 44–339) reveals classical PTP1B fold with WPD loop in closed conformation and phosphate bound at active site; structure shows that ERK2-mediated phosphorylation of HePTP at Thr45 and Ser72, and HePTP dephosphorylation of ERK2 at pTyr185, both require significant conformational changes in both proteins.","method":"X-ray crystallography of HePTP catalytic domain","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional interpretation of active-site geometry and phosphorylation sites","pmids":["16226275"],"is_preprint":false},{"year":2006,"finding":"Crystal structures of all three human KIM-PTP family members (PTPN5, PTPRR, PTPN7) were determined; PTPN7 structure shows WPD loop in closed conformation with the KIM Thr66 phosphorylation site accessible; two classes of small-molecule inhibitors (cyclopenta[c]quinolinecarboxylic acids and 2,5-dimethylpyrrolyl benzoic acids) were identified for the family.","method":"X-ray crystallography, compound library screening (24,000 compounds), docking","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution structures of full family with inhibitor SAR, single study with orthogonal structural and biochemical methods","pmids":["16441242"],"is_preprint":false},{"year":2010,"finding":"Crystal structures of HePTP in open (WPD loop open, 'atypically open' conformation) and closed states reveal that WPD loop opening involves coordinated movement of the E loop; E-loop residue Lys182 enhances catalytic activity through interaction with WPD-loop Asp236; a secondary oxyanion-binding site coordinates PTP, WPD, and E loops.","method":"X-ray crystallography (novel crystal form enabling open/closed transition), kinetic assays of E-loop mutants","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures combined with kinetic mutagenesis data establishing E-loop catalytic role","pmids":["21094165"],"is_preprint":false},{"year":2011,"finding":"SAXS combined with EROS ensemble refinement shows that the resting-state ERK2:HePTP complex adopts a highly extended, dynamic conformation, whereas the active-state complex (with phosphorylated ERK2) is compact and ordered, demonstrating significant dynamic structural reorganization upon activation.","method":"Small-angle X-ray scattering (SAXS), EROS ensemble refinement","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — solution structural characterization of both resting and active complexes with rigorous ensemble modeling, single lab","pmids":["21985012"],"is_preprint":false},{"year":2019,"finding":"In platelets, PTPN7 negatively regulates ERK1/2 phosphorylation and thromboxane A2 generation downstream of GPCR agonists (but not GPVI agonists); PTPN7 KO mice show elevated platelet aggregation, dense granule secretion, TXA2 generation, and faster thromboembolism death, all attributable to elevated ERK activity.","method":"PTPN7 knockout mouse model, platelet aggregometry, dense granule secretion assay, TXA2 ELISA, phospho-ERK immunoblot, pulmonary thromboembolism model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal functional readouts (aggregation, secretion, TXA2, ERK phosphorylation, in vivo model), clearly places PTPN7 in GPCR-ERK-TXA2 axis in platelets","pmids":["31266805"],"is_preprint":false},{"year":2019,"finding":"In triple-negative breast cancer cells, HePTP promotes migration and invasion by dephosphorylating GSK3β, thereby activating Wnt/β-catenin signaling; knockdown of HePTP suppresses metastatic capacity.","method":"siRNA knockdown, wound healing assay, transwell invasion assay, luciferase reporter for Wnt/β-catenin, nuclear fractionation for β-catenin, western blot for pGSK3β","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with multiple phenotypic readouts and proposed substrate (GSK3β), single lab; mechanistic link to GSK3β dephosphorylation needs direct in vitro validation","pmids":["31545274"],"is_preprint":false}],"current_model":"PTPN7 (HePTP/LC-PTP) is a hematopoietic cytoplasmic protein-tyrosine phosphatase that binds ERK1/2 and p38 MAP kinases via an N-terminal kinase-interaction motif (KIM), dephosphorylates ERK2 at its activation-loop tyrosine (pTyr185) to suppress T cell activation and platelet thromboxane generation, and is itself regulated by PKA phosphorylation at KIM-Ser23 (promoting MAPK dissociation) and dephosphorylation by PP1; it also participates in a cholesterol-sensitive ~440 kDa PP2A/HePTP dual-specificity pERK phosphatase complex, and structural studies reveal that its catalytic cycle involves coordinated WPD- and E-loop dynamics, while the ERK2:HePTP complex transitions from an extended dynamic resting state to a compact active state."},"narrative":{"mechanistic_narrative":"PTPN7 (HePTP/LC-PTP) is a hematopoietic cytoplasmic protein-tyrosine phosphatase that functions as a dedicated negative regulator of MAP kinase signaling [PMID:1510684, PMID:10702794]. It docks onto ERK1/2 and p38 (but not JNK) through a noncatalytic N-terminal kinase-interaction motif (KIM), and through this engagement dephosphorylates ERK2 at its activation-loop tyrosine, identifying ERK2 as its specific direct substrate [PMID:10206983, PMID:10702794]. By retaining dephosphorylated ERK2 in the cytosol, PTPN7 limits ERK2 nuclear translocation and the downstream transcriptional output (NFAT/AP-1), thereby dampening T-cell activation and shaping megakaryocytic differentiation [PMID:9624114, PMID:12592337]. The phosphatase activity is dynamically gated: PKA phosphorylates the KIM at Ser-23 to drive MAPK dissociation, and PP1 reverses this mark, so that the writer/eraser pair continuously toggles PTPN7–MAPK association in response to cAMP-elevating signals such as prostaglandin E2 [PMID:14613483]. PTPN7 also assembles into a cholesterol-sensitive ~440 kDa complex with PP2A that confers dual-specificity (pTyr and pThr) ERK phosphatase activity, an arrangement disrupted by cholesterol depletion [PMID:12773382]. Structural studies define a classical PTP1B-like catalytic fold whose cycle depends on coordinated WPD- and E-loop dynamics, with the ERK2:HePTP complex reorganizing from an extended, dynamic resting state to a compact active conformation upon ERK2 phosphorylation [PMID:16226275, PMID:21094165, PMID:21985012]. Physiologically, PTPN7 restrains GPCR-driven ERK1/2 signaling and thromboxane A2 generation in platelets [PMID:31266805], and a distinct role in dephosphorylating GSK3β to activate Wnt/β-catenin signaling has been described in triple-negative breast cancer cells [PMID:31545274].","teleology":[{"year":1992,"claim":"Established the molecular identity of PTPN7 as a hematopoietic-restricted cytoplasmic phosphatase, defining the protein class before any function was known.","evidence":"cDNA cloning, Northern blot, and sequence analysis","pmids":["1510684"],"confidence":"Medium","gaps":["No enzymatic activity demonstrated","No substrate or pathway identified"]},{"year":1995,"claim":"Linked PTPN7 to immune-receptor signaling by showing it occupies discrete cytoplasmic compartments and becomes tyrosine-phosphorylated in a Ca2+-dependent manner after IgE receptor aggregation.","evidence":"Immunofluorescence and 2D electrophoresis in stimulated rat mast cells","pmids":["7545170"],"confidence":"Medium","gaps":["Functional consequence of its phosphorylation unresolved","No substrate identified"]},{"year":1998,"claim":"Identified the MAPK arm targeted by PTPN7, showing it selectively suppresses ERK2 and downstream NFAT/AP-1 transcription in TCR signaling, dependent on catalytic activity.","evidence":"Reporter assays and phospho-ERK blots with WT vs catalytically dead C270S in T cells","pmids":["9624114"],"confidence":"Medium","gaps":["Direct vs indirect dephosphorylation of ERK2 not distinguished","Mechanism of MAPK selectivity unknown"]},{"year":1999,"claim":"Mapped the docking determinant, showing the noncatalytic N-terminus mediates association with ERK1/2 and p38 but not JNK.","evidence":"Co-IP, deletion mutants, and kinase assays in intact T cells","pmids":["10206983"],"confidence":"Medium","gaps":["Did not establish which kinase is the direct enzymatic substrate","Structural basis of KIM binding not defined"]},{"year":2000,"claim":"Proved ERK2 is the specific direct substrate via phosphorylation-dependent substrate trapping and in vitro activation-loop tyrosine dephosphorylation, with the N-terminal region required for interaction.","evidence":"Substrate-trapping C/S and D/A mutants, Co-IP, and in vitro phosphatase assay","pmids":["10702794"],"confidence":"High","gaps":["Regulation of the dephosphorylation in vivo not addressed","Basis of ERK2 selectivity over ERK1 unexplained"]},{"year":2003,"claim":"Revealed that PTPN7 acts beyond a solo tyrosine phosphatase by forming a cholesterol-dependent ~440 kDa PP2A complex with combined pTyr/pThr ERK phosphatase activity.","evidence":"Complex isolation, dual-substrate phosphatase assays, and cholesterol depletion","pmids":["12773382"],"confidence":"High","gaps":["Stoichiometry and architecture of the complex unresolved","Physiological trigger for cholesterol-dependent assembly unknown"]},{"year":2003,"claim":"Defined the sequence determinants and redox sensitivity of MAPK selectivity, showing kinase-specificity sequences adjacent to the KIM bias ERK1/2 vs p38α binding.","evidence":"Co-IP under oxidizing/reducing conditions with chimeric constructs and nuclear translocation assays","pmids":["12583813"],"confidence":"Medium","gaps":["Physiological relevance of redox switching in vivo unclear","Molecular target of the redox modulation not identified"]},{"year":2003,"claim":"Connected PTPN7 to a differentiation program by showing it controls ERK2 nuclear translocation and megakaryocytic markers in K562 cells.","evidence":"Overexpression, antisense knockdown, fractionation, and flow cytometry","pmids":["12592337"],"confidence":"Medium","gaps":["Direct vs indirect control of differentiation not separated","Endogenous regulation not addressed"]},{"year":2004,"claim":"Established the regulatory switch governing PTPN7–MAPK engagement, identifying PKA as the Ser-23 writer that drives ERK2 dissociation and PP1 as the eraser.","evidence":"Phospho-specific blots, kinase/phosphatase inhibitors, PP1 transfection, and in vitro assays in T cells","pmids":["14613483"],"confidence":"High","gaps":["Structural impact of Ser-23 phosphorylation on KIM not resolved","Integration with the PP2A complex regulation unknown"]},{"year":2011,"claim":"Resolved the catalytic and conformational mechanism, defining the PTP1B-like fold, coordinated WPD/E-loop dynamics, and the extended-to-compact transition of the ERK2:HePTP complex.","evidence":"Multiple crystal structures of open/closed states with kinetic mutagenesis, plus SAXS/EROS ensemble modeling and inhibitor discovery","pmids":["16226275","16441242","21094165","21985012"],"confidence":"High","gaps":["No structure of the full ERK2:HePTP catalytic complex","Conformational coupling to KIM-Ser23 regulation not visualized"]},{"year":2019,"claim":"Extended PTPN7 function to platelet hemostasis and cancer, placing it in a GPCR-ERK-thromboxane axis in vivo and linking it to GSK3β/Wnt-driven invasion.","evidence":"PTPN7 knockout mice with platelet aggregometry, TXA2 ELISA, and thromboembolism model; siRNA, migration/invasion, and Wnt reporter assays in TNBC cells","pmids":["31266805","31545274"],"confidence":"High","gaps":["Direct dephosphorylation of GSK3β not validated in vitro","Whether platelet and tumor roles share the same regulatory mechanisms unknown"]},{"year":null,"claim":"How the distinct PTPN7 activities — ERK2 dephosphorylation, the PP2A dual-specificity complex, PKA/PP1 toggling, and the proposed GSK3β/Wnt axis — are integrated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of context-dependent substrate choice","Relationship between the PP2A complex and the KIM regulatory switch unexplored","GSK3β as a direct substrate awaits in vitro reconstitution"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,4,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[4,9,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,3,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[13]}],"complexes":["PP2A/HePTP ~440 kDa dual-specificity pERK phosphatase complex"],"partners":["MAPK1","MAPK3","MAPK14","PRKACA","PPP1CA","PPP2CA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35236","full_name":"Tyrosine-protein phosphatase non-receptor type 7","aliases":["Hematopoietic protein-tyrosine phosphatase","HEPTP","Protein-tyrosine phosphatase LC-PTP"],"length_aa":360,"mass_kda":40.5,"function":"Protein phosphatase that acts preferentially on tyrosine-phosphorylated MAPK1. Plays a role in the regulation of T and B-lymphocyte development and signal transduction","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/P35236/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPN7","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTPN7","total_profiled":1310},"omim":[{"mim_id":"176889","title":"PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 7; PTPN7","url":"https://www.omim.org/entry/176889"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":64.9},{"tissue":"lymphoid tissue","ntpm":71.0}],"url":"https://www.proteinatlas.org/search/PTPN7"},"hgnc":{"alias_symbol":["HEPTP","LC-PTP"],"prev_symbol":[]},"alphafold":{"accession":"P35236","domains":[{"cath_id":"3.90.190.10","chopping":"67-351","consensus_level":"medium","plddt":94.1518,"start":67,"end":351}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35236","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35236-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35236-F1-predicted_aligned_error_v6.png","plddt_mean":85.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPN7","jax_strain_url":"https://www.jax.org/strain/search?query=PTPN7"},"sequence":{"accession":"P35236","fasta_url":"https://rest.uniprot.org/uniprotkb/P35236.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35236/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35236"}},"corpus_meta":[{"pmid":"10206983","id":"PMC_10206983","title":"Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP).","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10206983","citation_count":120,"is_preprint":false},{"pmid":"12583813","id":"PMC_12583813","title":"Differential interaction of the tyrosine phosphatases PTP-SL, STEP and HePTP with the mitogen-activated protein kinases ERK1/2 and p38alpha is determined by a kinase specificity sequence and influenced by reducing agents.","date":"2003","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12583813","citation_count":103,"is_preprint":false},{"pmid":"12773382","id":"PMC_12773382","title":"A cholesterol-regulated PP2A/HePTP complex with dual specificity ERK1/2 phosphatase activity.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12773382","citation_count":70,"is_preprint":false},{"pmid":"9624114","id":"PMC_9624114","title":"Negative regulation of T cell antigen receptor signal transduction by hematopoietic tyrosine phosphatase (HePTP).","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9624114","citation_count":68,"is_preprint":false},{"pmid":"8309248","id":"PMC_8309248","title":"A hematopoietic protein tyrosine phosphatase (HePTP) gene that is amplified and overexpressed in myeloid malignancies maps to chromosome 1q32.1.","date":"1994","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/8309248","citation_count":62,"is_preprint":false},{"pmid":"16441242","id":"PMC_16441242","title":"Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases.","date":"2006","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/16441242","citation_count":58,"is_preprint":false},{"pmid":"1510684","id":"PMC_1510684","title":"Molecular cloning and chromosomal mapping of a human protein-tyrosine phosphatase LC-PTP.","date":"1992","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1510684","citation_count":55,"is_preprint":false},{"pmid":"14613483","id":"PMC_14613483","title":"Haematopoietic protein tyrosine phosphatase (HePTP) phosphorylation by cAMP-dependent protein kinase in T-cells: dynamics and subcellular location.","date":"2004","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/14613483","citation_count":38,"is_preprint":false},{"pmid":"10702794","id":"PMC_10702794","title":"The MAP-kinase ERK2 is a specific substrate of the protein tyrosine phosphatase HePTP.","date":"2000","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10702794","citation_count":37,"is_preprint":false},{"pmid":"16226275","id":"PMC_16226275","title":"Structure of the hematopoietic tyrosine phosphatase (HePTP) catalytic domain: structure of a KIM phosphatase with phosphate bound at the active site.","date":"2005","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16226275","citation_count":34,"is_preprint":false},{"pmid":"21094165","id":"PMC_21094165","title":"Visualizing active-site dynamics in single crystals of HePTP: opening of the WPD loop involves coordinated movement of the E loop.","date":"2010","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21094165","citation_count":31,"is_preprint":false},{"pmid":"36302748","id":"PMC_36302748","title":"Extracellular vesicles microRNA-592 of melanoma stem cells promotes metastasis through activation of MAPK/ERK signaling pathway by targeting PTPN7 in non-stemness melanoma cells.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36302748","citation_count":30,"is_preprint":false},{"pmid":"21985012","id":"PMC_21985012","title":"Resting and active states of the ERK2:HePTP complex.","date":"2011","source":"Journal of the American Chemical 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CDKN2B-AS1/miR-126-5p/PTPN7.","date":"2021","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/34384839","citation_count":23,"is_preprint":false},{"pmid":"31266805","id":"PMC_31266805","title":"The protein tyrosine phosphatase PTPN7 is a negative regulator of ERK activation and thromboxane generation in platelets.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31266805","citation_count":21,"is_preprint":false},{"pmid":"8307155","id":"PMC_8307155","title":"Induction of protein-tyrosine phosphatase LC-PTP by IL-2 in human T cells. LC-PTP is an early response gene.","date":"1994","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8307155","citation_count":21,"is_preprint":false},{"pmid":"36226189","id":"PMC_36226189","title":"Comprehensive analysis of PTPN gene family revealing PTPN7 as a novel biomarker for immuno-hot tumors in breast cancer.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36226189","citation_count":13,"is_preprint":false},{"pmid":"18728972","id":"PMC_18728972","title":"Immunohistochemical analyses of phosphatases in childhood B-cell lymphoma: lower expression of PTEN and HePTP and higher number of positive cells for nuclear SHP2 in B-cell lymphoma cases compared to controls.","date":"2008","source":"Pediatric hematology and oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18728972","citation_count":12,"is_preprint":false},{"pmid":"31545274","id":"PMC_31545274","title":"HePTP promotes migration and invasion in triple-negative breast cancer cells via activation of Wnt/β-catenin signaling.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/31545274","citation_count":11,"is_preprint":false},{"pmid":"19636879","id":"PMC_19636879","title":"Sequence-specific 1H, 13C and 15N backbone resonance assignments of the 34 kDa catalytic domain of human PTPN7.","date":"2008","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/19636879","citation_count":9,"is_preprint":false},{"pmid":"8084610","id":"PMC_8084610","title":"Structure of the human LC-PTP (HePTP) gene: similarity in genomic organization within protein-tyrosine phosphatase genes.","date":"1994","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8084610","citation_count":8,"is_preprint":false},{"pmid":"35155446","id":"PMC_35155446","title":"piR-121380 Is Involved in Cryo-Capacitation and Regulates Post-Thawed Boar Sperm Quality Through Phosphorylation of ERK2 via Targeting PTPN7.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35155446","citation_count":8,"is_preprint":false},{"pmid":"38581214","id":"PMC_38581214","title":"PTPN7 mediates macrophage-polarization and determines immunotherapy in gliomas: A single-cell sequencing analysis.","date":"2024","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38581214","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14007,"output_tokens":3656,"usd":0.048431,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11333,"output_tokens":3674,"usd":0.074258,"stage2_stop_reason":"end_turn"},"total_usd":0.122689,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"PTPN7 (LC-PTP/HePTP) encodes a ~40 kDa non-transmembrane protein-tyrosine phosphatase preferentially expressed in hematopoietic cells, establishing it as a cytoplasmic PTP.\",\n      \"method\": \"cDNA cloning, Northern blot, sequence analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, molecular cloning with sequence analysis but no functional enzymatic assay\",\n      \"pmids\": [\"1510684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"In rat mast cells (basophilic leukemia 2H3 cells), HePTP localizes to discrete cytoplasmic compartments (not nucleus or plasma membrane) and is tyrosine-phosphorylated upon IgE receptor aggregation in a Ca2+-dependent manner.\",\n      \"method\": \"Immunofluorescence microscopy, two-dimensional electrophoresis, cell stimulation assays in Ca2+-free media\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence and functional phosphorylation assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"7545170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"HePTP negatively regulates TCR signaling by dephosphorylating ERK2 (but not JNK); phosphatase-dead mutant C270S abolishes suppression of NFAT/AP-1 transcription and ERK activation.\",\n      \"method\": \"Reporter gene assay (NFAT/AP-1 luciferase), overexpression of WT and C270S mutant HePTP, immunoblot for phospho-ERK\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — active-site mutagenesis plus reporter assay and phospho-blot, single lab\",\n      \"pmids\": [\"9624114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HePTP physically associates via its noncatalytic N-terminus with ERK1/2 and p38 (but not JNK), and overexpression reduces ERK catalytic activation in T cells; HePTP acts specifically on MAP kinases in the cytosol.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutant analysis, kinase activity assays in intact T cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal association and kinase assay, single lab, two orthogonal approaches\",\n      \"pmids\": [\"10206983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ERK2 (but not ERK1, p38, or JNK1) is a specific direct substrate of HePTP; substrate-trapping mutants (C/S and D/A) bind tyrosine-phosphorylated ERK2 in a phosphorylation-dependent manner; HePTP dephosphorylates ERK2 at the activation-loop tyrosine in vitro; the N-terminal region outside the catalytic domain is required for interaction.\",\n      \"method\": \"Substrate-trapping mutants (C/S and D/A), co-immunoprecipitation, in vitro phosphatase assay, deletion mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphatase assay with mutagenesis and substrate trapping, replicated conceptually with earlier T cell data\",\n      \"pmids\": [\"10702794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HePTP and PP2A form a ~440 kDa complex that displays dual specificity pERK phosphatase activity (dephosphorylating both phosphotyrosine and phosphothreonine on ERK activation loop); acute cholesterol depletion disassembles this complex and abolishes dual-specificity pERK phosphatase activity.\",\n      \"method\": \"Biochemical fractionation/isolation of high MW complex, phosphatase activity assays (pTyr and pThr substrates), cholesterol depletion experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — complex isolation with in vitro dual-specificity phosphatase assay and pharmacological disassembly, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12773382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The binding specificity of HePTP, STEP, and PTP-SL to ERK1/2 vs. p38α is determined by kinase-specificity sequences (KSS) adjacent to the KIM; under control conditions HePTP binds preferentially to p38α, but under reducing conditions p38α association is impaired while ERK1/2 association increases, indicating redox modulation of MAPK binding.\",\n      \"method\": \"Co-immunoprecipitation under control and reducing conditions, deletion/chimeric constructs, intact-cell assays of MAPK nuclear translocation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mutants and two conditions (oxidizing/reducing), single lab\",\n      \"pmids\": [\"12583813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HePTP regulates nuclear translocation of ERK2 in K562 cells; overexpression retains ERK2 in cytosol and impairs megakaryocytic differentiation markers (CD41, IL-6), while antisense knockdown enhances ERK2 nuclear translocation and those markers.\",\n      \"method\": \"Overexpression and antisense knockdown, subcellular fractionation/nuclear translocation assays, flow cytometry for CD41\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with nuclear translocation readout, single lab\",\n      \"pmids\": [\"12592337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PKA phosphorylates HePTP at Ser-23 within the KIM, causing dissociation from ERK2; this phosphorylation is basally present in resting T cells, increased by cAMP-elevating agents (e.g., prostaglandin E2), and reversed by PP1 (not PP2A or calcineurin); PKA/PP1 thus continuously toggle HePTP–MAPK association.\",\n      \"method\": \"Phospho-specific immunoblot in intact T cells, PKA/PP1/PP2A inhibitors, ceramide treatment, transfection of PP1 catalytic subunit, in vitro phosphatase assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphatase assay identifying writer (PKA) and eraser (PP1) of Ser-23, corroborated by multiple pharmacological and genetic approaches in intact cells, single lab\",\n      \"pmids\": [\"14613483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of HePTP catalytic domain (residues 44–339) reveals classical PTP1B fold with WPD loop in closed conformation and phosphate bound at active site; structure shows that ERK2-mediated phosphorylation of HePTP at Thr45 and Ser72, and HePTP dephosphorylation of ERK2 at pTyr185, both require significant conformational changes in both proteins.\",\n      \"method\": \"X-ray crystallography of HePTP catalytic domain\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional interpretation of active-site geometry and phosphorylation sites\",\n      \"pmids\": [\"16226275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structures of all three human KIM-PTP family members (PTPN5, PTPRR, PTPN7) were determined; PTPN7 structure shows WPD loop in closed conformation with the KIM Thr66 phosphorylation site accessible; two classes of small-molecule inhibitors (cyclopenta[c]quinolinecarboxylic acids and 2,5-dimethylpyrrolyl benzoic acids) were identified for the family.\",\n      \"method\": \"X-ray crystallography, compound library screening (24,000 compounds), docking\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution structures of full family with inhibitor SAR, single study with orthogonal structural and biochemical methods\",\n      \"pmids\": [\"16441242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structures of HePTP in open (WPD loop open, 'atypically open' conformation) and closed states reveal that WPD loop opening involves coordinated movement of the E loop; E-loop residue Lys182 enhances catalytic activity through interaction with WPD-loop Asp236; a secondary oxyanion-binding site coordinates PTP, WPD, and E loops.\",\n      \"method\": \"X-ray crystallography (novel crystal form enabling open/closed transition), kinetic assays of E-loop mutants\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures combined with kinetic mutagenesis data establishing E-loop catalytic role\",\n      \"pmids\": [\"21094165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SAXS combined with EROS ensemble refinement shows that the resting-state ERK2:HePTP complex adopts a highly extended, dynamic conformation, whereas the active-state complex (with phosphorylated ERK2) is compact and ordered, demonstrating significant dynamic structural reorganization upon activation.\",\n      \"method\": \"Small-angle X-ray scattering (SAXS), EROS ensemble refinement\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — solution structural characterization of both resting and active complexes with rigorous ensemble modeling, single lab\",\n      \"pmids\": [\"21985012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In platelets, PTPN7 negatively regulates ERK1/2 phosphorylation and thromboxane A2 generation downstream of GPCR agonists (but not GPVI agonists); PTPN7 KO mice show elevated platelet aggregation, dense granule secretion, TXA2 generation, and faster thromboembolism death, all attributable to elevated ERK activity.\",\n      \"method\": \"PTPN7 knockout mouse model, platelet aggregometry, dense granule secretion assay, TXA2 ELISA, phospho-ERK immunoblot, pulmonary thromboembolism model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal functional readouts (aggregation, secretion, TXA2, ERK phosphorylation, in vivo model), clearly places PTPN7 in GPCR-ERK-TXA2 axis in platelets\",\n      \"pmids\": [\"31266805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In triple-negative breast cancer cells, HePTP promotes migration and invasion by dephosphorylating GSK3β, thereby activating Wnt/β-catenin signaling; knockdown of HePTP suppresses metastatic capacity.\",\n      \"method\": \"siRNA knockdown, wound healing assay, transwell invasion assay, luciferase reporter for Wnt/β-catenin, nuclear fractionation for β-catenin, western blot for pGSK3β\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with multiple phenotypic readouts and proposed substrate (GSK3β), single lab; mechanistic link to GSK3β dephosphorylation needs direct in vitro validation\",\n      \"pmids\": [\"31545274\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPN7 (HePTP/LC-PTP) is a hematopoietic cytoplasmic protein-tyrosine phosphatase that binds ERK1/2 and p38 MAP kinases via an N-terminal kinase-interaction motif (KIM), dephosphorylates ERK2 at its activation-loop tyrosine (pTyr185) to suppress T cell activation and platelet thromboxane generation, and is itself regulated by PKA phosphorylation at KIM-Ser23 (promoting MAPK dissociation) and dephosphorylation by PP1; it also participates in a cholesterol-sensitive ~440 kDa PP2A/HePTP dual-specificity pERK phosphatase complex, and structural studies reveal that its catalytic cycle involves coordinated WPD- and E-loop dynamics, while the ERK2:HePTP complex transitions from an extended dynamic resting state to a compact active state.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPN7 (HePTP/LC-PTP) is a hematopoietic cytoplasmic protein-tyrosine phosphatase that functions as a dedicated negative regulator of MAP kinase signaling [#0, #4]. It docks onto ERK1/2 and p38 (but not JNK) through a noncatalytic N-terminal kinase-interaction motif (KIM), and through this engagement dephosphorylates ERK2 at its activation-loop tyrosine, identifying ERK2 as its specific direct substrate [#3, #4]. By retaining dephosphorylated ERK2 in the cytosol, PTPN7 limits ERK2 nuclear translocation and the downstream transcriptional output (NFAT/AP-1), thereby dampening T-cell activation and shaping megakaryocytic differentiation [#2, #7]. The phosphatase activity is dynamically gated: PKA phosphorylates the KIM at Ser-23 to drive MAPK dissociation, and PP1 reverses this mark, so that the writer/eraser pair continuously toggles PTPN7–MAPK association in response to cAMP-elevating signals such as prostaglandin E2 [#8]. PTPN7 also assembles into a cholesterol-sensitive ~440 kDa complex with PP2A that confers dual-specificity (pTyr and pThr) ERK phosphatase activity, an arrangement disrupted by cholesterol depletion [#5]. Structural studies define a classical PTP1B-like catalytic fold whose cycle depends on coordinated WPD- and E-loop dynamics, with the ERK2:HePTP complex reorganizing from an extended, dynamic resting state to a compact active conformation upon ERK2 phosphorylation [#9, #11, #12]. Physiologically, PTPN7 restrains GPCR-driven ERK1/2 signaling and thromboxane A2 generation in platelets [#13], and a distinct role in dephosphorylating GSK3β to activate Wnt/β-catenin signaling has been described in triple-negative breast cancer cells [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the molecular identity of PTPN7 as a hematopoietic-restricted cytoplasmic phosphatase, defining the protein class before any function was known.\",\n      \"evidence\": \"cDNA cloning, Northern blot, and sequence analysis\",\n      \"pmids\": [\"1510684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity demonstrated\", \"No substrate or pathway identified\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Linked PTPN7 to immune-receptor signaling by showing it occupies discrete cytoplasmic compartments and becomes tyrosine-phosphorylated in a Ca2+-dependent manner after IgE receptor aggregation.\",\n      \"evidence\": \"Immunofluorescence and 2D electrophoresis in stimulated rat mast cells\",\n      \"pmids\": [\"7545170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of its phosphorylation unresolved\", \"No substrate identified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identified the MAPK arm targeted by PTPN7, showing it selectively suppresses ERK2 and downstream NFAT/AP-1 transcription in TCR signaling, dependent on catalytic activity.\",\n      \"evidence\": \"Reporter assays and phospho-ERK blots with WT vs catalytically dead C270S in T cells\",\n      \"pmids\": [\"9624114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect dephosphorylation of ERK2 not distinguished\", \"Mechanism of MAPK selectivity unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapped the docking determinant, showing the noncatalytic N-terminus mediates association with ERK1/2 and p38 but not JNK.\",\n      \"evidence\": \"Co-IP, deletion mutants, and kinase assays in intact T cells\",\n      \"pmids\": [\"10206983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish which kinase is the direct enzymatic substrate\", \"Structural basis of KIM binding not defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Proved ERK2 is the specific direct substrate via phosphorylation-dependent substrate trapping and in vitro activation-loop tyrosine dephosphorylation, with the N-terminal region required for interaction.\",\n      \"evidence\": \"Substrate-trapping C/S and D/A mutants, Co-IP, and in vitro phosphatase assay\",\n      \"pmids\": [\"10702794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of the dephosphorylation in vivo not addressed\", \"Basis of ERK2 selectivity over ERK1 unexplained\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed that PTPN7 acts beyond a solo tyrosine phosphatase by forming a cholesterol-dependent ~440 kDa PP2A complex with combined pTyr/pThr ERK phosphatase activity.\",\n      \"evidence\": \"Complex isolation, dual-substrate phosphatase assays, and cholesterol depletion\",\n      \"pmids\": [\"12773382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the complex unresolved\", \"Physiological trigger for cholesterol-dependent assembly unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the sequence determinants and redox sensitivity of MAPK selectivity, showing kinase-specificity sequences adjacent to the KIM bias ERK1/2 vs p38α binding.\",\n      \"evidence\": \"Co-IP under oxidizing/reducing conditions with chimeric constructs and nuclear translocation assays\",\n      \"pmids\": [\"12583813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of redox switching in vivo unclear\", \"Molecular target of the redox modulation not identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected PTPN7 to a differentiation program by showing it controls ERK2 nuclear translocation and megakaryocytic markers in K562 cells.\",\n      \"evidence\": \"Overexpression, antisense knockdown, fractionation, and flow cytometry\",\n      \"pmids\": [\"12592337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect control of differentiation not separated\", \"Endogenous regulation not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the regulatory switch governing PTPN7–MAPK engagement, identifying PKA as the Ser-23 writer that drives ERK2 dissociation and PP1 as the eraser.\",\n      \"evidence\": \"Phospho-specific blots, kinase/phosphatase inhibitors, PP1 transfection, and in vitro assays in T cells\",\n      \"pmids\": [\"14613483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural impact of Ser-23 phosphorylation on KIM not resolved\", \"Integration with the PP2A complex regulation unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the catalytic and conformational mechanism, defining the PTP1B-like fold, coordinated WPD/E-loop dynamics, and the extended-to-compact transition of the ERK2:HePTP complex.\",\n      \"evidence\": \"Multiple crystal structures of open/closed states with kinetic mutagenesis, plus SAXS/EROS ensemble modeling and inhibitor discovery\",\n      \"pmids\": [\"16226275\", \"16441242\", \"21094165\", \"21985012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the full ERK2:HePTP catalytic complex\", \"Conformational coupling to KIM-Ser23 regulation not visualized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended PTPN7 function to platelet hemostasis and cancer, placing it in a GPCR-ERK-thromboxane axis in vivo and linking it to GSK3β/Wnt-driven invasion.\",\n      \"evidence\": \"PTPN7 knockout mice with platelet aggregometry, TXA2 ELISA, and thromboembolism model; siRNA, migration/invasion, and Wnt reporter assays in TNBC cells\",\n      \"pmids\": [\"31266805\", \"31545274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct dephosphorylation of GSK3β not validated in vitro\", \"Whether platelet and tumor roles share the same regulatory mechanisms unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct PTPN7 activities — ERK2 dephosphorylation, the PP2A dual-specificity complex, PKA/PP1 toggling, and the proposed GSK3β/Wnt axis — are integrated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of context-dependent substrate choice\", \"Relationship between the PP2A complex and the KIM regulatory switch unexplored\", \"GSK3β as a direct substrate awaits in vitro reconstitution\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 4, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [4, 9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"PP2A/HePTP ~440 kDa dual-specificity pERK phosphatase complex\"],\n    \"partners\": [\"MAPK1\", \"MAPK3\", \"MAPK14\", \"PRKACA\", \"PPP1CA\", \"PPP2CA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}