{"gene":"PTPN9","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2010,"finding":"PTPN9 directly dephosphorylates ErbB2 and EGFR (but not ErbB3 or Shc) as substrates, demonstrated by substrate-trapping mutant (DA) co-immunoprecipitation and GST pulldown showing preferential association with phospho-ErbB2/EGFR, and by WT overexpression inhibiting while DA mutant enhancing their tyrosyl phosphorylation. PTPN9 WT expression also specifically impairs EGF-induced STAT3 and STAT5 activation.","method":"Substrate-trapping mutant (DA) overexpression, co-immunoprecipitation, GST-fusion pulldown, siRNA knockdown, soft agar growth assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — substrate-trapping mutagenesis plus reciprocal Co-IP/pulldown, multiple orthogonal methods in one study, replicated by miR-24 study (PMID:23418360)","pmids":["20335174"],"is_preprint":false},{"year":2012,"finding":"PTPN9 (PTPMeg2) directly interacts with STAT3 and mediates its dephosphorylation in the cytoplasm; overexpression decreases STAT3 tyrosine phosphorylation and suppresses STAT3 transcriptional activity, while depletion increases phosphorylation.","method":"Immunoprecipitation, biochemical dephosphorylation assays, siRNA knockdown, overexpression in MCF7 and MDA-MB-231 cells, in vivo tumor growth assay","journal":"Breast cancer research : BCR","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct interaction by Co-IP, biochemical dephosphorylation assay, loss- and gain-of-function, replicated across multiple studies (PMID:24727614, PMID:30804683, PMID:38656553)","pmids":["22394684"],"is_preprint":false},{"year":2002,"finding":"Overexpression of PTP-MEG2 causes striking enlargement of secretory vesicles in mast cells and Jurkat T cells and reduces IL-2 secretion; these effects require the catalytic activity of PTP-MEG2 (reversed by pervanadate and abolished by catalytic mutants).","method":"Overexpression in RBL mast cells and Jurkat T cells, immunofluorescence, electron microscopy, IL-2 secretion assay, catalytic mutant analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional imaging plus catalytic mutant requirement established in two cell types, replicated in genetic knockout model (PMID:16330817)","pmids":["11971009"],"is_preprint":false},{"year":2003,"finding":"The N-terminal Sec14p homology domain of PTP-MEG2 binds PtdIns(3,4,5)P3 in vitro and colocalizes with this lipid on secretory vesicle membranes; point mutations preventing PtdIns(3,4,5)P3 binding abolish homotypic secretory vesicle fusion. Inhibition of cellular PtdIns(3,4,5)P3 synthesis rapidly reverses vesicle fusion by PTP-MEG2.","method":"In vitro lipid binding assay, point mutagenesis, immunofluorescence colocalization, PI3K inhibitor treatment, cell-based vesicle fusion assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding plus structure-function mutagenesis plus pharmacological perturbation, multiple orthogonal methods","pmids":["14662869"],"is_preprint":false},{"year":2003,"finding":"PTP-MEG2 specifically binds phosphatidylserine among >20 lipids tested, mediated by its N-terminal Sec14 domain; the Sec14 domain is responsible for perinuclear localization of PTP-MEG2 in intact cells, and exogenous phosphatidylserine loading causes translocation of PTP-MEG2 to the plasma membrane.","method":"Lipid-membrane overlay assay, liposome binding assay, deletion mutant analysis, cell fractionation/immunofluorescence localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro lipid binding with domain mapping plus cell localization assay, multiple orthogonal methods in one study","pmids":["12702726"],"is_preprint":false},{"year":2001,"finding":"MEG2 is localized predominantly in the cytosol with components in secondary/tertiary granules and secretory vesicles of neutrophils, and associates at an early stage with nascent phagosomes. Cysteine 515 is essential for catalytic activity. The N-terminal domain negatively regulates enzymatic activity of the C-terminal phosphatase domain. PTP-MEG2 activity is activated by polyphosphoinositides (PI 4,5-P2 > PI 3,4,5-P3 > PI 4-P) and inhibited by opsonized zymosan or PMA stimulation.","method":"Immunofluorescence, cell fractionation, immunoblotting, immunoprecipitation, in vitro phosphatase assay, GST-fusion protein mutagenesis (C515 mutation)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro activity assay with mutagenesis, cell fractionation, and lipid activation, multiple orthogonal methods","pmids":["11711529"],"is_preprint":false},{"year":2002,"finding":"Purified full-length PTP-MEG2 exhibits classical Michaelis-Menten kinetics with pNPP and phosphotyrosine substrates; the N-terminal lipid-binding domain has an inhibitory role on catalytic activity (truncated form lacking the domain shows significantly higher Vmax and lower Km than full-length enzyme).","method":"Recombinant protein purification (adenovirus and E. coli expression), in vitro phosphatase kinetics assay, gel exclusion chromatography","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic characterization with purified full-length vs. truncated proteins, quantitative kinetic comparison","pmids":["12112018"],"is_preprint":false},{"year":2005,"finding":"MEG2-deficient mice show >90% late embryonic lethality with hemorrhages, neural tube defects, and bone abnormalities. T lymphocytes and platelets from Meg2-/- hematopoietic chimeras display profound activation defects; T lymphocytes show impaired IL-2 secretion with near-complete absence of mature secretory vesicles by ultrastructural analysis. MEG2 binds PI(4,5)P2 and PI(3,4,5)P3 via its N-terminal lipid-binding domain.","method":"Knockout mouse generation, hematopoietic reconstitution (RAG2-/- chimeras), T cell activation assays, platelet activation assays, electron microscopy, lipid binding assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined cellular phenotype, ultrastructural validation, functional reconstitution in chimeric animals","pmids":["16330817"],"is_preprint":false},{"year":2006,"finding":"PTP-MEG2 antagonizes hepatic insulin signaling: ectopic expression inhibits insulin-induced phosphorylation of the insulin receptor and blocks insulin-dependent FOXO1 nuclear exclusion, while RNAi-mediated reduction enhances insulin action. Adenoviral depletion of PTP-MEG2 in livers of diabetic db/db mice normalizes hyperglycemia.","method":"Genome-scale functional screen, quantitative image analysis of FOXO1 localization, ectopic expression, RNAi knockdown, adenoviral liver-specific depletion in db/db mice, glucose homeostasis measurements","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro gain/loss of function plus in vivo mouse model with defined metabolic phenotype, multiple orthogonal approaches","pmids":["16679294"],"is_preprint":false},{"year":2007,"finding":"The N-terminal Sec14p domain (residues 1–261) of PTPMEG2 is necessary and sufficient for targeting to secretory vesicle membranes. Yeast two-hybrid screening identified TIP47 and Arfaptin2 as direct binding partners of the SEC14 domain; TIP47 overexpression alters PTPMEG2 localization and elimination of TIP47 causes loss of PTPMEG2 function. PTPMEG2 dephosphorylates NSF (N-ethylmaleimide-sensitive factor) to promote homotypic vesicle fusion.","method":"Deletion mutant analysis, yeast two-hybrid screen, Co-IP, overexpression/knockdown of TIP47, subcellular localization imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus functional co-localization with domain mapping and loss-of-function validation","pmids":["17387180"],"is_preprint":false},{"year":2003,"finding":"Elevated PTP-MEG2 activity in polycythemia vera (PV) erythroid progenitor cells is due to increased distribution of PTP-MEG2 in the membrane fraction. Expression of dominant-negative mutant forms of PTP-MEG2 suppresses in vitro growth and expansion of both normal and PV erythroid colony-forming cells.","method":"Cell fractionation, phosphatase activity assay, dominant-negative mutant overexpression, colony-forming assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative functional assay plus cell fractionation, single study with two methods","pmids":["12920026"],"is_preprint":false},{"year":2012,"finding":"PTP-MEG2 dephosphorylates VEGFR2 at Tyr1175 (a critical autophosphorylation site) in endothelial cells; substrate-trapping DA mutant preferentially co-immunoprecipitates with VEGFR2 but not WT PTP-MEG2. PTP-MEG2 DA mutant also preferentially associates with JAK1 (but not Tyk2 or JAK2) and regulates JAK1 tyrosine phosphorylation. PTP-MEG2 knockdown enhances VEGF-induced IL-6 production.","method":"Substrate-trapping (DA) mutant co-immunoprecipitation, overexpression/knockdown, phospho-specific immunoblotting, IL-6 ELISA","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate-trapping mutant Co-IP with phosphorylation readout, single lab, two substrates identified","pmids":["22763125"],"is_preprint":false},{"year":2012,"finding":"Crystal structures of PTP-MEG2–inhibitor complexes reveal that potent and selective inhibition is achieved by engaging both the active site and unique peripheral binding pockets on PTP-MEG2, with F2Pmp scaffold modifications providing selectivity. A selective cell-permeable inhibitor augments insulin signaling and improves glucose homeostasis in diet-induced obese mice.","method":"X-ray crystallography of inhibitor complexes, in vitro phosphatase inhibition assays, cell-based insulin signaling assays, diet-induced obese mouse model","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of enzyme-inhibitor complex with in vitro and in vivo functional validation","pmids":["23075115"],"is_preprint":false},{"year":2014,"finding":"Zebrafish ptpn9a is required for erythroid cell maturation; morpholino knockdown of ptpn9a impairs erythrocyte maturation and increases phosphorylated STAT3. Hyper-phosphorylated STAT3 sequesters transcription factors GATA1 and ZBP-89 into an inhibitory complex, preventing erythroid gene expression. Both dominant-negative PTPN9 (C515S) and siRNA in human K562 cells inhibit erythroid differentiation.","method":"Morpholino knockdown in zebrafish, dominant-negative overexpression, siRNA in K562 cells, immunoprecipitation, erythroid differentiation assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockdown in vivo (zebrafish), dominant-negative and siRNA in human cells, mechanistic epistasis via STAT3-GATA1-ZBP89 complex, multiple orthogonal methods","pmids":["24727614"],"is_preprint":false},{"year":2016,"finding":"PTP-MEG2 identifies TrkA (neurotrophin receptor) as a novel substrate and cargo; PTP-MEG2 dephosphorylates both Tyr-490 and Tyr-674/Tyr-675 of TrkA, and also facilitates TrkA transport to the cell surface via its vesicle fusion activity (dephosphorylation of NSF). Overexpression of PTP-MEG2 down-regulates NGF/TrkA signaling and blocks neurite outgrowth and differentiation in PC12 cells and cortical neurons.","method":"Substrate-trapping mutant, phospho-specific immunoblotting, neurite outgrowth assay in PC12 cells, overexpression in cortical neurons","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate-trapping identification with phosphorylation site mapping and functional neurite outgrowth phenotype, single lab","pmids":["27655914"],"is_preprint":false},{"year":2020,"finding":"PTPN9 promotes homotypic fusion of ATG16L1+ autophagosome precursor vesicles and is required for autophagosome formation and autophagic flux. PTPN9 dephosphorylates the Q-SNARE VTI1B; the nonphosphorylatable VTI1B mutant (but not phosphomimetic) enhances SNARE complex assembly and autophagic flux. Loss of PTPN9 and its Drosophila homolog Ptpmeg2 impairs autophagosome formation.","method":"siRNA knockdown in mammalian cells, RNAi in Drosophila, immunofluorescence colocalization, phospho-mutant analysis, SNARE complex assembly assay, autophagic flux assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — substrate identification with phospho-mutant epistasis, conserved function in Drosophila, SNARE complex assembly assay, multiple orthogonal methods across species","pmids":["33112705"],"is_preprint":false},{"year":2021,"finding":"PTP-MEG2 controls multiple steps of catecholamine secretion. Crystallographic and biochemical analyses reveal key residues governing PTP-MEG2 interaction with phosphorylated NSF-pY83, specifying substrate selectivity and modulating vesicle fusion. PTP-MEG2 controls fusion pore opening through NSF-independent mechanisms by dephosphorylating DYNAMIN2-pY125 and MUNC18-1-pY145, with a distinct structural basis from the NSF-pY83 interaction.","method":"X-ray crystallography, biochemical interaction assays, electrochemical secretion assays, site-directed mutagenesis, bioinformatics substrate screening","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of substrate-enzyme complex plus mutagenesis plus functional secretion assay, three substrates identified with distinct structural interfaces","pmids":["33764618"],"is_preprint":false},{"year":2023,"finding":"PTPN9 interacts with FGFR2 through ACAP1 mediation (via the Sec14p domain of PTPN9) and dephosphorylates FGFR2 at pY656/657. Key interaction residues include the 'YRETRRKE' motif of Sec14p, Y471 of PTPN9, and the PH and Arf-GAP domains of ACAP1. The FGFR2 I654V substitution decreases PTPN9-FGFR2 interaction and reduces pemigatinib effectiveness. PTPN9 synergistically enhances pemigatinib efficacy in cholangiocarcinoma.","method":"Co-immunoprecipitation, phosphatase activity assays, structural modeling of FGFR2-PTPN9 complex, site-directed mutagenesis, patient-derived xenograft models, in vitro and in vivo functional experiments","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structural modeling with mutagenesis, biochemical phosphatase assays, PDX in vivo model, multiple orthogonal methods identifying a three-protein complex","pmids":["37505213"],"is_preprint":false},{"year":2018,"finding":"MEG2 inhibits AKT phosphorylation in hepatocellular carcinoma cells; MEG2 overexpression inhibits EMT and AKT phosphorylation, and the promoting effects of MEG2 knockdown on cell viability, migration, and invasion are blocked by AKT phosphorylation inhibition, placing MEG2 upstream of AKT in this pathway.","method":"Western blot, overexpression and siRNA knockdown, cell viability/migration/invasion assays, AKT inhibitor epistasis, subcutaneous and tail-vein injection mouse models","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with AKT inhibitor plus gain/loss of function, single lab, pathway placement supported by pharmacological rescue","pmids":["30399427"],"is_preprint":false},{"year":2024,"finding":"MEG2 and PKCε competitively bind STAT3; PKCε displays stronger binding to STAT3 than MEG2. STAT3 Ser727 phosphorylation increases interaction with both PKCε and MEG2. MEG2 binding to STAT3 suppresses IL-6 promoter activity and reduces inflammatory pain signaling in microglia, while PKCε promotes it. ERK1/2 facilitates MEG2-STAT3 interaction leading to STAT3 Tyr705 dephosphorylation.","method":"Co-immunoprecipitation, ELISA, dual-luciferase assay, Western blot, overexpression in vivo (FCA mouse model) and in vitro (LPS-stimulated microglia), von Frey test","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with competition assay, functional in vivo and in vitro, single lab","pmids":["38656553"],"is_preprint":false},{"year":2025,"finding":"PTPN9 dephosphorylates IGF1R preferentially at Y1166 (within the Y1165/1166 activation loop); crystal structure analysis identified Tyr333 and Asp335 as key PTPN9 residues interacting with IGF1R, and mutation of these residues restores IGF1R signaling and abolishes tumor-suppressive effects of PTPN9 in cholangiocarcinoma.","method":"IP-MS substrate identification, crystal structure analysis, biochemical dephosphorylation assay, site-directed mutagenesis, orthotopic mouse models, surufatinib-resistant cell line","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with active-site mutagenesis plus biochemical assay plus in vivo model, single lab but multiple orthogonal methods","pmids":["41275311"],"is_preprint":false},{"year":2026,"finding":"ERK1/2 (activated by SARS-CoV-2 Mpro via TRAF6-TAK1 signaling) facilitates interaction between STAT3 and MEG2, leading to dephosphorylation of STAT3 at Tyr705 and suppression of ACE2 expression; ERK1/2 inhibition restores STAT3 activity and ACE2 levels.","method":"Overexpression of Mpro and catalytic mutant, ERK1/2 inhibitor treatment, immunoprecipitation, Western blot for pSTAT3/ACE2, SARS-CoV-2 single-round infectious particles","journal":"Journal of medical virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with pharmacological perturbation and rescue experiments, single lab, functional pathway placement","pmids":["41728757"],"is_preprint":false}],"current_model":"PTPN9 (PTP-MEG2) is a non-receptor protein tyrosine phosphatase with an N-terminal Sec14p/lipid-binding domain that targets the enzyme to secretory vesicle membranes via phosphatidylserine and PtdIns(3,4,5)P3 binding and interactions with TIP47/Arfaptin2; at vesicles it dephosphorylates NSF-pY83, DYNAMIN2-pY125, and MUNC18-1-pY145 to control vesicle fusion, quantal size, and fusion pore opening, and dephosphorylates VTI1B to promote ATG16L1+ autophagosome precursor fusion; in growth-factor and cytokine signaling it acts as a negative regulator by directly dephosphorylating EGFR, ErbB2, VEGFR2, TrkA, FGFR2 (pY656/657 via ACAP1 scaffold), and IGF1R (pY1165/1166), and dephosphorylates STAT3-pY705 in the cytoplasm to suppress STAT3 transcriptional activity; in insulin/metabolic signaling it antagonizes insulin receptor phosphorylation and downstream FOXO1 nuclear exclusion; and its localization and activity are regulated by polyphosphoinositides and competitive interactions with kinases such as PKCε."},"narrative":{"mechanistic_narrative":"PTPN9 (PTP-MEG2) is a non-receptor protein tyrosine phosphatase that couples membrane lipid sensing to the control of secretory vesicle dynamics and the negative regulation of receptor tyrosine kinase and STAT signaling [PMID:14662869, PMID:17387180, PMID:20335174]. Its catalytic activity depends on the active-site cysteine C515 and is intramolecularly restrained by an N-terminal Sec14p/lipid-binding domain, which lowers the enzyme's Vmax until it is engaged by membrane phosphoinositides; polyphosphoinositides (PI(4,5)P2 > PI(3,4,5)P3) activate the phosphatase, while opsonized zymosan or PMA stimulation inhibits it [PMID:11711529, PMID:12112018]. The Sec14p domain binds phosphatidylserine and PtdIns(3,4,5)P3 and is necessary and sufficient to target the enzyme to secretory vesicle membranes, where, together with its partners TIP47 and Arfaptin2, it drives homotypic vesicle fusion [PMID:14662869, PMID:12702726, PMID:17387180]. At these membranes PTP-MEG2 dephosphorylates the fusion machinery — NSF-pY83, and through NSF-independent routes DYNAMIN2-pY125 and MUNC18-1-pY145 — to regulate vesicle enlargement, fusion pore opening, and quantal secretion, and dephosphorylates the Q-SNARE VTI1B to promote SNARE assembly and ATG16L1+ autophagosome precursor fusion during autophagy [PMID:17387180, PMID:33764618, PMID:33112705]. As a signaling antagonist, PTP-MEG2 directly dephosphorylates the receptor tyrosine kinases ErbB2/EGFR, VEGFR2 (Tyr1175), TrkA, FGFR2 (pY656/657, via an ACAP1 scaffold engaging its Sec14p domain), and IGF1R (Y1166), and dephosphorylates cytoplasmic STAT3 at Tyr705 to suppress STAT3-dependent transcription [PMID:20335174, PMID:22763125, PMID:27655914, PMID:37505213, PMID:41275311, PMID:22394684]. Through these activities it restrains growth-factor and cytokine signaling, controls erythroid maturation by relieving STAT3-mediated sequestration of GATA1/ZBP-89 [PMID:24727614], and antagonizes hepatic insulin receptor signaling and FOXO1 nuclear exclusion, such that its depletion normalizes hyperglycemia in db/db mice [PMID:16679294]. Genetic loss in mice causes late embryonic lethality with secretory and hematopoietic defects, underscoring its essential role in regulated secretion [PMID:16330817].","teleology":[{"year":2001,"claim":"Established the catalytic and regulatory architecture of MEG2 — that activity requires Cys515 and is autoinhibited by the N-terminal domain and tuned by lipids — defining how a phosphatase could be membrane-regulated.","evidence":"Cell fractionation, in vitro phosphatase assay, and GST-fusion mutagenesis (C515) with lipid activation in neutrophils","pmids":["11711529"],"confidence":"High","gaps":["Did not identify physiological protein substrates","Mechanism by which lipids relieve N-terminal autoinhibition not resolved structurally"]},{"year":2002,"claim":"Showed catalytic activity controls secretory vesicle morphology and secretion, linking the phosphatase to regulated exocytosis rather than generic signaling.","evidence":"Overexpression in mast and Jurkat T cells with EM, IL-2 secretion assays, and catalytic mutant rescue; in vitro kinetics of full-length vs. truncated enzyme","pmids":["11971009","12112018"],"confidence":"High","gaps":["Vesicle substrate(s) at the fusion machinery not yet identified","Connection between enlargement and secretion block mechanistically unclear"]},{"year":2003,"claim":"Defined the Sec14p domain as a lipid sensor binding phosphatidylserine and PtdIns(3,4,5)P3 that targets the enzyme to vesicle membranes and is required for homotypic fusion, explaining how membrane lipids spatially control activity.","evidence":"In vitro lipid overlay/liposome binding, domain mapping, point mutagenesis, colocalization, and PI3K inhibitor perturbation","pmids":["14662869","12702726"],"confidence":"High","gaps":["Did not identify the dephosphorylated fusion substrate","Membrane partner proteins not yet defined"]},{"year":2005,"claim":"Genetic knockout established the organismal essentiality of MEG2 and confirmed its requirement for mature secretory vesicle biogenesis and immune cell activation.","evidence":"Meg2-/- mice and RAG2-/- hematopoietic chimeras with T cell/platelet activation assays, EM, and lipid binding","pmids":["16330817"],"confidence":"High","gaps":["Embryonic lethality obscures tissue-specific roles","Molecular substrate driving vesicle maturation not pinpointed here"]},{"year":2006,"claim":"Placed MEG2 as a negative regulator of insulin receptor signaling in liver, establishing a metabolic role and a therapeutic rationale.","evidence":"Functional screen, FOXO1 localization imaging, RNAi/ectopic expression, and adenoviral liver depletion in db/db mice","pmids":["16679294"],"confidence":"High","gaps":["Direct dephosphorylation of the insulin receptor by MEG2 not biochemically demonstrated here","Relationship to its vesicular role unaddressed"]},{"year":2007,"claim":"Identified TIP47 and Arfaptin2 as direct Sec14p-domain partners and NSF as a fusion substrate, providing the molecular machinery linking membrane targeting to vesicle fusion.","evidence":"Yeast two-hybrid, deletion mapping, Co-IP, TIP47 knockdown, and localization imaging","pmids":["17387180"],"confidence":"High","gaps":["NSF dephosphorylation site not defined in this study","How TIP47/Arfaptin2 coordinate with lipid binding unresolved"]},{"year":2010,"claim":"Established MEG2 as a direct phosphatase for ErbB2 and EGFR with substrate selectivity, extending its role to receptor tyrosine kinase signaling and downstream STAT activation.","evidence":"Substrate-trapping DA mutant Co-IP/GST pulldown, gain/loss of function, and STAT activation readouts","pmids":["20335174"],"confidence":"High","gaps":["Subcellular site of RTK dephosphorylation not localized","Whether vesicular targeting is required for RTK access unclear"]},{"year":2012,"claim":"Demonstrated direct STAT3 binding and Tyr705 dephosphorylation in the cytoplasm, and identified VEGFR2-Tyr1175 and JAK1 as additional targets, broadening MEG2 as a cytokine/growth-factor signaling brake.","evidence":"Co-IP and biochemical dephosphorylation in breast cancer cells; substrate-trapping Co-IP and phospho-immunoblot for VEGFR2/JAK1 in endothelial cells","pmids":["22394684","22763125"],"confidence":"High","gaps":["VEGFR2 and JAK1 findings from a single lab","Spatial coordination of STAT3 vs. RTK dephosphorylation not defined"]},{"year":2012,"claim":"Crystal structures of inhibitor complexes revealed unique peripheral pockets enabling selective inhibition and provided in vivo proof that pharmacological inhibition augments insulin signaling.","evidence":"X-ray crystallography of inhibitor complexes, phosphatase inhibition assays, and diet-induced obese mouse model","pmids":["23075115"],"confidence":"High","gaps":["No substrate-bound structure in this study","Selectivity over closely related phosphatases in cells not fully mapped"]},{"year":2014,"claim":"Connected MEG2-STAT3 regulation to erythroid maturation, showing loss elevates pSTAT3 which sequesters GATA1/ZBP-89, defining a developmental output of the phosphatase.","evidence":"Zebrafish morpholino knockdown, dominant-negative and siRNA in K562, and Co-IP of the STAT3-GATA1-ZBP89 complex","pmids":["24727614"],"confidence":"High","gaps":["Whether reduced erythroid maturation reflects STAT3 alone or additional substrates unclear"]},{"year":2016,"claim":"Identified TrkA as both a substrate and a cargo, uniting MEG2's dephosphorylation and vesicle-fusion functions in controlling neurotrophin receptor surface delivery and neurite outgrowth.","evidence":"Substrate-trapping, phospho-site mapping (Y490, Y674/675), and neurite outgrowth assays in PC12 cells and cortical neurons","pmids":["27655914"],"confidence":"Medium","gaps":["Single-lab finding","Quantitative contribution of trafficking vs. direct dephosphorylation to signaling output not separated"]},{"year":2020,"claim":"Extended the vesicle-fusion role into autophagy by identifying VTI1B as a Q-SNARE substrate required for ATG16L1+ precursor fusion, with conservation in Drosophila.","evidence":"siRNA in mammalian cells, Drosophila RNAi, phospho-mutant epistasis, SNARE assembly and autophagic flux assays","pmids":["33112705"],"confidence":"High","gaps":["Lipid/partner requirements for autophagosomal targeting not dissected","Upstream signals controlling VTI1B phosphorylation unknown"]},{"year":2021,"claim":"Provided structural basis for substrate selectivity at the fusion machinery, showing distinct interfaces for NSF-pY83 versus DYNAMIN2-pY125 and MUNC18-1-pY145 controlling separable secretion steps.","evidence":"X-ray crystallography of substrate-enzyme complexes, mutagenesis, and electrochemical catecholamine secretion assays","pmids":["33764618"],"confidence":"High","gaps":["How the same active site discriminates multiple substrates in cells not fully resolved","Regulation of step-specific substrate engagement unknown"]},{"year":2023,"claim":"Defined a scaffolded mechanism whereby ACAP1 bridges the Sec14p domain of PTPN9 to FGFR2, enabling pY656/657 dephosphorylation and modulating FGFR-inhibitor response in cholangiocarcinoma.","evidence":"Co-IP, phosphatase assays, structural modeling/mutagenesis (YRETRRKE motif, Y471; ACAP1 PH/Arf-GAP), and PDX models","pmids":["37505213"],"confidence":"High","gaps":["Whether ACAP1 scaffolding generalizes to other RTK substrates unknown","I654V resistance mechanism beyond reduced interaction not fully detailed"]},{"year":2024,"claim":"Revealed competitive regulation of STAT3 by MEG2 and PKCε and an ERK1/2-facilitated MEG2-STAT3 interaction, refining how MEG2 access to STAT3 is controlled in inflammatory contexts.","evidence":"Reciprocal Co-IP/competition, luciferase, and in vivo/in vitro inflammatory pain models","pmids":["38656553"],"confidence":"Medium","gaps":["Single-lab competition model","Structural basis of competitive STAT3 binding not resolved"]},{"year":2025,"claim":"Identified IGF1R-Y1166 as a substrate with structural definition of the interface (Tyr333, Asp335), linking PTPN9 tumor suppression to IGF1R signaling in cholangiocarcinoma.","evidence":"IP-MS, crystal structure analysis, biochemical dephosphorylation, active-site mutagenesis, and orthotopic mouse models","pmids":["41275311"],"confidence":"High","gaps":["Single-lab finding","Integration with parallel RTK substrates in the same tumor context not addressed"]},{"year":2026,"claim":"Placed the ERK1/2-facilitated MEG2-STAT3 axis in a viral context, showing SARS-CoV-2 Mpro signaling drives STAT3 Tyr705 dephosphorylation and ACE2 suppression.","evidence":"Mpro overexpression/catalytic mutant, ERK1/2 inhibitor rescue, Co-IP, and single-round infectious particle assays","pmids":["41728757"],"confidence":"Medium","gaps":["Single-lab pathway model","Direct ERK1/2 modification mediating MEG2-STAT3 assembly not biochemically defined"]},{"year":null,"claim":"How a single phosphatase coordinates its membrane-bound vesicle-fusion substrates with cytoplasmic RTK/STAT3 substrates — and what spatial or lipid cues partition these activities in vivo — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking lipid-regulated localization to substrate choice","Tissue-specific substrate priorities largely uncharacterized","In vivo relevance of individual RTK substrates outside cancer models unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,9,11,14,15,16,17,20]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[5,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,4,5,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,8]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,3,4,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,8,11,14,17,20]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,3,9,16]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,13]}],"complexes":[],"partners":["STAT3","EGFR","ERBB2","VEGFR2","FGFR2","ACAP1","NSF","TIP47"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43378","full_name":"Tyrosine-protein phosphatase non-receptor type 9","aliases":["Protein-tyrosine phosphatase MEG2","PTPase MEG2"],"length_aa":593,"mass_kda":68.0,"function":"Protein-tyrosine phosphatase that could participate in the transfer of hydrophobic ligands or in functions of the Golgi apparatus","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P43378/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPN9","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/PTPN9","total_profiled":1310},"omim":[{"mim_id":"601504","title":"SEC14-LIKE LIPID-BINDING PROTEIN 1; SEC14L1","url":"https://www.omim.org/entry/601504"},{"mim_id":"600768","title":"PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 9; PTPN9","url":"https://www.omim.org/entry/600768"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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2010,\n      \"finding\": \"PTPN9 directly dephosphorylates ErbB2 and EGFR (but not ErbB3 or Shc) as substrates, demonstrated by substrate-trapping mutant (DA) co-immunoprecipitation and GST pulldown showing preferential association with phospho-ErbB2/EGFR, and by WT overexpression inhibiting while DA mutant enhancing their tyrosyl phosphorylation. PTPN9 WT expression also specifically impairs EGF-induced STAT3 and STAT5 activation.\",\n      \"method\": \"Substrate-trapping mutant (DA) overexpression, co-immunoprecipitation, GST-fusion pulldown, siRNA knockdown, soft agar growth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — substrate-trapping mutagenesis plus reciprocal Co-IP/pulldown, multiple orthogonal methods in one study, replicated by miR-24 study (PMID:23418360)\",\n      \"pmids\": [\"20335174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTPN9 (PTPMeg2) directly interacts with STAT3 and mediates its dephosphorylation in the cytoplasm; overexpression decreases STAT3 tyrosine phosphorylation and suppresses STAT3 transcriptional activity, while depletion increases phosphorylation.\",\n      \"method\": \"Immunoprecipitation, biochemical dephosphorylation assays, siRNA knockdown, overexpression in MCF7 and MDA-MB-231 cells, in vivo tumor growth assay\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct interaction by Co-IP, biochemical dephosphorylation assay, loss- and gain-of-function, replicated across multiple studies (PMID:24727614, PMID:30804683, PMID:38656553)\",\n      \"pmids\": [\"22394684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Overexpression of PTP-MEG2 causes striking enlargement of secretory vesicles in mast cells and Jurkat T cells and reduces IL-2 secretion; these effects require the catalytic activity of PTP-MEG2 (reversed by pervanadate and abolished by catalytic mutants).\",\n      \"method\": \"Overexpression in RBL mast cells and Jurkat T cells, immunofluorescence, electron microscopy, IL-2 secretion assay, catalytic mutant analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional imaging plus catalytic mutant requirement established in two cell types, replicated in genetic knockout model (PMID:16330817)\",\n      \"pmids\": [\"11971009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The N-terminal Sec14p homology domain of PTP-MEG2 binds PtdIns(3,4,5)P3 in vitro and colocalizes with this lipid on secretory vesicle membranes; point mutations preventing PtdIns(3,4,5)P3 binding abolish homotypic secretory vesicle fusion. Inhibition of cellular PtdIns(3,4,5)P3 synthesis rapidly reverses vesicle fusion by PTP-MEG2.\",\n      \"method\": \"In vitro lipid binding assay, point mutagenesis, immunofluorescence colocalization, PI3K inhibitor treatment, cell-based vesicle fusion assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding plus structure-function mutagenesis plus pharmacological perturbation, multiple orthogonal methods\",\n      \"pmids\": [\"14662869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PTP-MEG2 specifically binds phosphatidylserine among >20 lipids tested, mediated by its N-terminal Sec14 domain; the Sec14 domain is responsible for perinuclear localization of PTP-MEG2 in intact cells, and exogenous phosphatidylserine loading causes translocation of PTP-MEG2 to the plasma membrane.\",\n      \"method\": \"Lipid-membrane overlay assay, liposome binding assay, deletion mutant analysis, cell fractionation/immunofluorescence localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro lipid binding with domain mapping plus cell localization assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12702726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MEG2 is localized predominantly in the cytosol with components in secondary/tertiary granules and secretory vesicles of neutrophils, and associates at an early stage with nascent phagosomes. Cysteine 515 is essential for catalytic activity. The N-terminal domain negatively regulates enzymatic activity of the C-terminal phosphatase domain. PTP-MEG2 activity is activated by polyphosphoinositides (PI 4,5-P2 > PI 3,4,5-P3 > PI 4-P) and inhibited by opsonized zymosan or PMA stimulation.\",\n      \"method\": \"Immunofluorescence, cell fractionation, immunoblotting, immunoprecipitation, in vitro phosphatase assay, GST-fusion protein mutagenesis (C515 mutation)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro activity assay with mutagenesis, cell fractionation, and lipid activation, multiple orthogonal methods\",\n      \"pmids\": [\"11711529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Purified full-length PTP-MEG2 exhibits classical Michaelis-Menten kinetics with pNPP and phosphotyrosine substrates; the N-terminal lipid-binding domain has an inhibitory role on catalytic activity (truncated form lacking the domain shows significantly higher Vmax and lower Km than full-length enzyme).\",\n      \"method\": \"Recombinant protein purification (adenovirus and E. coli expression), in vitro phosphatase kinetics assay, gel exclusion chromatography\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic characterization with purified full-length vs. truncated proteins, quantitative kinetic comparison\",\n      \"pmids\": [\"12112018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MEG2-deficient mice show >90% late embryonic lethality with hemorrhages, neural tube defects, and bone abnormalities. T lymphocytes and platelets from Meg2-/- hematopoietic chimeras display profound activation defects; T lymphocytes show impaired IL-2 secretion with near-complete absence of mature secretory vesicles by ultrastructural analysis. MEG2 binds PI(4,5)P2 and PI(3,4,5)P3 via its N-terminal lipid-binding domain.\",\n      \"method\": \"Knockout mouse generation, hematopoietic reconstitution (RAG2-/- chimeras), T cell activation assays, platelet activation assays, electron microscopy, lipid binding assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined cellular phenotype, ultrastructural validation, functional reconstitution in chimeric animals\",\n      \"pmids\": [\"16330817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PTP-MEG2 antagonizes hepatic insulin signaling: ectopic expression inhibits insulin-induced phosphorylation of the insulin receptor and blocks insulin-dependent FOXO1 nuclear exclusion, while RNAi-mediated reduction enhances insulin action. Adenoviral depletion of PTP-MEG2 in livers of diabetic db/db mice normalizes hyperglycemia.\",\n      \"method\": \"Genome-scale functional screen, quantitative image analysis of FOXO1 localization, ectopic expression, RNAi knockdown, adenoviral liver-specific depletion in db/db mice, glucose homeostasis measurements\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro gain/loss of function plus in vivo mouse model with defined metabolic phenotype, multiple orthogonal approaches\",\n      \"pmids\": [\"16679294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The N-terminal Sec14p domain (residues 1–261) of PTPMEG2 is necessary and sufficient for targeting to secretory vesicle membranes. Yeast two-hybrid screening identified TIP47 and Arfaptin2 as direct binding partners of the SEC14 domain; TIP47 overexpression alters PTPMEG2 localization and elimination of TIP47 causes loss of PTPMEG2 function. PTPMEG2 dephosphorylates NSF (N-ethylmaleimide-sensitive factor) to promote homotypic vesicle fusion.\",\n      \"method\": \"Deletion mutant analysis, yeast two-hybrid screen, Co-IP, overexpression/knockdown of TIP47, subcellular localization imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus functional co-localization with domain mapping and loss-of-function validation\",\n      \"pmids\": [\"17387180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Elevated PTP-MEG2 activity in polycythemia vera (PV) erythroid progenitor cells is due to increased distribution of PTP-MEG2 in the membrane fraction. Expression of dominant-negative mutant forms of PTP-MEG2 suppresses in vitro growth and expansion of both normal and PV erythroid colony-forming cells.\",\n      \"method\": \"Cell fractionation, phosphatase activity assay, dominant-negative mutant overexpression, colony-forming assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative functional assay plus cell fractionation, single study with two methods\",\n      \"pmids\": [\"12920026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTP-MEG2 dephosphorylates VEGFR2 at Tyr1175 (a critical autophosphorylation site) in endothelial cells; substrate-trapping DA mutant preferentially co-immunoprecipitates with VEGFR2 but not WT PTP-MEG2. PTP-MEG2 DA mutant also preferentially associates with JAK1 (but not Tyk2 or JAK2) and regulates JAK1 tyrosine phosphorylation. PTP-MEG2 knockdown enhances VEGF-induced IL-6 production.\",\n      \"method\": \"Substrate-trapping (DA) mutant co-immunoprecipitation, overexpression/knockdown, phospho-specific immunoblotting, IL-6 ELISA\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate-trapping mutant Co-IP with phosphorylation readout, single lab, two substrates identified\",\n      \"pmids\": [\"22763125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structures of PTP-MEG2–inhibitor complexes reveal that potent and selective inhibition is achieved by engaging both the active site and unique peripheral binding pockets on PTP-MEG2, with F2Pmp scaffold modifications providing selectivity. A selective cell-permeable inhibitor augments insulin signaling and improves glucose homeostasis in diet-induced obese mice.\",\n      \"method\": \"X-ray crystallography of inhibitor complexes, in vitro phosphatase inhibition assays, cell-based insulin signaling assays, diet-induced obese mouse model\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of enzyme-inhibitor complex with in vitro and in vivo functional validation\",\n      \"pmids\": [\"23075115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Zebrafish ptpn9a is required for erythroid cell maturation; morpholino knockdown of ptpn9a impairs erythrocyte maturation and increases phosphorylated STAT3. Hyper-phosphorylated STAT3 sequesters transcription factors GATA1 and ZBP-89 into an inhibitory complex, preventing erythroid gene expression. Both dominant-negative PTPN9 (C515S) and siRNA in human K562 cells inhibit erythroid differentiation.\",\n      \"method\": \"Morpholino knockdown in zebrafish, dominant-negative overexpression, siRNA in K562 cells, immunoprecipitation, erythroid differentiation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockdown in vivo (zebrafish), dominant-negative and siRNA in human cells, mechanistic epistasis via STAT3-GATA1-ZBP89 complex, multiple orthogonal methods\",\n      \"pmids\": [\"24727614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PTP-MEG2 identifies TrkA (neurotrophin receptor) as a novel substrate and cargo; PTP-MEG2 dephosphorylates both Tyr-490 and Tyr-674/Tyr-675 of TrkA, and also facilitates TrkA transport to the cell surface via its vesicle fusion activity (dephosphorylation of NSF). Overexpression of PTP-MEG2 down-regulates NGF/TrkA signaling and blocks neurite outgrowth and differentiation in PC12 cells and cortical neurons.\",\n      \"method\": \"Substrate-trapping mutant, phospho-specific immunoblotting, neurite outgrowth assay in PC12 cells, overexpression in cortical neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate-trapping identification with phosphorylation site mapping and functional neurite outgrowth phenotype, single lab\",\n      \"pmids\": [\"27655914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPN9 promotes homotypic fusion of ATG16L1+ autophagosome precursor vesicles and is required for autophagosome formation and autophagic flux. PTPN9 dephosphorylates the Q-SNARE VTI1B; the nonphosphorylatable VTI1B mutant (but not phosphomimetic) enhances SNARE complex assembly and autophagic flux. Loss of PTPN9 and its Drosophila homolog Ptpmeg2 impairs autophagosome formation.\",\n      \"method\": \"siRNA knockdown in mammalian cells, RNAi in Drosophila, immunofluorescence colocalization, phospho-mutant analysis, SNARE complex assembly assay, autophagic flux assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — substrate identification with phospho-mutant epistasis, conserved function in Drosophila, SNARE complex assembly assay, multiple orthogonal methods across species\",\n      \"pmids\": [\"33112705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTP-MEG2 controls multiple steps of catecholamine secretion. Crystallographic and biochemical analyses reveal key residues governing PTP-MEG2 interaction with phosphorylated NSF-pY83, specifying substrate selectivity and modulating vesicle fusion. PTP-MEG2 controls fusion pore opening through NSF-independent mechanisms by dephosphorylating DYNAMIN2-pY125 and MUNC18-1-pY145, with a distinct structural basis from the NSF-pY83 interaction.\",\n      \"method\": \"X-ray crystallography, biochemical interaction assays, electrochemical secretion assays, site-directed mutagenesis, bioinformatics substrate screening\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of substrate-enzyme complex plus mutagenesis plus functional secretion assay, three substrates identified with distinct structural interfaces\",\n      \"pmids\": [\"33764618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTPN9 interacts with FGFR2 through ACAP1 mediation (via the Sec14p domain of PTPN9) and dephosphorylates FGFR2 at pY656/657. Key interaction residues include the 'YRETRRKE' motif of Sec14p, Y471 of PTPN9, and the PH and Arf-GAP domains of ACAP1. The FGFR2 I654V substitution decreases PTPN9-FGFR2 interaction and reduces pemigatinib effectiveness. PTPN9 synergistically enhances pemigatinib efficacy in cholangiocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, phosphatase activity assays, structural modeling of FGFR2-PTPN9 complex, site-directed mutagenesis, patient-derived xenograft models, in vitro and in vivo functional experiments\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structural modeling with mutagenesis, biochemical phosphatase assays, PDX in vivo model, multiple orthogonal methods identifying a three-protein complex\",\n      \"pmids\": [\"37505213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MEG2 inhibits AKT phosphorylation in hepatocellular carcinoma cells; MEG2 overexpression inhibits EMT and AKT phosphorylation, and the promoting effects of MEG2 knockdown on cell viability, migration, and invasion are blocked by AKT phosphorylation inhibition, placing MEG2 upstream of AKT in this pathway.\",\n      \"method\": \"Western blot, overexpression and siRNA knockdown, cell viability/migration/invasion assays, AKT inhibitor epistasis, subcutaneous and tail-vein injection mouse models\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with AKT inhibitor plus gain/loss of function, single lab, pathway placement supported by pharmacological rescue\",\n      \"pmids\": [\"30399427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MEG2 and PKCε competitively bind STAT3; PKCε displays stronger binding to STAT3 than MEG2. STAT3 Ser727 phosphorylation increases interaction with both PKCε and MEG2. MEG2 binding to STAT3 suppresses IL-6 promoter activity and reduces inflammatory pain signaling in microglia, while PKCε promotes it. ERK1/2 facilitates MEG2-STAT3 interaction leading to STAT3 Tyr705 dephosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, ELISA, dual-luciferase assay, Western blot, overexpression in vivo (FCA mouse model) and in vitro (LPS-stimulated microglia), von Frey test\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with competition assay, functional in vivo and in vitro, single lab\",\n      \"pmids\": [\"38656553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPN9 dephosphorylates IGF1R preferentially at Y1166 (within the Y1165/1166 activation loop); crystal structure analysis identified Tyr333 and Asp335 as key PTPN9 residues interacting with IGF1R, and mutation of these residues restores IGF1R signaling and abolishes tumor-suppressive effects of PTPN9 in cholangiocarcinoma.\",\n      \"method\": \"IP-MS substrate identification, crystal structure analysis, biochemical dephosphorylation assay, site-directed mutagenesis, orthotopic mouse models, surufatinib-resistant cell line\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with active-site mutagenesis plus biochemical assay plus in vivo model, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41275311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ERK1/2 (activated by SARS-CoV-2 Mpro via TRAF6-TAK1 signaling) facilitates interaction between STAT3 and MEG2, leading to dephosphorylation of STAT3 at Tyr705 and suppression of ACE2 expression; ERK1/2 inhibition restores STAT3 activity and ACE2 levels.\",\n      \"method\": \"Overexpression of Mpro and catalytic mutant, ERK1/2 inhibitor treatment, immunoprecipitation, Western blot for pSTAT3/ACE2, SARS-CoV-2 single-round infectious particles\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with pharmacological perturbation and rescue experiments, single lab, functional pathway placement\",\n      \"pmids\": [\"41728757\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPN9 (PTP-MEG2) is a non-receptor protein tyrosine phosphatase with an N-terminal Sec14p/lipid-binding domain that targets the enzyme to secretory vesicle membranes via phosphatidylserine and PtdIns(3,4,5)P3 binding and interactions with TIP47/Arfaptin2; at vesicles it dephosphorylates NSF-pY83, DYNAMIN2-pY125, and MUNC18-1-pY145 to control vesicle fusion, quantal size, and fusion pore opening, and dephosphorylates VTI1B to promote ATG16L1+ autophagosome precursor fusion; in growth-factor and cytokine signaling it acts as a negative regulator by directly dephosphorylating EGFR, ErbB2, VEGFR2, TrkA, FGFR2 (pY656/657 via ACAP1 scaffold), and IGF1R (pY1165/1166), and dephosphorylates STAT3-pY705 in the cytoplasm to suppress STAT3 transcriptional activity; in insulin/metabolic signaling it antagonizes insulin receptor phosphorylation and downstream FOXO1 nuclear exclusion; and its localization and activity are regulated by polyphosphoinositides and competitive interactions with kinases such as PKCε.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPN9 (PTP-MEG2) is a non-receptor protein tyrosine phosphatase that couples membrane lipid sensing to the control of secretory vesicle dynamics and the negative regulation of receptor tyrosine kinase and STAT signaling [#3, #9, #0]. Its catalytic activity depends on the active-site cysteine C515 and is intramolecularly restrained by an N-terminal Sec14p/lipid-binding domain, which lowers the enzyme's Vmax until it is engaged by membrane phosphoinositides; polyphosphoinositides (PI(4,5)P2 > PI(3,4,5)P3) activate the phosphatase, while opsonized zymosan or PMA stimulation inhibits it [#5, #6]. The Sec14p domain binds phosphatidylserine and PtdIns(3,4,5)P3 and is necessary and sufficient to target the enzyme to secretory vesicle membranes, where, together with its partners TIP47 and Arfaptin2, it drives homotypic vesicle fusion [#3, #4, #9]. At these membranes PTP-MEG2 dephosphorylates the fusion machinery — NSF-pY83, and through NSF-independent routes DYNAMIN2-pY125 and MUNC18-1-pY145 — to regulate vesicle enlargement, fusion pore opening, and quantal secretion, and dephosphorylates the Q-SNARE VTI1B to promote SNARE assembly and ATG16L1+ autophagosome precursor fusion during autophagy [#9, #16, #15]. As a signaling antagonist, PTP-MEG2 directly dephosphorylates the receptor tyrosine kinases ErbB2/EGFR, VEGFR2 (Tyr1175), TrkA, FGFR2 (pY656/657, via an ACAP1 scaffold engaging its Sec14p domain), and IGF1R (Y1166), and dephosphorylates cytoplasmic STAT3 at Tyr705 to suppress STAT3-dependent transcription [#0, #11, #14, #17, #20, #1]. Through these activities it restrains growth-factor and cytokine signaling, controls erythroid maturation by relieving STAT3-mediated sequestration of GATA1/ZBP-89 [#13], and antagonizes hepatic insulin receptor signaling and FOXO1 nuclear exclusion, such that its depletion normalizes hyperglycemia in db/db mice [#8]. Genetic loss in mice causes late embryonic lethality with secretory and hematopoietic defects, underscoring its essential role in regulated secretion [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the catalytic and regulatory architecture of MEG2 — that activity requires Cys515 and is autoinhibited by the N-terminal domain and tuned by lipids — defining how a phosphatase could be membrane-regulated.\",\n      \"evidence\": \"Cell fractionation, in vitro phosphatase assay, and GST-fusion mutagenesis (C515) with lipid activation in neutrophils\",\n      \"pmids\": [\"11711529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify physiological protein substrates\", \"Mechanism by which lipids relieve N-terminal autoinhibition not resolved structurally\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed catalytic activity controls secretory vesicle morphology and secretion, linking the phosphatase to regulated exocytosis rather than generic signaling.\",\n      \"evidence\": \"Overexpression in mast and Jurkat T cells with EM, IL-2 secretion assays, and catalytic mutant rescue; in vitro kinetics of full-length vs. truncated enzyme\",\n      \"pmids\": [\"11971009\", \"12112018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Vesicle substrate(s) at the fusion machinery not yet identified\", \"Connection between enlargement and secretion block mechanistically unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the Sec14p domain as a lipid sensor binding phosphatidylserine and PtdIns(3,4,5)P3 that targets the enzyme to vesicle membranes and is required for homotypic fusion, explaining how membrane lipids spatially control activity.\",\n      \"evidence\": \"In vitro lipid overlay/liposome binding, domain mapping, point mutagenesis, colocalization, and PI3K inhibitor perturbation\",\n      \"pmids\": [\"14662869\", \"12702726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the dephosphorylated fusion substrate\", \"Membrane partner proteins not yet defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Genetic knockout established the organismal essentiality of MEG2 and confirmed its requirement for mature secretory vesicle biogenesis and immune cell activation.\",\n      \"evidence\": \"Meg2-/- mice and RAG2-/- hematopoietic chimeras with T cell/platelet activation assays, EM, and lipid binding\",\n      \"pmids\": [\"16330817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Embryonic lethality obscures tissue-specific roles\", \"Molecular substrate driving vesicle maturation not pinpointed here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed MEG2 as a negative regulator of insulin receptor signaling in liver, establishing a metabolic role and a therapeutic rationale.\",\n      \"evidence\": \"Functional screen, FOXO1 localization imaging, RNAi/ectopic expression, and adenoviral liver depletion in db/db mice\",\n      \"pmids\": [\"16679294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct dephosphorylation of the insulin receptor by MEG2 not biochemically demonstrated here\", \"Relationship to its vesicular role unaddressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified TIP47 and Arfaptin2 as direct Sec14p-domain partners and NSF as a fusion substrate, providing the molecular machinery linking membrane targeting to vesicle fusion.\",\n      \"evidence\": \"Yeast two-hybrid, deletion mapping, Co-IP, TIP47 knockdown, and localization imaging\",\n      \"pmids\": [\"17387180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NSF dephosphorylation site not defined in this study\", \"How TIP47/Arfaptin2 coordinate with lipid binding unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established MEG2 as a direct phosphatase for ErbB2 and EGFR with substrate selectivity, extending its role to receptor tyrosine kinase signaling and downstream STAT activation.\",\n      \"evidence\": \"Substrate-trapping DA mutant Co-IP/GST pulldown, gain/loss of function, and STAT activation readouts\",\n      \"pmids\": [\"20335174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subcellular site of RTK dephosphorylation not localized\", \"Whether vesicular targeting is required for RTK access unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated direct STAT3 binding and Tyr705 dephosphorylation in the cytoplasm, and identified VEGFR2-Tyr1175 and JAK1 as additional targets, broadening MEG2 as a cytokine/growth-factor signaling brake.\",\n      \"evidence\": \"Co-IP and biochemical dephosphorylation in breast cancer cells; substrate-trapping Co-IP and phospho-immunoblot for VEGFR2/JAK1 in endothelial cells\",\n      \"pmids\": [\"22394684\", \"22763125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"VEGFR2 and JAK1 findings from a single lab\", \"Spatial coordination of STAT3 vs. RTK dephosphorylation not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Crystal structures of inhibitor complexes revealed unique peripheral pockets enabling selective inhibition and provided in vivo proof that pharmacological inhibition augments insulin signaling.\",\n      \"evidence\": \"X-ray crystallography of inhibitor complexes, phosphatase inhibition assays, and diet-induced obese mouse model\",\n      \"pmids\": [\"23075115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No substrate-bound structure in this study\", \"Selectivity over closely related phosphatases in cells not fully mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected MEG2-STAT3 regulation to erythroid maturation, showing loss elevates pSTAT3 which sequesters GATA1/ZBP-89, defining a developmental output of the phosphatase.\",\n      \"evidence\": \"Zebrafish morpholino knockdown, dominant-negative and siRNA in K562, and Co-IP of the STAT3-GATA1-ZBP89 complex\",\n      \"pmids\": [\"24727614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether reduced erythroid maturation reflects STAT3 alone or additional substrates unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified TrkA as both a substrate and a cargo, uniting MEG2's dephosphorylation and vesicle-fusion functions in controlling neurotrophin receptor surface delivery and neurite outgrowth.\",\n      \"evidence\": \"Substrate-trapping, phospho-site mapping (Y490, Y674/675), and neurite outgrowth assays in PC12 cells and cortical neurons\",\n      \"pmids\": [\"27655914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Quantitative contribution of trafficking vs. direct dephosphorylation to signaling output not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the vesicle-fusion role into autophagy by identifying VTI1B as a Q-SNARE substrate required for ATG16L1+ precursor fusion, with conservation in Drosophila.\",\n      \"evidence\": \"siRNA in mammalian cells, Drosophila RNAi, phospho-mutant epistasis, SNARE assembly and autophagic flux assays\",\n      \"pmids\": [\"33112705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid/partner requirements for autophagosomal targeting not dissected\", \"Upstream signals controlling VTI1B phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided structural basis for substrate selectivity at the fusion machinery, showing distinct interfaces for NSF-pY83 versus DYNAMIN2-pY125 and MUNC18-1-pY145 controlling separable secretion steps.\",\n      \"evidence\": \"X-ray crystallography of substrate-enzyme complexes, mutagenesis, and electrochemical catecholamine secretion assays\",\n      \"pmids\": [\"33764618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same active site discriminates multiple substrates in cells not fully resolved\", \"Regulation of step-specific substrate engagement unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a scaffolded mechanism whereby ACAP1 bridges the Sec14p domain of PTPN9 to FGFR2, enabling pY656/657 dephosphorylation and modulating FGFR-inhibitor response in cholangiocarcinoma.\",\n      \"evidence\": \"Co-IP, phosphatase assays, structural modeling/mutagenesis (YRETRRKE motif, Y471; ACAP1 PH/Arf-GAP), and PDX models\",\n      \"pmids\": [\"37505213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ACAP1 scaffolding generalizes to other RTK substrates unknown\", \"I654V resistance mechanism beyond reduced interaction not fully detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed competitive regulation of STAT3 by MEG2 and PKCε and an ERK1/2-facilitated MEG2-STAT3 interaction, refining how MEG2 access to STAT3 is controlled in inflammatory contexts.\",\n      \"evidence\": \"Reciprocal Co-IP/competition, luciferase, and in vivo/in vitro inflammatory pain models\",\n      \"pmids\": [\"38656553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab competition model\", \"Structural basis of competitive STAT3 binding not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified IGF1R-Y1166 as a substrate with structural definition of the interface (Tyr333, Asp335), linking PTPN9 tumor suppression to IGF1R signaling in cholangiocarcinoma.\",\n      \"evidence\": \"IP-MS, crystal structure analysis, biochemical dephosphorylation, active-site mutagenesis, and orthotopic mouse models\",\n      \"pmids\": [\"41275311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-lab finding\", \"Integration with parallel RTK substrates in the same tumor context not addressed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed the ERK1/2-facilitated MEG2-STAT3 axis in a viral context, showing SARS-CoV-2 Mpro signaling drives STAT3 Tyr705 dephosphorylation and ACE2 suppression.\",\n      \"evidence\": \"Mpro overexpression/catalytic mutant, ERK1/2 inhibitor rescue, Co-IP, and single-round infectious particle assays\",\n      \"pmids\": [\"41728757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pathway model\", \"Direct ERK1/2 modification mediating MEG2-STAT3 assembly not biochemically defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single phosphatase coordinates its membrane-bound vesicle-fusion substrates with cytoplasmic RTK/STAT3 substrates — and what spatial or lipid cues partition these activities in vivo — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking lipid-regulated localization to substrate choice\", \"Tissue-specific substrate priorities largely uncharacterized\", \"In vivo relevance of individual RTK substrates outside cancer models unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 9, 11, 14, 15, 16, 17, 20]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 4, 5, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 3, 4, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 8, 11, 14, 17, 20]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 3, 9, 16]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STAT3\", \"EGFR\", \"ERBB2\", \"VEGFR2\", \"FGFR2\", \"ACAP1\", \"NSF\", \"TIP47\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}