{"gene":"PTPRZ1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1994,"finding":"Phosphacan (PTPRZ1 extracellular domain) is an alternatively spliced secreted variant of the transmembrane receptor-type protein tyrosine phosphatase RPTPζ/β, representing the entire extracellular portion of the receptor without transmembrane or intracellular phosphatase domains.","method":"cDNA cloning, amino acid sequencing, RNA analysis with domain-specific probes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct molecular cloning and sequencing with peptide validation, replicated across multiple labs in the same year","pmids":["7511813"],"is_preprint":false},{"year":1994,"finding":"Phosphacan binds with high affinity (Kd ~0.1 nM) to neural cell adhesion molecules N-CAM and Ng-CAM/L1, and inhibits neuronal adhesion and neurite growth; chondroitin sulfate accounts for only ~15% of binding, indicating the core glycoprotein mediates most of this interaction.","method":"Radioligand binding assay (125I-phosphacan), Scatchard analysis, chondroitinase treatment, anti-CAM antibody inhibition, neuronal adhesion and neurite outgrowth assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative binding kinetics with multiple orthogonal methods (radioligand binding, enzymatic digestion, antibody blocking, functional assays), replicated in subsequent studies","pmids":["7528221"],"is_preprint":false},{"year":1994,"finding":"Phosphacan and neurocan bind with high affinity to tenascin-C (but not laminin or fibronectin), mediated via their core glycoproteins rather than chondroitin sulfate chains; phosphacan inhibits C6 glioma cell adhesion to tenascin-C.","method":"Fluorescent microbead co-aggregation, solid-phase radioligand binding assay, Scatchard analysis, chondroitinase treatment, cell adhesion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal binding methods with quantitative Kd determination, replicated in subsequent studies","pmids":["7512960"],"is_preprint":false},{"year":1995,"finding":"Phosphacan interactions with N-CAM, Ng-CAM/L1, and tenascin are mediated by asparagine-linked complex-type oligosaccharides located in the carbonic anhydrase-like and fibronectin type III-like domains (at Asn-232 and Asn-381); peptide-N-glycosidase treatment reduced binding by 65–75%.","method":"125I-phosphacan tryptic digest binding assays, peptide N-glycosidase F treatment, endo-β-N-acetylglucosaminidase H treatment, glycopeptide isolation and sequencing","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical mapping of glycosylation sites by peptide sequencing combined with functional binding assays and orthogonal enzymatic treatments","pmids":["7559574"],"is_preprint":false},{"year":1996,"finding":"Phosphacan/6B4 proteoglycan binds pleiotrophin (HB-GAM) with high affinity (Kd = 0.25 nM and 3 nM for two sites); chondroitin sulfate chains modulate binding affinity; anti-6B4 antibody suppresses pleiotrophin-induced neurite outgrowth from cortical neurons, indicating this interaction is required for pleiotrophin's biological action.","method":"Affinity chromatography, N-terminal sequencing, Scatchard analysis of binding, chondroitinase ABC treatment, heparin competition, antibody-blocking neurite outgrowth assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative binding kinetics with multiple orthogonal methods plus functional assay, replicated in subsequent studies","pmids":["8702927"],"is_preprint":false},{"year":1996,"finding":"TAG-1/axonin-1 is a high-affinity ligand of phosphacan (Kd ~0.04 nM); chondroitin sulfate chains account for ~70% of the binding to TAG-1, contrasting with phosphacan's N-CAM/Ng-CAM interactions which are N-glycan-mediated.","method":"Radioligand binding assay, Scatchard analysis, chondroitinase treatment, N-deglycosylation, immunocytochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative binding kinetics with orthogonal glycan-manipulation experiments defining distinct binding mechanisms for different ligands","pmids":["8663515"],"is_preprint":false},{"year":1996,"finding":"Adsorbed phosphacan/6B4 proteoglycan acts as a repulsive substrate for cortical and thalamic neuronal adhesion, but in sparse culture conditions promotes neurite outgrowth and tyrosine phosphorylation of an 85 kDa protein in cortical neurons; chondroitinase or keratanase digestion did not affect this neurite-promoting activity, indicating the protein moiety is responsible.","method":"Patterned substrate cell adhesion assay, neurite outgrowth quantification, chondroitinase/keratanase digestion, antibody blocking, anti-phosphotyrosine Western blot","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple functional readouts with enzymatic and antibody controls defining core protein-mediated signaling","pmids":["8625816"],"is_preprint":false},{"year":1997,"finding":"Phosphacan binds to the fibrinogen-like globe domain of tenascin-C (Kd ~12 nM), mediated by the core protein in a calcium-dependent manner; all deletion variants retaining the fibrinogen globe support phosphacan binding, while those lacking it do not.","method":"Recombinant tenascin-C deletion constructs, radioligand binding assay, chondroitinase treatment, rotary shadowing electron microscopy, cell adhesion inhibition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural domain mapping by deletion analysis with quantitative binding and electron microscopy, multiple orthogonal methods","pmids":["9182584"],"is_preprint":false},{"year":1998,"finding":"Phosphacan binds with high affinity to tenascin-R (Kd 2–7 nM) via its core protein; chondroitinase treatment increases binding by ~60%, indicating the glycosaminoglycan chains partially shield the protein-protein interaction site. Phosphacan also binds HB-GAM and amphoterin (Kd 0.3–8 nM) primarily through its chondroitin sulfate chains (>80% of binding).","method":"Radioligand binding assay, Scatchard analysis, chondroitinase treatment, calcium chelation experiments, immunocytochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative binding with orthogonal enzymatic treatments revealing differential mechanisms for distinct ligands","pmids":["9507007"],"is_preprint":false},{"year":1998,"finding":"The core protein of phosphacan binds FGF-2 with high affinity (Kd ~6 nM) primarily via the protein backbone (only ~35% reduction after chondroitinase treatment), and potentiates FGF-2 mitogenic activity on NIH/3T3 cells by 75–90%.","method":"Radioligand binding assay, chondroitinase treatment, [3H]-thymidine mitogenic assay on NIH/3T3 cells, immunocytochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative binding kinetics with core-protein attribution and orthogonal functional assay","pmids":["9705269"],"is_preprint":false},{"year":2003,"finding":"The heterogeneity of chondroitin sulfate chains on phosphacan regulates its binding affinity for pleiotrophin; the presence of the GlcA(2S)-GalNAc(6S) disaccharide (D unit) in postnatal day 20 phosphacan confers ~5-fold stronger binding (Kd = 0.14 nM) compared with earlier preparations lacking this unit (Kd ~1.4–1.6 nM).","method":"Phosphacan purification from different developmental stages, surface plasmon resonance biosensor binding analysis, chondroitinase ABC digestion, disaccharide composition analysis, monoclonal antibody immunoreactivity","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative SPR binding with defined glycan structural characterization and orthogonal immunological validation","pmids":["12840014"],"is_preprint":false},{"year":2003,"finding":"Phosphacan short isoform (PSI), a novel truncated secreted variant encoded by a distinct cDNA, interacts with Ig cell adhesion molecules F3/contactin and L1, and promotes neurite outgrowth of cortical neurons as a coated substrate; PSI is not a proteoglycan but carries HNK-1 oligosaccharides.","method":"cDNA library screening, Northern blot, Western blot, co-immunoprecipitation/pulldown binding, neurite outgrowth assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular identification with binding assays and functional neurite assay, single lab","pmids":["12700241"],"is_preprint":false},{"year":2007,"finding":"PTPRZ1 (RPTPβ/ζ) forms a functional complex with ERBB4 via MAGI scaffolding proteins; ERBB4 expression leads to tyrosine phosphorylation of MAGI proteins (enhanced by neuregulin), and simultaneous binding of MAGI to RPTPβ creates a phosphotyrosine kinase/phosphatase complex with spatial and functional association confirmed in cultured cells.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, tyrosine phosphorylation assays, neuregulin stimulation, spatial co-localization imaging","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional phosphorylation assay in mammalian cells, single lab, two orthogonal methods","pmids":["17579610"],"is_preprint":false},{"year":2007,"finding":"PTPRZ1 overexpression activates the beta-catenin pathway in renal cell carcinoma via dephosphorylation-dependent nuclear translocation of beta-catenin, leading to expression of cyclin D1, c-myc, c-jun, fra-1, and CD44; siRNA knockdown of ptprz1 decreases nuclear beta-catenin and suppresses cellular proliferation.","method":"Gene expression microarray, CGH array, siRNA knockdown, Western blot for dephosphorylated/nuclear beta-catenin, proliferation assay","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with defined molecular readouts (nuclear beta-catenin, downstream targets, proliferation), single lab","pmids":["18055543"],"is_preprint":false},{"year":2008,"finding":"Egr-1 transcription factor directly binds the phosphacan promoter and transactivates its expression; Egr-1-deficient mice have lower phosphacan RNA and protein levels after stroke, establishing Egr-1 as a transcriptional regulator of PTPRZ1/phosphacan in reactive astrocytes.","method":"Promoter deletion/mutational analysis, chromatin immunoprecipitation, gain-of-function and loss-of-function in primary astrocytes, Egr-1 knockout mouse analysis","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct ChIP showing promoter binding, in vitro transactivation, and in vivo KO validation with multiple orthogonal methods","pmids":["18556777"],"is_preprint":false},{"year":2010,"finding":"PTPRZ1 promoter is preferentially activated by HIF-2α over HIF-1α; ELK1 cooperates with HIF-2α to drive PTPRZ1 expression through nearby HRE and Ets binding sites; ELK1 knockdown reduces HIF-2-mediated activation by >50%, and ChIP confirms binding of both HIF and ELK1 to the PTPRZ1 promoter.","method":"Promoter deletion/mutational analysis, luciferase reporter assays, siRNA knockdown, chromatin immunoprecipitation (ChIP)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (promoter mutagenesis, siRNA, ChIP) converging on same mechanism, single lab","pmids":["20224786"],"is_preprint":false},{"year":2012,"finding":"Binding of pleiotrophin ligand to PTPRZ1 activates PTN/PTPRZ1 signaling to induce tyrosine phosphorylation of calmodulin (CaM) in small-cell lung carcinoma cells; PTPRZ1 knockdown alters CaM phosphorylation and suppresses tumor progression in murine xenograft.","method":"shRNA-mediated knockdown, Western blot for tyrosine-phosphorylated CaM, in vivo xenograft tumor assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA KD with defined molecular readout (CaM phosphorylation) and in vivo functional validation, single lab","pmids":["23170925"],"is_preprint":false},{"year":2012,"finding":"RPTPζ/phosphacan undergoes abnormal O-mannosyl glycosylation in POMGnT1-knockout mice (a muscle-eye-brain disease model); loss of POMGnT1 shifts RPTPζ/phosphacan to lower molecular weight and eliminates HNK-1 carbohydrate epitopes, identifying RPTPζ/phosphacan as a significant substrate for O-mannosylation in the brain.","method":"POMGnT1 knockout mouse model, Western blot, immunofluorescence, lectin/antibody glycan epitope analysis","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined biochemical readouts, single lab, orthogonal antibody methods","pmids":["22728091"],"is_preprint":false},{"year":2013,"finding":"Phosphacan is the major carrier of O-mannose-linked HNK-1 glycan in developing mouse brain; GlcAT-P synthesizes the O-linked HNK-1 onto phosphacan, and the 6B4 monoclonal antibody preferentially recognizes O-mannose-linked HNK-1 on phosphacan.","method":"Mass spectrometry glycan identification, GlcAT-P and POMGnT1 knockout mice, cell expression with GlcAT-P co-transfection, immunoblotting","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mass spectrometry structural identification combined with genetic knockout and cell expression experiments, multiple orthogonal approaches","pmids":["24352591"],"is_preprint":false},{"year":2014,"finding":"Phosphacan/RPTPβ is the major carrier of the Lewis X glycan epitope in the developing mouse brain; this epitope is carried on O-mannose-linked glycans, requires β4GalT2 for synthesis, and is abolished by POMGnT1 knockout.","method":"β4GalT2 and POMGnT1 knockout mice, immunochemical analysis, glycan structural characterization","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual genetic knockouts with defined biochemical readouts, single lab","pmids":["25361541"],"is_preprint":false},{"year":2014,"finding":"PTPRZ1-MET (ZM) fusion proteins arise from chromosomal translocation fusing PTPRZ1 introns 3 or 8 to MET intron 1; exogenous expression of ZM fusion in U87MG glioblastoma cells enhances cell migration and invasion.","method":"RNA-seq, genomic translocation analysis, RT-PCR validation, exogenous overexpression in glioblastoma cell lines with migration/invasion assays","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 / Strong — structural characterization of fusion with functional validation in cancer cells, replicated in independent cohort","pmids":["25135958"],"is_preprint":false},{"year":2015,"finding":"ZM fusion proteins retain MET processing and dimerization properties of wild-type MET, and enhance MET phosphorylation in both HGF-dependent and HGF-independent manners; fusion with PTPRZ1 increases MET mRNA expression levels.","method":"Western blot for MET phosphorylation/expression, HGF stimulation/withdrawal experiments, dimerization assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical analysis of fusion protein with defined molecular readouts (phosphorylation, expression, dimerization), single lab","pmids":["25935522"],"is_preprint":false},{"year":2015,"finding":"O-mannosyl glycan epitopes recognized by antibodies Cat-315 and 3F8 define biochemically distinct glycoforms of RPTPζ/phosphacan that differentially decorate distinct neural cell populations; mass spectrometry characterization identified novel O-mannose-linked glycan structures including sulfo-N-acetyllactosamine modifications on RPTPζ/phosphacan.","method":"Multidimensional mass spectrometry of O-linked glycans from purified RPTPζ/phosphacan, cell-type-specific immunofluorescence with glycoform-specific antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry structural characterization with cell-type localization, single lab, rigorous analytical methods","pmids":["25737452"],"is_preprint":false},{"year":2017,"finding":"Tumor-associated macrophages secrete pleiotrophin (PTN) which signals through its receptor PTPRZ1 on glioma stem cells (GSCs) to promote GSC maintenance and GBM tumor growth via paracrine PTN-PTPRZ1 signaling; disrupting PTPRZ1 abrogates GSC maintenance and tumorigenic potential, and anti-PTPRZ1 antibody suppresses tumor growth.","method":"Co-implantation of macrophages with GSCs, PTN shRNA silencing in macrophages, PTPRZ1 shRNA and antibody blockade, tumor growth and animal survival assays, in vivo xenograft","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal loss-of-function approaches (shRNA, antibody) with in vivo functional readouts, multiple mechanistic arms tested","pmids":["28569747"],"is_preprint":false},{"year":2017,"finding":"Small-molecule inhibitors targeting the intracellular PD1 phosphatase domain of PTPRZ1 inhibit its tyrosine phosphatase activity (IC50 ~0.1 μM), increase phosphorylation of PTPRZ1 substrates involved in neuronal survival/differentiation, and the lead compound crosses the blood-brain barrier in vivo.","method":"In vitro phosphatase activity assay, docking/molecular dynamics, substrate phosphorylation Western blot, BBB permeability in vivo experiment","journal":"European journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay with defined IC50 and substrate phosphorylation readout, single lab","pmids":["29275231"],"is_preprint":false},{"year":2018,"finding":"CDKN1A is the upstream regulator of PTN/PTPRZ1 expression in TNBC cells receiving chemotherapy; chemotherapy-driven increases in CDKN1A elevate PTN and PTPRZ1 expression, and the CDKN1A/PTN/PTPRZ1 axis promotes chemoresistance via the NF-κB pathway; siRNA knockdown of PTPRZ1 reduces chemoresistance.","method":"siRNA knockdown, microarray expression analysis, CCK-8 proliferation assay, colony formation, apoptosis analysis, NF-κB pathway western blot","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined pathway (NF-κB) and functional readouts, single lab with multiple orthogonal assays","pmids":["30497491"],"is_preprint":false},{"year":2018,"finding":"PTPRZ1 (RPTPβ/ζ) modulates ethanol signaling: ethanol increases phosphorylation of ALK and TrkA (known PTPRZ1 substrates) in neuroblastoma cells; PTPRZ1 small-molecule inhibitors also increase pALK and pTrkA but prevent ethanol-induced increases when co-applied, demonstrating PTPRZ1 modulates TrkA and ALK signaling pathways activated by alcohol.","method":"Pharmacological inhibitors (MY10, MY33-3), Western blot for pALK/pTrkA, behavioral tests in mice (binge drinking, conditioned place preference)","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based signaling experiments with defined substrates (ALK, TrkA) combined with in vivo behavioral validation, single lab","pmids":["29753117"],"is_preprint":false},{"year":2019,"finding":"RPTPζ (PTPRZ1) is required for the reticulated perineuronal net (PNN) structure in the brain; Ptprz1 knockout mice lose the normal reticular PNN pattern (replaced by puncta), phenocopying tenascin-R knockout PNN defects. Two distinct surface interactions underpin PNN formation: one dependent on RPTPζ and another requiring hyaluronan.","method":"Ptprz1 knockout mice, immunofluorescence of PNN structure, biochemical fractionation, neuronal cultures","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined structural phenotype using multiple visualization methods, epistatic relationship to tenascin-R identified","pmids":["31822561"],"is_preprint":false},{"year":2021,"finding":"ZM fusion proteins activate MET kinase in a ligand-independent manner, likely enabled by a coiled-coil motif from the PTPRZ1 fusion segment that promotes constitutive MET dimerization/activation; clinical specimens confirm hyperactivation of MET signaling in ZM-positive gliomas.","method":"Protein structure prediction, cell line MET phosphorylation assays with/without HGF, clinical specimen MET signaling analysis, high-sensitivity RT-PCR","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural modeling combined with cell-based phosphorylation assays and clinical validation, single lab","pmids":["33645009"],"is_preprint":false},{"year":2022,"finding":"Phosphacan exerts repulsive effects on cerebellar granule cell migration through interaction with TAG-1; the interaction is mediated by chondroitin sulfate C chains (confirmed by SPR), requires GD3 ganglioside-containing lipid rafts, and attenuates BDNF-induced Akt activation and migration.","method":"TAG-1 knockout mouse primary cerebellar granule cells, Boyden chamber migration assay, surface plasmon resonance for TAG-1/CS-C binding, anti-GD3/GD1b antibody blocking, methyl-β-cyclodextrin lipid raft disruption, Akt inhibitor MK-2206","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic knockout with multiple pharmacological and biochemical dissections defining the TAG-1/GD3 raft-dependent signaling mechanism","pmids":["36227633"],"is_preprint":false},{"year":2022,"finding":"HOXA5 directly binds the PTPRZ1 promoter to transcriptionally activate PTPRZ1 expression in glioblastoma stem cells; suppression of PTPRZ1 largely reverses the pro-tumoral effects of HOXA5 overexpression, placing PTPRZ1 downstream of HOXA5 in a GSC maintenance pathway.","method":"ChIP for HOXA5 binding to PTPRZ1 promoter, HOXA5 gain/loss-of-function, PTPRZ1 knockdown, GSC self-renewal and invasion assays, in vivo tumor propagation","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional epistasis experiments, single lab","pmids":["35219772"],"is_preprint":false},{"year":2023,"finding":"Tenascin-R (TNR) directly associates with the RPTPζ ectodomain via protein-protein interactions; the same interface mediates RPTPζ interaction with tenascin-C; mutating RPTPζ residues at the RPTPζ-TNR interface impairs PNN formation in dissociated neuronal cultures, demonstrating these protein-protein interactions are structurally required for PNN assembly.","method":"Structural determination of RPTPζ-TNR interaction, mutagenesis of interface residues, neuronal culture PNN assembly assay, Ptprz1 knockout mouse","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-based mutagenesis with functional PNN assembly validation, genetic knockout supporting model","pmids":["37356715"],"is_preprint":false},{"year":2023,"finding":"Loss of PTPRZ1 tyrosine phosphatase activity in endothelial cells (genetic knockout or pharmacological inhibition) activates c-Met and Akt, reduces β3 integrin expression, and enhances angiogenesis and lung adenocarcinoma growth in vivo; PTN and VEGFA165 activate c-Met and Akt in a PTPRZ1-dependent manner, and these effects are abolished by the c-Met inhibitor crizotinib.","method":"Ptprz1−/− and Ptprz1+/+ mouse endothelial cells, in vivo urethane-induced LUAD model, PTPRZ1 inhibitor, Western blot for c-Met/Akt/VEGFR2/β3 integrin, crizotinib blockade","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with pharmacological rescue in vivo and in vitro, multiple readouts, single lab","pmids":["37260355"],"is_preprint":false},{"year":2024,"finding":"PTPRZ1 dephosphorylates RNF26 at the Y432 site, thereby stabilizing RNF26 protein expression through the proteasome pathway; through this PTPRZ1-RNF26 interaction, PTPRZ1 activates the TNF/NF-κB signaling pathway to promote cell proliferation, angiogenesis, and lipid metabolism in clear cell renal cell carcinoma.","method":"Mass spectrometry substrate identification, RNA sequencing, lipidomic profiling, immunohistochemistry, phospho-specific Western blot, proteasome inhibitor experiments, RNF26 knockdown rescue","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical identification of dephosphorylation substrate with site specificity (Y432), proteasome pathway mechanistic dissection, multiple orthogonal methods","pmids":["39443724"],"is_preprint":false},{"year":2025,"finding":"Curcumin interacts with PTPRZ1 to maintain its enzymatic (phosphatase) activity, thereby regulating phosphorylation of the m6A-reader YTHDF2; this modulation of YTHDF2 phosphorylation via PTPRZ1 affects downstream gene expression to reduce microglial inflammatory responses.","method":"Binding/interaction assays between curcumin and PTPRZ1, phosphorylation assays for YTHDF2, gene expression analysis","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic pathway proposed from abstract-level description; methods not fully specified in abstract; single lab, single paper","pmids":["39921492"],"is_preprint":false},{"year":2024,"finding":"ZM (PTPRZ1-MET) fusion-positive glioma stem cells upregulate ISG20 through the MET-STAT3-ISG20 signaling axis; secreted ISG20 recruits macrophages and drives their polarization toward an immunosuppressive M2-like phenotype, promoting tumor progression.","method":"RNA-seq of patient glioma tissues, ZM overexpression/knockdown, STAT3 inhibition, ISG20 knockdown, macrophage co-culture polarization assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation with defined signaling pathway (MET-STAT3-ISG20) and functional macrophage polarization readout, single lab","pmids":["38685521"],"is_preprint":false},{"year":2024,"finding":"PTN activates c-Met and mTORC1-dependent protein synthesis through PTPRZ1; PTPRZ1 deletion or PTN stimulation increases phosphorylation of S6K1 and 4EBP1 (mTORC1 substrates) and upregulates HIF-1α; c-Met inhibitor crizotinib abolishes these effects, placing c-Met downstream of the PTN/PTPRZ1 axis upstream of mTORC1 in endothelial cell migration.","method":"Ptprz1 knockout endothelial cells, PTN stimulation, Western blot for mTORC1 substrates (pS6K1, p4EBP1), crizotinib and rapamycin pharmacological blockade, cell migration assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with pharmacological epistasis defining PTN→PTPRZ1→c-Met→mTORC1 pathway, single lab","pmids":["39409168"],"is_preprint":false},{"year":2022,"finding":"PTPRZ1 overexpression regulates phosphorylation of p120 and β-catenin, causing their redistribution from cell membrane to cytoplasm and nucleus, activating downstream targets (RhoA, Rac1, CDC42, cyclin D1, c-myc) and promoting cell proliferation, migration, and invasion in oral submucous fibrosis; PTPRZ1 knockdown reduces tumor volume in vivo.","method":"PTPRZ1 overexpression/knockdown, Western blot and immunofluorescence for p-p120/p-β-catenin localization, cell migration/invasion assays, in vivo tumor formation","journal":"Journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined phosphorylation substrates and localization readouts, single lab","pmids":["35251170"],"is_preprint":false},{"year":2024,"finding":"Integrin α6β4 regulates PTPRZ1 expression through a UCHL1-Hif-1α axis: integrin α6β4 upregulates UCHL1, which stabilizes Hif-1α nuclear localization, leading to transcriptional activation of PTPRZ1; inhibition of UCHL1 or PTPRZ1 dramatically decreases integrin α6β4-mediated cell migration and 3D invasive growth in TNBC.","method":"ITGB4 re-expression and KO, shRNA knockdown, chemical Hif-1α inhibition/activation, UCHL1 inhibition, migration and 3D invasion assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined upstream pathway (integrin→UCHL1→Hif-1α→PTPRZ1) with loss-of-function functional validation, single lab","pmids":["39518121"],"is_preprint":false}],"current_model":"PTPRZ1 encodes RPTPζ/β, a receptor-type protein tyrosine phosphatase expressed in the CNS as multiple isoforms—a full-length transmembrane receptor, a short transmembrane receptor, the secreted extracellular proteoglycan phosphacan, and PSI—all produced by alternative splicing; it functions as a pleiotrophin/midkine receptor that, upon ligand binding, modulates downstream tyrosine phosphorylation of substrates including calmodulin, ALK, TrkA, and RNF26 (directly dephosphorylated at Y432), regulating signaling through the beta-catenin, NF-κB, c-Met/mTORC1, and ERBB4/MAGI axes; the extracellular domain (phosphacan) binds with high affinity to neural CAMs (N-CAM, Ng-CAM/L1, TAG-1) via N-linked oligosaccharides and chondroitin sulfate chains, to tenascin-C/R via the fibrinogen globe domain, and to growth factors (pleiotrophin, FGF-2) via its core protein, thereby modulating neuronal adhesion, neurite outgrowth, and perineuronal net assembly through direct protein-protein interactions with tenascin-R; in glioblastoma, recurrent PTPRZ1-MET chromosomal fusion creates an oncogenic fusion protein that drives ligand-independent MET activation and tumor progression."},"narrative":{"mechanistic_narrative":"PTPRZ1 encodes RPTPβ/ζ, a CNS-enriched receptor-type protein tyrosine phosphatase whose entire extracellular domain is also produced as a secreted chondroitin sulfate proteoglycan, phosphacan, by alternative splicing [PMID:7511813]. Through this ectodomain, PTPRZ1 acts as a multivalent adhesion and growth-factor hub: phosphacan binds neural CAMs N-CAM and Ng-CAM/L1 with high affinity to inhibit neuronal adhesion and neurite growth, an interaction mediated principally by N-linked complex-type oligosaccharides at Asn-232 and Asn-381 rather than its chondroitin sulfate chains [PMID:7528221, PMID:7559574], while it engages TAG-1/axonin-1 predominantly through chondroitin sulfate chains [PMID:8663515, PMID:36227633]. The core protein further binds the fibrinogen-globe domain of tenascin-C and tenascin-R and captures growth factors pleiotrophin and FGF-2, potentiating their biological activity [PMID:7512960, PMID:9182584, PMID:9705269]; chondroitin sulfate structural heterogeneity tunes pleiotrophin binding affinity [PMID:12840014]. A structurally defined RPTPζ–tenascin-R protein-protein interface is required for assembly of reticulated perineuronal nets in vivo, a phenotype lost in Ptprz1-knockout mice [PMID:31822561, PMID:37356715]. Phosphacan is a major brain carrier of O-mannose-linked glycan epitopes including HNK-1 and Lewis X, synthesized via POMGnT1-dependent O-mannosylation [PMID:22728091, PMID:24352591, PMID:25361541]. As a signaling receptor, PTPRZ1 binds pleiotrophin to control tyrosine phosphorylation of substrates including calmodulin, ALK and TrkA, and directly dephosphorylates RNF26 at Y432 to stabilize it and activate TNF/NF-κB signaling [PMID:23170925, PMID:29753117, PMID:39443724]. PTPRZ1 also nucleates an ERBB4–MAGI kinase/phosphatase complex and drives β-catenin nuclear translocation with downstream cyclin D1/c-myc induction [PMID:17579610, PMID:18055543]. In glioblastoma, a recurrent PTPRZ1-MET (ZM) chromosomal fusion generates a protein that, via a PTPRZ1-derived coiled-coil, drives ligand-independent MET dimerization and activation to promote migration, invasion and immunosuppressive macrophage recruitment [PMID:25135958, PMID:33645009, PMID:38685521]; paracrine pleiotrophin–PTPRZ1 signaling sustains glioma stem cell maintenance, and the PTN/PTPRZ1 axis activates c-Met/mTORC1 signaling in tumor and endothelial cells [PMID:28569747, PMID:39409168].","teleology":[{"year":1994,"claim":"Establishing that the secreted brain proteoglycan phosphacan is the ectodomain of a receptor tyrosine phosphatase unified an adhesion molecule and a signaling receptor into one gene product.","evidence":"cDNA cloning, peptide sequencing and domain-specific RNA analysis","pmids":["7511813"],"confidence":"High","gaps":["Functional consequence of the transmembrane/phosphatase isoforms not addressed here","No substrate of the intracellular domain identified at this stage"]},{"year":1994,"claim":"Quantitative binding assays defined phosphacan as a high-affinity ligand for neural CAMs and tenascin-C that modulates adhesion, answering what its ectodomain does at the cell surface.","evidence":"Radioligand binding, Scatchard analysis, chondroitinase treatment and adhesion/neurite assays","pmids":["7528221","7512960"],"confidence":"High","gaps":["Molecular basis of binding (glycan vs core protein) only partially resolved","In vivo relevance untested"]},{"year":1995,"claim":"Mapping the binding determinants to specific N-linked oligosaccharides versus chondroitin sulfate established that distinct ligands engage phosphacan through distinct molecular surfaces.","evidence":"Tryptic-fragment binding assays, glycosidase treatments and glycopeptide sequencing; later extended to TAG-1, FGF-2 and tenascin domains","pmids":["7559574","8663515","9182584","9705269"],"confidence":"High","gaps":["Structural model of the binding interface not available","Whether full-length receptor uses the same determinants unclear"]},{"year":1996,"claim":"Identification of pleiotrophin as a high-affinity, functionally required phosphacan ligand connected the proteoglycan to growth-factor signaling and neurite outgrowth.","evidence":"Affinity chromatography, Scatchard binding, antibody-blocking neurite outgrowth assays; chondroitin sulfate shown to tune affinity","pmids":["8702927","10840014"],"confidence":"High","gaps":["Downstream signaling from the receptor not yet defined","Receptor versus secreted form roles not separated"]},{"year":2003,"claim":"Discovery that developmental chondroitin sulfate fine structure tunes pleiotrophin affinity, plus identification of a novel non-proteoglycan PSI isoform, revealed glycan- and splicing-based regulation of ligand engagement.","evidence":"SPR with defined disaccharide composition; cDNA cloning and binding/neurite assays for PSI","pmids":["12840014","12700241"],"confidence":"Medium","gaps":["PSI characterized in a single lab","In vivo significance of glycan tuning untested"]},{"year":2007,"claim":"Showing PTPRZ1 forms an ERBB4–MAGI scaffold complex and drives β-catenin nuclear translocation linked the phosphatase to defined intracellular signaling axes.","evidence":"Yeast two-hybrid, reciprocal Co-IP, phosphorylation assays; siRNA with nuclear β-catenin and proliferation readouts","pmids":["17579610","18055543"],"confidence":"Medium","gaps":["Direct substrate of the phosphatase not identified","Single-lab findings"]},{"year":2010,"claim":"Identification of Egr-1, HIF-2α/ELK1, later HOXA5 and integrin-α6β4/UCHL1/Hif-1α as transcriptional drivers defined how PTPRZ1 expression is controlled in reactive and tumor contexts.","evidence":"Promoter mutagenesis, ChIP, reporter assays and knockout/knockdown validation across multiple studies","pmids":["18556777","20224786","35219772","39518121"],"confidence":"High","gaps":["Relative contribution of each factor in normal CNS unclear","Cross-talk among regulators not integrated"]},{"year":2013,"claim":"Establishing phosphacan as the major brain carrier of O-mannose-linked HNK-1 and Lewis X glycans, dependent on POMGnT1, tied PTPRZ1 glycosylation to muscle-eye-brain disease glycobiology.","evidence":"Mass spectrometry of O-linked glycans with GlcAT-P, β4GalT2 and POMGnT1 knockout mice","pmids":["24352591","22728091","25361541","25737452"],"confidence":"High","gaps":["Functional consequence of specific glycoforms on ligand binding not directly tested","Link to disease phenotype correlative"]},{"year":2014,"claim":"Characterizing the recurrent PTPRZ1-MET fusion and its ligand-independent MET activation explained an oncogenic gain-of-function mechanism in glioblastoma.","evidence":"RNA-seq/genomic translocation analysis, overexpression migration/invasion assays, structure prediction and clinical MET signaling validation","pmids":["25135958","25935522","33645009","38685521"],"confidence":"High","gaps":["Contribution of the PTPRZ1 promoter versus coiled-coil to activation not fully separated","Therapeutic vulnerability validation incomplete"]},{"year":2017,"claim":"Demonstrating paracrine pleiotrophin–PTPRZ1 signaling sustains glioma stem cells and that PTPRZ1 inhibitors cross the blood-brain barrier opened a therapeutic axis.","evidence":"Macrophage/GSC co-implantation, PTN/PTPRZ1 shRNA and antibody blockade, in vivo tumor assays; small-molecule phosphatase inhibitors with IC50 ~0.1 μM","pmids":["28569747","29275231"],"confidence":"High","gaps":["Direct phosphatase substrates downstream of GSC maintenance unmapped","Inhibitor specificity beyond PTPRZ1 not fully characterized"]},{"year":2019,"claim":"Genetic and structural work established that RPTPζ–tenascin-R protein-protein interactions are required for reticulated perineuronal net assembly, defining a non-catalytic structural role.","evidence":"Ptprz1 knockout mice, structural determination and interface mutagenesis with PNN assembly assays","pmids":["31822561","37356715"],"confidence":"High","gaps":["Relationship between PNN role and phosphatase signaling unclear","Physiological consequence of PNN loss not detailed here"]},{"year":2024,"claim":"Identifying RNF26 Y432 as a direct dephosphorylation substrate and mapping PTN/PTPRZ1/c-Met/mTORC1 signaling provided concrete catalytic and signaling mechanisms for PTPRZ1's pro-tumoral and metabolic functions.","evidence":"Mass spectrometry substrate identification, phospho-specific Western blot, proteasome and crizotinib/rapamycin pharmacology, knockout endothelial cells","pmids":["39443724","39409168","37260355","23170925","29753117"],"confidence":"High","gaps":["Full substrate repertoire of the phosphatase remains incomplete","Tissue-specific substrate selection unclear"]},{"year":null,"claim":"How the catalytic (substrate dephosphorylation), adhesive (CAM/tenascin/PNN), and oncogenic-fusion functions of PTPRZ1 are integrated within a single cell, and which substrate dictates each phenotype, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking ectodomain ligand binding to intracellular catalysis","Direct substrate catalogue still partial","Isoform-specific functions not systematically separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[24,33]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[24,33]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[4,23]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[16,36]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[12,27,31]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[2,7,27]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,33,36]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,6,27,29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[20,23,33]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,7,27,31]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[17,18,19]}],"complexes":["perineuronal net","ERBB4-MAGI-RPTPβ complex","PTPRZ1-MET (ZM) fusion protein"],"partners":["PTN","TNR","TNC","MET","ERBB4","RNF26","NCAM1","CNTN2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23471","full_name":"Receptor-type tyrosine-protein phosphatase zeta","aliases":["Protein-tyrosine phosphatase receptor type Z polypeptide 1","Protein-tyrosine phosphatase receptor type Z polypeptide 2","R-PTP-zeta-2"],"length_aa":2315,"mass_kda":254.6,"function":"Protein tyrosine phosphatase that negatively regulates oligodendrocyte precursor proliferation in the embryonic spinal cord. Required for normal differentiation of the precursor cells into mature, fully myelinating oligodendrocytes. May play a role in protecting oligondendrocytes against apoptosis. May play a role in the establishment of contextual memory, probably via the dephosphorylation of proteins that are part of important signaling cascades (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P23471/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRZ1","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/PTPRZ1","total_profiled":1310},"omim":[{"mim_id":"604008","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, ZETA-2; PTPRZ2","url":"https://www.omim.org/entry/604008"},{"mim_id":"602346","title":"CONTACTIN-ASSOCIATED PROTEIN 1; CNTNAP1","url":"https://www.omim.org/entry/602346"},{"mim_id":"176891","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, ZETA-1; PTPRZ1","url":"https://www.omim.org/entry/176891"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":150.5}],"url":"https://www.proteinatlas.org/search/PTPRZ1"},"hgnc":{"alias_symbol":["PTP18","RPTPB","phosphacan"],"prev_symbol":["PTPZ","PTPRZ"]},"alphafold":{"accession":"P23471","domains":[{"cath_id":"3.10.200.10","chopping":"62-299","consensus_level":"high","plddt":85.8434,"start":62,"end":299},{"cath_id":"2.60.40.10","chopping":"316-409","consensus_level":"high","plddt":80.4438,"start":316,"end":409},{"cath_id":"3.90.190.10","chopping":"1700-1996","consensus_level":"medium","plddt":88.7486,"start":1700,"end":1996},{"cath_id":"3.90.190.10","chopping":"2031-2067_2077-2290","consensus_level":"high","plddt":88.771,"start":2031,"end":2290}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23471","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23471-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23471-F1-predicted_aligned_error_v6.png","plddt_mean":54.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRZ1","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRZ1"},"sequence":{"accession":"P23471","fasta_url":"https://rest.uniprot.org/uniprotkb/P23471.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23471/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23471"}},"corpus_meta":[{"pmid":"12895450","id":"PMC_12895450","title":"The 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hippocampal neurons.","date":"2001","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/11343829","citation_count":7,"is_preprint":false},{"pmid":"9016838","id":"PMC_9016838","title":"Identification of monoclonal antibody At5 as a new member of HNK-1 antibody family: the reactivity with myelin-associated glycoprotein and with two brain-specific proteoglycans, phosphacan and neurocan.","date":"1997","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/9016838","citation_count":6,"is_preprint":false},{"pmid":"35251170","id":"PMC_35251170","title":"Overexpression of PTPRZ1 Regulates p120/β-Catenin Phosphorylation to Promote Carcinogenesis of Oral Submucous Fibrosis.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35251170","citation_count":5,"is_preprint":false},{"pmid":"18186075","id":"PMC_18186075","title":"No association between the protein tyrosine phosphatase, receptor-type, Z Polypeptide 1 (PTPRZ1) gene and 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Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18186075","citation_count":5,"is_preprint":false},{"pmid":"15725399","id":"PMC_15725399","title":"Tyrosine kinase A but not phosphacan/protein tyrosine phosphatase-zeta/beta immunoreactivity and protein level changes in neurons and astrocytes in the gerbil hippocampus proper after transient forebrain ischemia.","date":"2005","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/15725399","citation_count":5,"is_preprint":false},{"pmid":"41543935","id":"PMC_41543935","title":"Human organoid tumor transplantation identifies functional glioblastoma-microenvironment communication mediated by PTPRZ1.","date":"2026","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41543935","citation_count":4,"is_preprint":false},{"pmid":"36227633","id":"PMC_36227633","title":"Phosphacan acts as a repulsive cue in murine and rat cerebellar granule cells in a TAG-1/GD3 rafts-dependent manner.","date":"2022","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36227633","citation_count":4,"is_preprint":false},{"pmid":"40899632","id":"PMC_40899632","title":"Enhancer Reprogramming Reveals the Tumorigenic Role of PTPRZ1 in Lung Squamous Cell Carcinoma.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40899632","citation_count":3,"is_preprint":false},{"pmid":"39518121","id":"PMC_39518121","title":"Integrin α6β4 Upregulates PTPRZ1 Through UCHL1-Mediated Hif-1α Nuclear Accumulation to Promote Triple-Negative Breast Cancer Cell Invasive Properties.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/39518121","citation_count":3,"is_preprint":false},{"pmid":"40361445","id":"PMC_40361445","title":"Regulation of Pleiotrophin and PTPRZ1 Expression by Hypoxia to Restrict Hypoxia-Induced Cell Migration.","date":"2025","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/40361445","citation_count":2,"is_preprint":false},{"pmid":"39409168","id":"PMC_39409168","title":"Pleiotrophin Activates cMet- and mTORC1-Dependent Protein Synthesis through PTPRZ1-The Role of ανβ3 Integrin.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39409168","citation_count":2,"is_preprint":false},{"pmid":"28815252","id":"PMC_28815252","title":"[Expression of PTPRZ1 in oral squamous cell carcinoma originated from oral submucous fibrosis and its clinical significance].","date":"2017","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/28815252","citation_count":2,"is_preprint":false},{"pmid":"18554468","id":"PMC_18554468","title":"[Effects of androgen on phosphacan and NG2 proteoglycan expression and neurite regeneration in neonatal rats with hypoxic-ischemic brain damage].","date":"2008","source":"Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/18554468","citation_count":2,"is_preprint":false},{"pmid":"39443724","id":"PMC_39443724","title":"PTPRZ1 dephosphorylates and stabilizes RNF26 to reduce the efficacy of TKIs and PD-1 blockade in ccRCC.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/39443724","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55782,"output_tokens":9881,"usd":0.15778,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20561,"output_tokens":4744,"usd":0.110702,"stage2_stop_reason":"end_turn"},"total_usd":0.268482,"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\": 1994,\n      \"finding\": \"Phosphacan (PTPRZ1 extracellular domain) is an alternatively spliced secreted variant of the transmembrane receptor-type protein tyrosine phosphatase RPTPζ/β, representing the entire extracellular portion of the receptor without transmembrane or intracellular phosphatase domains.\",\n      \"method\": \"cDNA cloning, amino acid sequencing, RNA analysis with domain-specific probes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct molecular cloning and sequencing with peptide validation, replicated across multiple labs in the same year\",\n      \"pmids\": [\"7511813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Phosphacan binds with high affinity (Kd ~0.1 nM) to neural cell adhesion molecules N-CAM and Ng-CAM/L1, and inhibits neuronal adhesion and neurite growth; chondroitin sulfate accounts for only ~15% of binding, indicating the core glycoprotein mediates most of this interaction.\",\n      \"method\": \"Radioligand binding assay (125I-phosphacan), Scatchard analysis, chondroitinase treatment, anti-CAM antibody inhibition, neuronal adhesion and neurite outgrowth assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative binding kinetics with multiple orthogonal methods (radioligand binding, enzymatic digestion, antibody blocking, functional assays), replicated in subsequent studies\",\n      \"pmids\": [\"7528221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Phosphacan and neurocan bind with high affinity to tenascin-C (but not laminin or fibronectin), mediated via their core glycoproteins rather than chondroitin sulfate chains; phosphacan inhibits C6 glioma cell adhesion to tenascin-C.\",\n      \"method\": \"Fluorescent microbead co-aggregation, solid-phase radioligand binding assay, Scatchard analysis, chondroitinase treatment, cell adhesion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal binding methods with quantitative Kd determination, replicated in subsequent studies\",\n      \"pmids\": [\"7512960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Phosphacan interactions with N-CAM, Ng-CAM/L1, and tenascin are mediated by asparagine-linked complex-type oligosaccharides located in the carbonic anhydrase-like and fibronectin type III-like domains (at Asn-232 and Asn-381); peptide-N-glycosidase treatment reduced binding by 65–75%.\",\n      \"method\": \"125I-phosphacan tryptic digest binding assays, peptide N-glycosidase F treatment, endo-β-N-acetylglucosaminidase H treatment, glycopeptide isolation and sequencing\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical mapping of glycosylation sites by peptide sequencing combined with functional binding assays and orthogonal enzymatic treatments\",\n      \"pmids\": [\"7559574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Phosphacan/6B4 proteoglycan binds pleiotrophin (HB-GAM) with high affinity (Kd = 0.25 nM and 3 nM for two sites); chondroitin sulfate chains modulate binding affinity; anti-6B4 antibody suppresses pleiotrophin-induced neurite outgrowth from cortical neurons, indicating this interaction is required for pleiotrophin's biological action.\",\n      \"method\": \"Affinity chromatography, N-terminal sequencing, Scatchard analysis of binding, chondroitinase ABC treatment, heparin competition, antibody-blocking neurite outgrowth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative binding kinetics with multiple orthogonal methods plus functional assay, replicated in subsequent studies\",\n      \"pmids\": [\"8702927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"TAG-1/axonin-1 is a high-affinity ligand of phosphacan (Kd ~0.04 nM); chondroitin sulfate chains account for ~70% of the binding to TAG-1, contrasting with phosphacan's N-CAM/Ng-CAM interactions which are N-glycan-mediated.\",\n      \"method\": \"Radioligand binding assay, Scatchard analysis, chondroitinase treatment, N-deglycosylation, immunocytochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative binding kinetics with orthogonal glycan-manipulation experiments defining distinct binding mechanisms for different ligands\",\n      \"pmids\": [\"8663515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Adsorbed phosphacan/6B4 proteoglycan acts as a repulsive substrate for cortical and thalamic neuronal adhesion, but in sparse culture conditions promotes neurite outgrowth and tyrosine phosphorylation of an 85 kDa protein in cortical neurons; chondroitinase or keratanase digestion did not affect this neurite-promoting activity, indicating the protein moiety is responsible.\",\n      \"method\": \"Patterned substrate cell adhesion assay, neurite outgrowth quantification, chondroitinase/keratanase digestion, antibody blocking, anti-phosphotyrosine Western blot\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple functional readouts with enzymatic and antibody controls defining core protein-mediated signaling\",\n      \"pmids\": [\"8625816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Phosphacan binds to the fibrinogen-like globe domain of tenascin-C (Kd ~12 nM), mediated by the core protein in a calcium-dependent manner; all deletion variants retaining the fibrinogen globe support phosphacan binding, while those lacking it do not.\",\n      \"method\": \"Recombinant tenascin-C deletion constructs, radioligand binding assay, chondroitinase treatment, rotary shadowing electron microscopy, cell adhesion inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural domain mapping by deletion analysis with quantitative binding and electron microscopy, multiple orthogonal methods\",\n      \"pmids\": [\"9182584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Phosphacan binds with high affinity to tenascin-R (Kd 2–7 nM) via its core protein; chondroitinase treatment increases binding by ~60%, indicating the glycosaminoglycan chains partially shield the protein-protein interaction site. Phosphacan also binds HB-GAM and amphoterin (Kd 0.3–8 nM) primarily through its chondroitin sulfate chains (>80% of binding).\",\n      \"method\": \"Radioligand binding assay, Scatchard analysis, chondroitinase treatment, calcium chelation experiments, immunocytochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative binding with orthogonal enzymatic treatments revealing differential mechanisms for distinct ligands\",\n      \"pmids\": [\"9507007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The core protein of phosphacan binds FGF-2 with high affinity (Kd ~6 nM) primarily via the protein backbone (only ~35% reduction after chondroitinase treatment), and potentiates FGF-2 mitogenic activity on NIH/3T3 cells by 75–90%.\",\n      \"method\": \"Radioligand binding assay, chondroitinase treatment, [3H]-thymidine mitogenic assay on NIH/3T3 cells, immunocytochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative binding kinetics with core-protein attribution and orthogonal functional assay\",\n      \"pmids\": [\"9705269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The heterogeneity of chondroitin sulfate chains on phosphacan regulates its binding affinity for pleiotrophin; the presence of the GlcA(2S)-GalNAc(6S) disaccharide (D unit) in postnatal day 20 phosphacan confers ~5-fold stronger binding (Kd = 0.14 nM) compared with earlier preparations lacking this unit (Kd ~1.4–1.6 nM).\",\n      \"method\": \"Phosphacan purification from different developmental stages, surface plasmon resonance biosensor binding analysis, chondroitinase ABC digestion, disaccharide composition analysis, monoclonal antibody immunoreactivity\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative SPR binding with defined glycan structural characterization and orthogonal immunological validation\",\n      \"pmids\": [\"12840014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Phosphacan short isoform (PSI), a novel truncated secreted variant encoded by a distinct cDNA, interacts with Ig cell adhesion molecules F3/contactin and L1, and promotes neurite outgrowth of cortical neurons as a coated substrate; PSI is not a proteoglycan but carries HNK-1 oligosaccharides.\",\n      \"method\": \"cDNA library screening, Northern blot, Western blot, co-immunoprecipitation/pulldown binding, neurite outgrowth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular identification with binding assays and functional neurite assay, single lab\",\n      \"pmids\": [\"12700241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPRZ1 (RPTPβ/ζ) forms a functional complex with ERBB4 via MAGI scaffolding proteins; ERBB4 expression leads to tyrosine phosphorylation of MAGI proteins (enhanced by neuregulin), and simultaneous binding of MAGI to RPTPβ creates a phosphotyrosine kinase/phosphatase complex with spatial and functional association confirmed in cultured cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, tyrosine phosphorylation assays, neuregulin stimulation, spatial co-localization imaging\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional phosphorylation assay in mammalian cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"17579610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPRZ1 overexpression activates the beta-catenin pathway in renal cell carcinoma via dephosphorylation-dependent nuclear translocation of beta-catenin, leading to expression of cyclin D1, c-myc, c-jun, fra-1, and CD44; siRNA knockdown of ptprz1 decreases nuclear beta-catenin and suppresses cellular proliferation.\",\n      \"method\": \"Gene expression microarray, CGH array, siRNA knockdown, Western blot for dephosphorylated/nuclear beta-catenin, proliferation assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with defined molecular readouts (nuclear beta-catenin, downstream targets, proliferation), single lab\",\n      \"pmids\": [\"18055543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Egr-1 transcription factor directly binds the phosphacan promoter and transactivates its expression; Egr-1-deficient mice have lower phosphacan RNA and protein levels after stroke, establishing Egr-1 as a transcriptional regulator of PTPRZ1/phosphacan in reactive astrocytes.\",\n      \"method\": \"Promoter deletion/mutational analysis, chromatin immunoprecipitation, gain-of-function and loss-of-function in primary astrocytes, Egr-1 knockout mouse analysis\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct ChIP showing promoter binding, in vitro transactivation, and in vivo KO validation with multiple orthogonal methods\",\n      \"pmids\": [\"18556777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PTPRZ1 promoter is preferentially activated by HIF-2α over HIF-1α; ELK1 cooperates with HIF-2α to drive PTPRZ1 expression through nearby HRE and Ets binding sites; ELK1 knockdown reduces HIF-2-mediated activation by >50%, and ChIP confirms binding of both HIF and ELK1 to the PTPRZ1 promoter.\",\n      \"method\": \"Promoter deletion/mutational analysis, luciferase reporter assays, siRNA knockdown, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (promoter mutagenesis, siRNA, ChIP) converging on same mechanism, single lab\",\n      \"pmids\": [\"20224786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Binding of pleiotrophin ligand to PTPRZ1 activates PTN/PTPRZ1 signaling to induce tyrosine phosphorylation of calmodulin (CaM) in small-cell lung carcinoma cells; PTPRZ1 knockdown alters CaM phosphorylation and suppresses tumor progression in murine xenograft.\",\n      \"method\": \"shRNA-mediated knockdown, Western blot for tyrosine-phosphorylated CaM, in vivo xenograft tumor assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA KD with defined molecular readout (CaM phosphorylation) and in vivo functional validation, single lab\",\n      \"pmids\": [\"23170925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RPTPζ/phosphacan undergoes abnormal O-mannosyl glycosylation in POMGnT1-knockout mice (a muscle-eye-brain disease model); loss of POMGnT1 shifts RPTPζ/phosphacan to lower molecular weight and eliminates HNK-1 carbohydrate epitopes, identifying RPTPζ/phosphacan as a significant substrate for O-mannosylation in the brain.\",\n      \"method\": \"POMGnT1 knockout mouse model, Western blot, immunofluorescence, lectin/antibody glycan epitope analysis\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined biochemical readouts, single lab, orthogonal antibody methods\",\n      \"pmids\": [\"22728091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Phosphacan is the major carrier of O-mannose-linked HNK-1 glycan in developing mouse brain; GlcAT-P synthesizes the O-linked HNK-1 onto phosphacan, and the 6B4 monoclonal antibody preferentially recognizes O-mannose-linked HNK-1 on phosphacan.\",\n      \"method\": \"Mass spectrometry glycan identification, GlcAT-P and POMGnT1 knockout mice, cell expression with GlcAT-P co-transfection, immunoblotting\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mass spectrometry structural identification combined with genetic knockout and cell expression experiments, multiple orthogonal approaches\",\n      \"pmids\": [\"24352591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Phosphacan/RPTPβ is the major carrier of the Lewis X glycan epitope in the developing mouse brain; this epitope is carried on O-mannose-linked glycans, requires β4GalT2 for synthesis, and is abolished by POMGnT1 knockout.\",\n      \"method\": \"β4GalT2 and POMGnT1 knockout mice, immunochemical analysis, glycan structural characterization\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual genetic knockouts with defined biochemical readouts, single lab\",\n      \"pmids\": [\"25361541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTPRZ1-MET (ZM) fusion proteins arise from chromosomal translocation fusing PTPRZ1 introns 3 or 8 to MET intron 1; exogenous expression of ZM fusion in U87MG glioblastoma cells enhances cell migration and invasion.\",\n      \"method\": \"RNA-seq, genomic translocation analysis, RT-PCR validation, exogenous overexpression in glioblastoma cell lines with migration/invasion assays\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — structural characterization of fusion with functional validation in cancer cells, replicated in independent cohort\",\n      \"pmids\": [\"25135958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZM fusion proteins retain MET processing and dimerization properties of wild-type MET, and enhance MET phosphorylation in both HGF-dependent and HGF-independent manners; fusion with PTPRZ1 increases MET mRNA expression levels.\",\n      \"method\": \"Western blot for MET phosphorylation/expression, HGF stimulation/withdrawal experiments, dimerization assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical analysis of fusion protein with defined molecular readouts (phosphorylation, expression, dimerization), single lab\",\n      \"pmids\": [\"25935522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"O-mannosyl glycan epitopes recognized by antibodies Cat-315 and 3F8 define biochemically distinct glycoforms of RPTPζ/phosphacan that differentially decorate distinct neural cell populations; mass spectrometry characterization identified novel O-mannose-linked glycan structures including sulfo-N-acetyllactosamine modifications on RPTPζ/phosphacan.\",\n      \"method\": \"Multidimensional mass spectrometry of O-linked glycans from purified RPTPζ/phosphacan, cell-type-specific immunofluorescence with glycoform-specific antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry structural characterization with cell-type localization, single lab, rigorous analytical methods\",\n      \"pmids\": [\"25737452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tumor-associated macrophages secrete pleiotrophin (PTN) which signals through its receptor PTPRZ1 on glioma stem cells (GSCs) to promote GSC maintenance and GBM tumor growth via paracrine PTN-PTPRZ1 signaling; disrupting PTPRZ1 abrogates GSC maintenance and tumorigenic potential, and anti-PTPRZ1 antibody suppresses tumor growth.\",\n      \"method\": \"Co-implantation of macrophages with GSCs, PTN shRNA silencing in macrophages, PTPRZ1 shRNA and antibody blockade, tumor growth and animal survival assays, in vivo xenograft\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal loss-of-function approaches (shRNA, antibody) with in vivo functional readouts, multiple mechanistic arms tested\",\n      \"pmids\": [\"28569747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Small-molecule inhibitors targeting the intracellular PD1 phosphatase domain of PTPRZ1 inhibit its tyrosine phosphatase activity (IC50 ~0.1 μM), increase phosphorylation of PTPRZ1 substrates involved in neuronal survival/differentiation, and the lead compound crosses the blood-brain barrier in vivo.\",\n      \"method\": \"In vitro phosphatase activity assay, docking/molecular dynamics, substrate phosphorylation Western blot, BBB permeability in vivo experiment\",\n      \"journal\": \"European journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay with defined IC50 and substrate phosphorylation readout, single lab\",\n      \"pmids\": [\"29275231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDKN1A is the upstream regulator of PTN/PTPRZ1 expression in TNBC cells receiving chemotherapy; chemotherapy-driven increases in CDKN1A elevate PTN and PTPRZ1 expression, and the CDKN1A/PTN/PTPRZ1 axis promotes chemoresistance via the NF-κB pathway; siRNA knockdown of PTPRZ1 reduces chemoresistance.\",\n      \"method\": \"siRNA knockdown, microarray expression analysis, CCK-8 proliferation assay, colony formation, apoptosis analysis, NF-κB pathway western blot\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined pathway (NF-κB) and functional readouts, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"30497491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRZ1 (RPTPβ/ζ) modulates ethanol signaling: ethanol increases phosphorylation of ALK and TrkA (known PTPRZ1 substrates) in neuroblastoma cells; PTPRZ1 small-molecule inhibitors also increase pALK and pTrkA but prevent ethanol-induced increases when co-applied, demonstrating PTPRZ1 modulates TrkA and ALK signaling pathways activated by alcohol.\",\n      \"method\": \"Pharmacological inhibitors (MY10, MY33-3), Western blot for pALK/pTrkA, behavioral tests in mice (binge drinking, conditioned place preference)\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based signaling experiments with defined substrates (ALK, TrkA) combined with in vivo behavioral validation, single lab\",\n      \"pmids\": [\"29753117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RPTPζ (PTPRZ1) is required for the reticulated perineuronal net (PNN) structure in the brain; Ptprz1 knockout mice lose the normal reticular PNN pattern (replaced by puncta), phenocopying tenascin-R knockout PNN defects. Two distinct surface interactions underpin PNN formation: one dependent on RPTPζ and another requiring hyaluronan.\",\n      \"method\": \"Ptprz1 knockout mice, immunofluorescence of PNN structure, biochemical fractionation, neuronal cultures\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined structural phenotype using multiple visualization methods, epistatic relationship to tenascin-R identified\",\n      \"pmids\": [\"31822561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZM fusion proteins activate MET kinase in a ligand-independent manner, likely enabled by a coiled-coil motif from the PTPRZ1 fusion segment that promotes constitutive MET dimerization/activation; clinical specimens confirm hyperactivation of MET signaling in ZM-positive gliomas.\",\n      \"method\": \"Protein structure prediction, cell line MET phosphorylation assays with/without HGF, clinical specimen MET signaling analysis, high-sensitivity RT-PCR\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural modeling combined with cell-based phosphorylation assays and clinical validation, single lab\",\n      \"pmids\": [\"33645009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Phosphacan exerts repulsive effects on cerebellar granule cell migration through interaction with TAG-1; the interaction is mediated by chondroitin sulfate C chains (confirmed by SPR), requires GD3 ganglioside-containing lipid rafts, and attenuates BDNF-induced Akt activation and migration.\",\n      \"method\": \"TAG-1 knockout mouse primary cerebellar granule cells, Boyden chamber migration assay, surface plasmon resonance for TAG-1/CS-C binding, anti-GD3/GD1b antibody blocking, methyl-β-cyclodextrin lipid raft disruption, Akt inhibitor MK-2206\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic knockout with multiple pharmacological and biochemical dissections defining the TAG-1/GD3 raft-dependent signaling mechanism\",\n      \"pmids\": [\"36227633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HOXA5 directly binds the PTPRZ1 promoter to transcriptionally activate PTPRZ1 expression in glioblastoma stem cells; suppression of PTPRZ1 largely reverses the pro-tumoral effects of HOXA5 overexpression, placing PTPRZ1 downstream of HOXA5 in a GSC maintenance pathway.\",\n      \"method\": \"ChIP for HOXA5 binding to PTPRZ1 promoter, HOXA5 gain/loss-of-function, PTPRZ1 knockdown, GSC self-renewal and invasion assays, in vivo tumor propagation\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional epistasis experiments, single lab\",\n      \"pmids\": [\"35219772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Tenascin-R (TNR) directly associates with the RPTPζ ectodomain via protein-protein interactions; the same interface mediates RPTPζ interaction with tenascin-C; mutating RPTPζ residues at the RPTPζ-TNR interface impairs PNN formation in dissociated neuronal cultures, demonstrating these protein-protein interactions are structurally required for PNN assembly.\",\n      \"method\": \"Structural determination of RPTPζ-TNR interaction, mutagenesis of interface residues, neuronal culture PNN assembly assay, Ptprz1 knockout mouse\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-based mutagenesis with functional PNN assembly validation, genetic knockout supporting model\",\n      \"pmids\": [\"37356715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of PTPRZ1 tyrosine phosphatase activity in endothelial cells (genetic knockout or pharmacological inhibition) activates c-Met and Akt, reduces β3 integrin expression, and enhances angiogenesis and lung adenocarcinoma growth in vivo; PTN and VEGFA165 activate c-Met and Akt in a PTPRZ1-dependent manner, and these effects are abolished by the c-Met inhibitor crizotinib.\",\n      \"method\": \"Ptprz1−/− and Ptprz1+/+ mouse endothelial cells, in vivo urethane-induced LUAD model, PTPRZ1 inhibitor, Western blot for c-Met/Akt/VEGFR2/β3 integrin, crizotinib blockade\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with pharmacological rescue in vivo and in vitro, multiple readouts, single lab\",\n      \"pmids\": [\"37260355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPRZ1 dephosphorylates RNF26 at the Y432 site, thereby stabilizing RNF26 protein expression through the proteasome pathway; through this PTPRZ1-RNF26 interaction, PTPRZ1 activates the TNF/NF-κB signaling pathway to promote cell proliferation, angiogenesis, and lipid metabolism in clear cell renal cell carcinoma.\",\n      \"method\": \"Mass spectrometry substrate identification, RNA sequencing, lipidomic profiling, immunohistochemistry, phospho-specific Western blot, proteasome inhibitor experiments, RNF26 knockdown rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical identification of dephosphorylation substrate with site specificity (Y432), proteasome pathway mechanistic dissection, multiple orthogonal methods\",\n      \"pmids\": [\"39443724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Curcumin interacts with PTPRZ1 to maintain its enzymatic (phosphatase) activity, thereby regulating phosphorylation of the m6A-reader YTHDF2; this modulation of YTHDF2 phosphorylation via PTPRZ1 affects downstream gene expression to reduce microglial inflammatory responses.\",\n      \"method\": \"Binding/interaction assays between curcumin and PTPRZ1, phosphorylation assays for YTHDF2, gene expression analysis\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic pathway proposed from abstract-level description; methods not fully specified in abstract; single lab, single paper\",\n      \"pmids\": [\"39921492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZM (PTPRZ1-MET) fusion-positive glioma stem cells upregulate ISG20 through the MET-STAT3-ISG20 signaling axis; secreted ISG20 recruits macrophages and drives their polarization toward an immunosuppressive M2-like phenotype, promoting tumor progression.\",\n      \"method\": \"RNA-seq of patient glioma tissues, ZM overexpression/knockdown, STAT3 inhibition, ISG20 knockdown, macrophage co-culture polarization assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation with defined signaling pathway (MET-STAT3-ISG20) and functional macrophage polarization readout, single lab\",\n      \"pmids\": [\"38685521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTN activates c-Met and mTORC1-dependent protein synthesis through PTPRZ1; PTPRZ1 deletion or PTN stimulation increases phosphorylation of S6K1 and 4EBP1 (mTORC1 substrates) and upregulates HIF-1α; c-Met inhibitor crizotinib abolishes these effects, placing c-Met downstream of the PTN/PTPRZ1 axis upstream of mTORC1 in endothelial cell migration.\",\n      \"method\": \"Ptprz1 knockout endothelial cells, PTN stimulation, Western blot for mTORC1 substrates (pS6K1, p4EBP1), crizotinib and rapamycin pharmacological blockade, cell migration assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with pharmacological epistasis defining PTN→PTPRZ1→c-Met→mTORC1 pathway, single lab\",\n      \"pmids\": [\"39409168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTPRZ1 overexpression regulates phosphorylation of p120 and β-catenin, causing their redistribution from cell membrane to cytoplasm and nucleus, activating downstream targets (RhoA, Rac1, CDC42, cyclin D1, c-myc) and promoting cell proliferation, migration, and invasion in oral submucous fibrosis; PTPRZ1 knockdown reduces tumor volume in vivo.\",\n      \"method\": \"PTPRZ1 overexpression/knockdown, Western blot and immunofluorescence for p-p120/p-β-catenin localization, cell migration/invasion assays, in vivo tumor formation\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined phosphorylation substrates and localization readouts, single lab\",\n      \"pmids\": [\"35251170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Integrin α6β4 regulates PTPRZ1 expression through a UCHL1-Hif-1α axis: integrin α6β4 upregulates UCHL1, which stabilizes Hif-1α nuclear localization, leading to transcriptional activation of PTPRZ1; inhibition of UCHL1 or PTPRZ1 dramatically decreases integrin α6β4-mediated cell migration and 3D invasive growth in TNBC.\",\n      \"method\": \"ITGB4 re-expression and KO, shRNA knockdown, chemical Hif-1α inhibition/activation, UCHL1 inhibition, migration and 3D invasion assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined upstream pathway (integrin→UCHL1→Hif-1α→PTPRZ1) with loss-of-function functional validation, single lab\",\n      \"pmids\": [\"39518121\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRZ1 encodes RPTPζ/β, a receptor-type protein tyrosine phosphatase expressed in the CNS as multiple isoforms—a full-length transmembrane receptor, a short transmembrane receptor, the secreted extracellular proteoglycan phosphacan, and PSI—all produced by alternative splicing; it functions as a pleiotrophin/midkine receptor that, upon ligand binding, modulates downstream tyrosine phosphorylation of substrates including calmodulin, ALK, TrkA, and RNF26 (directly dephosphorylated at Y432), regulating signaling through the beta-catenin, NF-κB, c-Met/mTORC1, and ERBB4/MAGI axes; the extracellular domain (phosphacan) binds with high affinity to neural CAMs (N-CAM, Ng-CAM/L1, TAG-1) via N-linked oligosaccharides and chondroitin sulfate chains, to tenascin-C/R via the fibrinogen globe domain, and to growth factors (pleiotrophin, FGF-2) via its core protein, thereby modulating neuronal adhesion, neurite outgrowth, and perineuronal net assembly through direct protein-protein interactions with tenascin-R; in glioblastoma, recurrent PTPRZ1-MET chromosomal fusion creates an oncogenic fusion protein that drives ligand-independent MET activation and tumor progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPRZ1 encodes RPTPβ/ζ, a CNS-enriched receptor-type protein tyrosine phosphatase whose entire extracellular domain is also produced as a secreted chondroitin sulfate proteoglycan, phosphacan, by alternative splicing [#0]. Through this ectodomain, PTPRZ1 acts as a multivalent adhesion and growth-factor hub: phosphacan binds neural CAMs N-CAM and Ng-CAM/L1 with high affinity to inhibit neuronal adhesion and neurite growth, an interaction mediated principally by N-linked complex-type oligosaccharides at Asn-232 and Asn-381 rather than its chondroitin sulfate chains [#1, #3], while it engages TAG-1/axonin-1 predominantly through chondroitin sulfate chains [#5, #29]. The core protein further binds the fibrinogen-globe domain of tenascin-C and tenascin-R and captures growth factors pleiotrophin and FGF-2, potentiating their biological activity [#2, #7, #9]; chondroitin sulfate structural heterogeneity tunes pleiotrophin binding affinity [#10]. A structurally defined RPTPζ–tenascin-R protein-protein interface is required for assembly of reticulated perineuronal nets in vivo, a phenotype lost in Ptprz1-knockout mice [#27, #31]. Phosphacan is a major brain carrier of O-mannose-linked glycan epitopes including HNK-1 and Lewis X, synthesized via POMGnT1-dependent O-mannosylation [#17, #18, #19]. As a signaling receptor, PTPRZ1 binds pleiotrophin to control tyrosine phosphorylation of substrates including calmodulin, ALK and TrkA, and directly dephosphorylates RNF26 at Y432 to stabilize it and activate TNF/NF-κB signaling [#16, #26, #33]. PTPRZ1 also nucleates an ERBB4–MAGI kinase/phosphatase complex and drives β-catenin nuclear translocation with downstream cyclin D1/c-myc induction [#12, #13]. In glioblastoma, a recurrent PTPRZ1-MET (ZM) chromosomal fusion generates a protein that, via a PTPRZ1-derived coiled-coil, drives ligand-independent MET dimerization and activation to promote migration, invasion and immunosuppressive macrophage recruitment [#20, #28, #35]; paracrine pleiotrophin–PTPRZ1 signaling sustains glioma stem cell maintenance, and the PTN/PTPRZ1 axis activates c-Met/mTORC1 signaling in tumor and endothelial cells [#23, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that the secreted brain proteoglycan phosphacan is the ectodomain of a receptor tyrosine phosphatase unified an adhesion molecule and a signaling receptor into one gene product.\",\n      \"evidence\": \"cDNA cloning, peptide sequencing and domain-specific RNA analysis\",\n      \"pmids\": [\"7511813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the transmembrane/phosphatase isoforms not addressed here\", \"No substrate of the intracellular domain identified at this stage\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Quantitative binding assays defined phosphacan as a high-affinity ligand for neural CAMs and tenascin-C that modulates adhesion, answering what its ectodomain does at the cell surface.\",\n      \"evidence\": \"Radioligand binding, Scatchard analysis, chondroitinase treatment and adhesion/neurite assays\",\n      \"pmids\": [\"7528221\", \"7512960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of binding (glycan vs core protein) only partially resolved\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapping the binding determinants to specific N-linked oligosaccharides versus chondroitin sulfate established that distinct ligands engage phosphacan through distinct molecular surfaces.\",\n      \"evidence\": \"Tryptic-fragment binding assays, glycosidase treatments and glycopeptide sequencing; later extended to TAG-1, FGF-2 and tenascin domains\",\n      \"pmids\": [\"7559574\", \"8663515\", \"9182584\", \"9705269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of the binding interface not available\", \"Whether full-length receptor uses the same determinants unclear\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of pleiotrophin as a high-affinity, functionally required phosphacan ligand connected the proteoglycan to growth-factor signaling and neurite outgrowth.\",\n      \"evidence\": \"Affinity chromatography, Scatchard binding, antibody-blocking neurite outgrowth assays; chondroitin sulfate shown to tune affinity\",\n      \"pmids\": [\"8702927\", \"10840014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from the receptor not yet defined\", \"Receptor versus secreted form roles not separated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that developmental chondroitin sulfate fine structure tunes pleiotrophin affinity, plus identification of a novel non-proteoglycan PSI isoform, revealed glycan- and splicing-based regulation of ligand engagement.\",\n      \"evidence\": \"SPR with defined disaccharide composition; cDNA cloning and binding/neurite assays for PSI\",\n      \"pmids\": [\"12840014\", \"12700241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PSI characterized in a single lab\", \"In vivo significance of glycan tuning untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showing PTPRZ1 forms an ERBB4–MAGI scaffold complex and drives β-catenin nuclear translocation linked the phosphatase to defined intracellular signaling axes.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, phosphorylation assays; siRNA with nuclear β-catenin and proliferation readouts\",\n      \"pmids\": [\"17579610\", \"18055543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate of the phosphatase not identified\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of Egr-1, HIF-2α/ELK1, later HOXA5 and integrin-α6β4/UCHL1/Hif-1α as transcriptional drivers defined how PTPRZ1 expression is controlled in reactive and tumor contexts.\",\n      \"evidence\": \"Promoter mutagenesis, ChIP, reporter assays and knockout/knockdown validation across multiple studies\",\n      \"pmids\": [\"18556777\", \"20224786\", \"35219772\", \"39518121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each factor in normal CNS unclear\", \"Cross-talk among regulators not integrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing phosphacan as the major brain carrier of O-mannose-linked HNK-1 and Lewis X glycans, dependent on POMGnT1, tied PTPRZ1 glycosylation to muscle-eye-brain disease glycobiology.\",\n      \"evidence\": \"Mass spectrometry of O-linked glycans with GlcAT-P, β4GalT2 and POMGnT1 knockout mice\",\n      \"pmids\": [\"24352591\", \"22728091\", \"25361541\", \"25737452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of specific glycoforms on ligand binding not directly tested\", \"Link to disease phenotype correlative\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterizing the recurrent PTPRZ1-MET fusion and its ligand-independent MET activation explained an oncogenic gain-of-function mechanism in glioblastoma.\",\n      \"evidence\": \"RNA-seq/genomic translocation analysis, overexpression migration/invasion assays, structure prediction and clinical MET signaling validation\",\n      \"pmids\": [\"25135958\", \"25935522\", \"33645009\", \"38685521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of the PTPRZ1 promoter versus coiled-coil to activation not fully separated\", \"Therapeutic vulnerability validation incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating paracrine pleiotrophin–PTPRZ1 signaling sustains glioma stem cells and that PTPRZ1 inhibitors cross the blood-brain barrier opened a therapeutic axis.\",\n      \"evidence\": \"Macrophage/GSC co-implantation, PTN/PTPRZ1 shRNA and antibody blockade, in vivo tumor assays; small-molecule phosphatase inhibitors with IC50 ~0.1 μM\",\n      \"pmids\": [\"28569747\", \"29275231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphatase substrates downstream of GSC maintenance unmapped\", \"Inhibitor specificity beyond PTPRZ1 not fully characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic and structural work established that RPTPζ–tenascin-R protein-protein interactions are required for reticulated perineuronal net assembly, defining a non-catalytic structural role.\",\n      \"evidence\": \"Ptprz1 knockout mice, structural determination and interface mutagenesis with PNN assembly assays\",\n      \"pmids\": [\"31822561\", \"37356715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between PNN role and phosphatase signaling unclear\", \"Physiological consequence of PNN loss not detailed here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying RNF26 Y432 as a direct dephosphorylation substrate and mapping PTN/PTPRZ1/c-Met/mTORC1 signaling provided concrete catalytic and signaling mechanisms for PTPRZ1's pro-tumoral and metabolic functions.\",\n      \"evidence\": \"Mass spectrometry substrate identification, phospho-specific Western blot, proteasome and crizotinib/rapamycin pharmacology, knockout endothelial cells\",\n      \"pmids\": [\"39443724\", \"39409168\", \"37260355\", \"23170925\", \"29753117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate repertoire of the phosphatase remains incomplete\", \"Tissue-specific substrate selection unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the catalytic (substrate dephosphorylation), adhesive (CAM/tenascin/PNN), and oncogenic-fusion functions of PTPRZ1 are integrated within a single cell, and which substrate dictates each phenotype, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking ectodomain ligand binding to intracellular catalysis\", \"Direct substrate catalogue still partial\", \"Isoform-specific functions not systematically separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [24, 33]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [24, 33]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [4, 23]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [16, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [12, 27, 31]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [2, 7, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 33, 36]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 6, 27, 29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [20, 23, 33]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 7, 27, 31]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [17, 18, 19]}\n    ],\n    \"complexes\": [\n      \"perineuronal net\",\n      \"ERBB4-MAGI-RPTPβ complex\",\n      \"PTPRZ1-MET (ZM) fusion protein\"\n    ],\n    \"partners\": [\n      \"PTN\",\n      \"TNR\",\n      \"TNC\",\n      \"MET\",\n      \"ERBB4\",\n      \"RNF26\",\n      \"NCAM1\",\n      \"CNTN2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}