{"gene":"PTPRG","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2010,"finding":"Crystal structures of the carbonic anhydrase-like domains of PTPRG and PTPRZ revealed that PTPRG directly interacts with the second and third immunoglobulin repeats of contactins CNTN3, CNTN4, CNTN5, and CNTN6 (but not CNTN1, which is specific to PTPRZ). Crystal structure of mouse CNTN4 N-terminal Ig repeats in complex with the carbonic anhydrase-like domain of mouse PTPRG showed CNTN4 adopts a horseshoe-like conformation and contacts a discrete beta-hairpin loop region of PTPRG.","method":"X-ray crystallography; direct binding assay; structure of PTPRG carbonic anhydrase-like domain alone and in complex with CNTN4","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional validation of direct interaction, multiple contactin partners tested, rigorous structural data","pmids":["20133774"],"is_preprint":false},{"year":2013,"finding":"Molecular modeling of human contactin 4, 5, and 6 interaction with PTPRG showed that interactive residues between contactin 4-6 and PTPRG are strictly conserved, and no differences in PTPRG binding were observed experimentally among contactin 5 and 6, suggesting differential neurite outgrowth effects of contactins do not result from distinct interactions with PTPRG.","method":"3D structural modeling; co-culture neuritogenesis assay; comparative binding analysis","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — computational modeling with functional assay, single lab, result is a negative finding (no differential PTPRG binding) supported by structural conservation analysis","pmids":["23519440"],"is_preprint":false},{"year":2018,"finding":"PTPRG interacts with and colocalizes with FGFR1 at the plasma membrane in osteosarcoma cells, and directly dephosphorylates activated FGFR1. Depletion of PTPRG increased FGFR1 activity, hypersensitized cells to FGF1 stimulation, elevated cell growth, and reduced efficacy of FGFR kinase inhibitors.","method":"Proximity-dependent biotin labeling (BioID) combined with label-free quantitative mass spectrometry; co-immunoprecipitation; colocalization imaging; PTPRG knockdown with phenotypic readouts; in vitro dephosphorylation assay","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct dephosphorylation shown in vitro, reciprocal interaction confirmed, multiple orthogonal methods (BioID-MS, Co-IP, KD with functional readout), single lab","pmids":["29371290"],"is_preprint":false},{"year":2018,"finding":"PTPRG, restricted to cholesterol-rich lipid domains, dephosphorylates the RTK AXL when AXL is recruited to lipid domains through its interaction with the GPI-anchored tumour suppressor OPCML (which binds activated AXL). This OPCML-PTPRG cooperation prevents AXL-mediated transactivation of cMET and EGFR, inhibits sustained phospho-ERK signalling, reduces EMT transcription factor Slug induction, and suppresses cell migration and invasion in ovarian cancer.","method":"Co-immunoprecipitation; lipid domain fractionation; phosphatase activity assay; OPCML/PTPRG functional knockdown; in vitro and in vivo tumor models","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct dephosphorylation demonstrated, mechanism defined through lipid domain co-localization and epistasis, multiple orthogonal methods, in vitro and in vivo validation","pmids":["29907679"],"is_preprint":false},{"year":2015,"finding":"PTPRG dephosphorylates EGFR at Y1068 and Y1086 in nasopharyngeal carcinoma (NPC) cells, inactivating the PI3K/Akt signaling cascade and downregulating pro-angiogenic and pro-invasive proteins VEGF, IL6, and IL8, thereby suppressing tumor cell proliferation, angiogenesis, and invasion in vitro and in vivo.","method":"Co-immunoprecipitation (PTPRG-EGFR interaction); phospho-specific western blot; PTPRG overexpression and Akt knockdown; in vitro and in vivo tumor models","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, phospho-site specific readout, epistasis via Akt KD, in vivo validation, single lab","pmids":["25970784"],"is_preprint":false},{"year":2010,"finding":"Overexpression of PTPRG in MCF-7 breast cancer cells inhibited tumor formation in vivo (athymic mouse model), upregulated p21(cip) and p27(kip) cell cycle inhibitors, delayed cell cycle re-entry after serum starvation, and reduced ERK1/2 phosphorylation, indicating PTPRG acts as a tumor suppressor through the ERK1/2 pathway.","method":"Xenograft tumor model; western blot for cell cycle regulators; ERK1/2 phosphorylation assay; cell cycle re-entry assay; methylation assay","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo tumor suppression confirmed, multiple mechanistic readouts (ERK1/2, p21, p27), single lab with orthogonal methods","pmids":["20651337"],"is_preprint":false},{"year":2012,"finding":"PTPRG (RPTPγ) exhibits tyrosine phosphatase activity in vitro; a C1060S catalytic mutant is completely inactive. PTPRG auto-dephosphorylates at Y1307 in its D2 domain, as demonstrated by substrate trapping mutant analysis (C1060S, D1028A) and in vitro dephosphorylation experiments. Loss of PTPRG phosphatase activity (knockdown or catalytically inactive knock-in mice) produces antidepressive-like behavior in mice.","method":"In vitro phosphatase activity assay; active-site mutagenesis (C1060S, D1028A); substrate trapping; truncation and mutagenesis mapping; knock-in and knockdown mouse models; behavioral assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis, auto-dephosphorylation site mapped by mutagenesis, validated in mouse models, single lab with multiple orthogonal methods","pmids":["23029056"],"is_preprint":false},{"year":2014,"finding":"In 293 cells, PTPRG expression induces dephosphorylation of ERK, a downstream RAS target, implicating PTPRG as a direct negative regulator of RAS/ERK signaling. DNA methylation of the PTPRG promoter silences PTPRG expression and cooperates with RAS mutations in childhood ALL oncogenesis; the PTPRG promoter contains a binding site for the RAS-responsive transcription factor RREB1.","method":"PTPRG expression in 293 cells with ERK phosphorylation readout; genome-wide methylation profiling; ChIP for RREB1 at PTPRG promoter; correlation of methylation with gene expression","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ERK dephosphorylation shown in cell assay, ChIP for RREB1, methylation-expression correlation, single lab","pmids":["24496747"],"is_preprint":false},{"year":2020,"finding":"RPTPγ (encoded by PTPRG) functions as an HCO3−-sensor in endothelial cells of resistance arteries. Its presence enhances endothelial intracellular Ca2+ responses and facilitates endothelium-dependent vasorelaxation only when CO2/HCO3− is present. RPTPγ limits increases in cerebral perfusion during neuronal activity, amplifies decreases during hyperventilation, and augments hyperventilation-induced blood pressure elevations, without affecting resting blood pressure.","method":"Transgenic (knockout) mouse model; Ca2+ imaging in resistance artery endothelial cells; myography for vasorelaxation; cerebral perfusion measurement; blood pressure recording","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with multiple orthogonal functional readouts (Ca2+, vascular tone, perfusion, blood pressure), mechanistic role as HCO3- sensor established","pmids":["32955439"],"is_preprint":false},{"year":2018,"finding":"PTPRG expression positively modulates nilotinib response in CML cells and negatively affects BCR-ABL1-dependent transformation. PTPRG knockout by CRISPR/Cas9 in CML cell lines revealed that loss of PTPRG increases BCR-ABL1 signaling events, while overexpression reduces them.","method":"CRISPR/Cas9 gene knockout; PTPRG overexpression in CML cell lines; BCR-ABL1 signaling readout; functional nilotinib response assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with functional signaling readout and drug response phenotype, single lab","pmids":["29507701"],"is_preprint":false},{"year":2024,"finding":"Within neurons, PTPRG physically binds and upregulates the m6A methyltransferase VIRMA, which inhibits translation of PRKN mRNA, thereby suppressing mitophagy and leading to neuronal death in Alzheimer's disease. This interaction was validated by co-immunoprecipitation in mouse brains.","method":"Single-cell RNA sequencing; spatial transcriptomics; co-immunoprecipitation in mouse brain; western blot; 5xFAD mouse model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP in mouse brain confirms physical interaction, but mechanistic chain (VIRMA upregulation → PRKN translation suppression → mitophagy inhibition) relies primarily on sequencing/computational data with limited direct experimental validation in the abstract","pmids":["38325728"],"is_preprint":false},{"year":2016,"finding":"miR-19b directly suppresses PTPRG expression by binding two specific sites in the 3'-UTR of PTPRG, leading to increased cell proliferation, stimulated migration, and reduced apoptosis in breast cancer cells.","method":"miR-19b overexpression and knockdown in MCF-7 and MDA-231 cells; western blot for PTPRG protein; 3'-UTR luciferase reporter assay; proliferation, migration, and apoptosis assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validated by 3'-UTR reporter assay and western blot in two cell lines, loss/gain of function with phenotypic readout, single lab","pmids":["27602768"],"is_preprint":false},{"year":1993,"finding":"Mouse L-cells (a sarcoma-producing cell line) exhibit homozygous intragenic deletion of the Ptprg gene within the carbonic anhydrase-like domain (exons 2-4 deleted), resulting in a mutant transcript 400 bp shorter than wild type, and loss of one allele—consistent with biallelic inactivation of a tumor suppressor locus.","method":"RT-PCR on L-cell mRNA; PCR on genomic DNA; interspecific backcross mapping; sequencing of deletion boundaries","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic and transcript analysis demonstrating biallelic deletion, clear molecular characterization, single lab","pmids":["8453613"],"is_preprint":false},{"year":2025,"finding":"siRNA-mediated knockdown of PTPRG in cultured dorsal root ganglion (DRG) neurons and explants increased neurite outgrowth and enhanced sensory axonal regeneration. RNA sequencing after PTPRG knockdown revealed activation of metabolism-related pathways and altered expression of the transcription factor PROX1, identifying PTPRG as a negative regulator of axonal regeneration.","method":"siRNA knockdown; neurite outgrowth and axonal regeneration assays in DRG neurons and explants; RNA sequencing","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct KD with specific phenotypic readout (neurite outgrowth), transcriptomic pathway analysis, single lab, single method for mechanistic follow-up","pmids":["41323734"],"is_preprint":false},{"year":2010,"finding":"Methylation of PTPRG intron 1 in colorectal cancer is associated with loss of binding of the insulator protein CTCF to the methylated region, as demonstrated by chromatin immunoprecipitation (ChIP). This methylation does not directly affect PTPRG expression levels but may affect tumor gene expression through CTCF-dependent enhancer blocking or chromosome loop formation.","method":"CpG island microarray; bisulfite sequencing; ChIP for CTCF binding","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly demonstrates loss of CTCF binding at methylated locus, two orthogonal methods (methylation profiling and ChIP), single lab","pmids":["21150880"],"is_preprint":false},{"year":2025,"finding":"In multiple myeloma cell lines (U266 and NCI-H929), siRNA-mediated knockdown of PTPRG reduced cell viability and increased apoptosis, identifying PTPRG as a positive regulator of survival/stemness in malignant plasma cells (in contrast to its tumor suppressor role in solid tumors).","method":"siRNA knockdown in MM cell lines; cell viability assay; apoptosis assay; single-cell RNA sequencing for context","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional KD experiment in cell lines with viability/apoptosis readout, limited mechanistic detail in abstract, single lab","pmids":["41050668"],"is_preprint":false}],"current_model":"PTPRG is a receptor-type protein tyrosine phosphatase that directly dephosphorylates multiple receptor tyrosine kinases (including FGFR1, EGFR, and AXL) at the plasma membrane or in lipid domains to suppress PI3K/Akt and ERK/MAPK signaling; it binds contactins CNTN3-6 via its carbonic anhydrase-like domain (structurally defined by X-ray crystallography); it acts as an HCO3−-sensor in endothelial cells to regulate vasorelaxation and tissue perfusion; it auto-dephosphorylates at Y1307 in its D2 domain; it physically interacts with the m6A methyltransferase VIRMA in neurons; and it functions as a tumor suppressor in most cancers but paradoxically promotes survival in multiple myeloma plasma cells, with its expression regulated by promoter CpG methylation in multiple cancer types."},"narrative":{"mechanistic_narrative":"PTPRG is a receptor-type protein tyrosine phosphatase that functions broadly as a negative regulator of receptor tyrosine kinase signaling and, in most contexts, as a tumor suppressor [PMID:20651337, PMID:8453613]. Its catalytic activity resides in a phosphatase domain whose C1060 active-site cysteine is essential, and it auto-dephosphorylates at Y1307 within its D2 domain [PMID:23029056]. At the plasma membrane and within cholesterol-rich lipid domains it directly dephosphorylates activated receptor tyrosine kinases, including FGFR1 in osteosarcoma [PMID:29371290], EGFR at Y1068/Y1086 in nasopharyngeal carcinoma [PMID:25970784], and AXL when AXL is recruited to lipid domains through the GPI-anchored partner OPCML [PMID:29907679]; through these substrates it suppresses PI3K/Akt and RAS/ERK signaling, restraining proliferation, angiogenesis, migration, and invasion [PMID:29907679, PMID:25970784, PMID:20651337, PMID:24496747]. PTPRG also dampens BCR-ABL1 signaling and modulates nilotinib response in CML [PMID:29507701]. Its extracellular carbonic anhydrase-like domain mediates direct, structurally defined binding to contactins CNTN3-6 via their N-terminal Ig repeats [PMID:20133774, PMID:23519440], and in endothelial cells of resistance arteries the protein acts as an HCO3−-sensor that couples bicarbonate sensing to endothelium-dependent vasorelaxation, cerebral perfusion, and blood pressure control [PMID:32955439]. PTPRG expression is silenced or attenuated through promoter and intronic CpG methylation and by miR-19b targeting of its 3'-UTR [PMID:24496747, PMID:27602768, PMID:21150880]. In contrast to its solid-tumor suppressor role, PTPRG supports survival of malignant plasma cells in multiple myeloma [PMID:41050668].","teleology":[{"year":1993,"claim":"Established PTPRG as a candidate tumor suppressor by showing biallelic inactivation of the locus in a transformed cell line.","evidence":"RT-PCR, genomic PCR, and deletion-boundary sequencing in mouse L-cells","pmids":["8453613"],"confidence":"Medium","gaps":["Did not define the phosphatase substrates or signaling pathways PTPRG restrains","Deletion within the carbonic anhydrase-like domain; functional consequence for catalysis not tested"]},{"year":2010,"claim":"Defined the structural basis of PTPRG's extracellular adhesion function, showing its carbonic anhydrase-like domain selectively binds contactins CNTN3-6.","evidence":"X-ray crystallography of PTPRG CA-like domain alone and in complex with CNTN4, plus direct binding assays","pmids":["20133774"],"confidence":"High","gaps":["Functional downstream consequence of contactin binding not resolved","Did not connect adhesion to phosphatase signaling output"]},{"year":2010,"claim":"Linked PTPRG re-expression to tumor suppression through cell-cycle arrest and ERK pathway attenuation.","evidence":"PTPRG overexpression in MCF-7 breast cancer cells, xenografts, and western blots for p21/p27 and ERK1/2","pmids":["20651337"],"confidence":"Medium","gaps":["Did not identify the direct RTK substrate upstream of ERK in this system","Mechanism by which PTPRG raises p21/p27 unresolved"]},{"year":2012,"claim":"Demonstrated PTPRG is an active tyrosine phosphatase and mapped an intramolecular auto-dephosphorylation event, providing the catalytic ground truth for its signaling roles.","evidence":"In vitro phosphatase assays, active-site (C1060S) and substrate-trapping (D1028A) mutagenesis, and knock-in/knockdown mouse behavioral models","pmids":["23029056"],"confidence":"High","gaps":["Physiological substrates dephosphorylated in neurons not identified","Functional role of Y1307 auto-dephosphorylation in vivo unclear"]},{"year":2010,"claim":"Showed that PTPRG intronic methylation acts non-canonically by displacing the CTCF insulator rather than simply silencing expression.","evidence":"CpG island microarray, bisulfite sequencing, and CTCF ChIP in colorectal cancer","pmids":["21150880"],"confidence":"Medium","gaps":["Downstream genes affected by altered CTCF looping not defined","Did not link to PTPRG phosphatase activity"]},{"year":2014,"claim":"Positioned PTPRG as a direct negative regulator of RAS/ERK and explained its silencing through RREB1/methylation-controlled transcription in leukemia.","evidence":"ERK dephosphorylation in 293 cells, genome-wide methylation profiling, and RREB1 ChIP at the PTPRG promoter in childhood ALL","pmids":["24496747"],"confidence":"Medium","gaps":["Direct RTK substrate upstream of RAS/ERK not identified","Cooperation with RAS mutations correlative"]},{"year":2015,"claim":"Identified EGFR as a direct PTPRG substrate and connected dephosphorylation to suppression of pro-angiogenic/pro-invasive output.","evidence":"Co-IP, phospho-site-specific western blot, Akt knockdown, and in vitro/in vivo tumor models in nasopharyngeal carcinoma","pmids":["25970784"],"confidence":"Medium","gaps":["Single-lab Co-IP for interaction","Whether EGFR dephosphorylation occurs directly or via an intermediate not fully resolved"]},{"year":2016,"claim":"Established post-transcriptional control of PTPRG by miR-19b, adding a regulatory layer to its loss in cancer.","evidence":"miR-19b gain/loss of function, 3'-UTR luciferase reporter, and phenotypic assays in breast cancer lines","pmids":["27602768"],"confidence":"Medium","gaps":["In vivo relevance of the miR-19b–PTPRG axis not tested","Downstream signaling not mapped"]},{"year":2018,"claim":"Demonstrated direct dephosphorylation of FGFR1 by PTPRG at the membrane, showing its loss confers RTK inhibitor resistance.","evidence":"BioID-MS, Co-IP, colocalization, in vitro dephosphorylation, and knockdown phenotypes in osteosarcoma cells","pmids":["29371290"],"confidence":"High","gaps":["Site-specific FGFR1 residues dephosphorylated not detailed","Generality across FGFR family members untested"]},{"year":2018,"claim":"Defined a lipid-domain-restricted mechanism whereby OPCML recruits AXL to PTPRG for dephosphorylation, blocking RTK transactivation and EMT.","evidence":"Co-IP, lipid domain fractionation, phosphatase assays, OPCML/PTPRG knockdown, and in vitro/in vivo ovarian cancer models","pmids":["29907679"],"confidence":"High","gaps":["Stoichiometry and dynamics of the OPCML-AXL-PTPRG assembly not resolved"]},{"year":2018,"claim":"Extended PTPRG's RTK-suppressor role to oncogenic fusion kinase signaling and drug sensitivity in CML.","evidence":"CRISPR/Cas9 knockout and overexpression with BCR-ABL1 signaling and nilotinib response readouts in CML lines","pmids":["29507701"],"confidence":"Medium","gaps":["Whether PTPRG dephosphorylates BCR-ABL1 directly not established","Clinical correlation absent"]},{"year":2020,"claim":"Revealed a non-tumor physiological function: PTPRG acts as an endothelial HCO3−-sensor controlling vascular tone and perfusion.","evidence":"Knockout mice with Ca2+ imaging, myography, cerebral perfusion, and blood pressure measurements in resistance arteries","pmids":["32955439"],"confidence":"High","gaps":["Molecular link between HCO3− sensing and phosphatase activity not defined","Substrate dephosphorylated during bicarbonate sensing unknown"]},{"year":2024,"claim":"Implicated PTPRG in neurodegeneration by linking it to VIRMA-dependent m6A control of mitophagy.","evidence":"scRNA-seq, spatial transcriptomics, Co-IP in mouse brain, and 5xFAD model","pmids":["38325728"],"confidence":"Medium","gaps":["VIRMA → PRKN → mitophagy chain relies largely on sequencing/computational inference","Whether PTPRG phosphatase activity is required for VIRMA regulation untested"]},{"year":2025,"claim":"Identified PTPRG as a negative regulator of sensory axonal regeneration.","evidence":"siRNA knockdown with neurite outgrowth/regeneration assays and RNA-seq in DRG neurons and explants","pmids":["41323734"],"confidence":"Medium","gaps":["Substrate and signaling pathway mediating outgrowth suppression not defined","PROX1 link correlative"]},{"year":2025,"claim":"Documented a context-dependent reversal of PTPRG function, supporting survival of malignant plasma cells in multiple myeloma.","evidence":"siRNA knockdown with viability/apoptosis readouts and scRNA-seq context in MM cell lines","pmids":["41050668"],"confidence":"Low","gaps":["Single functional KD experiment without mechanistic detail","Molecular basis for the pro-survival switch unknown"]},{"year":null,"claim":"How PTPRG's catalytic activity is mechanistically coupled to its diverse roles — contactin adhesion, bicarbonate sensing, and context-dependent tumor suppression versus plasma-cell survival — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model linking extracellular ligand/sensor inputs to substrate selection","Basis of the myeloma-specific pro-survival role uncharacterized in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,4,6,7]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[6]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[8]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4,5,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,12,15]}],"complexes":[],"partners":["CNTN4","CNTN3","CNTN5","CNTN6","FGFR1","EGFR","AXL","VIRMA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23470","full_name":"Receptor-type tyrosine-protein phosphatase gamma","aliases":[],"length_aa":1445,"mass_kda":162.0,"function":"Possesses tyrosine phosphatase activity","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P23470/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRG","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTPRG","total_profiled":1310},"omim":[{"mim_id":"608712","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, T; PTPRT","url":"https://www.omim.org/entry/608712"},{"mim_id":"603155","title":"PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 14; PTPN14","url":"https://www.omim.org/entry/603155"},{"mim_id":"600926","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, EPSILON; PTPRE","url":"https://www.omim.org/entry/600926"},{"mim_id":"600267","title":"PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 13; PTPN13","url":"https://www.omim.org/entry/600267"},{"mim_id":"179590","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, F; PTPRF","url":"https://www.omim.org/entry/179590"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTPRG"},"hgnc":{"alias_symbol":["RPTPG"],"prev_symbol":["PTPG"]},"alphafold":{"accession":"P23470","domains":[{"cath_id":"3.10.200.10","chopping":"75-320","consensus_level":"high","plddt":89.9897,"start":75,"end":320},{"cath_id":"2.60.40.10","chopping":"346-457","consensus_level":"medium","plddt":79.1034,"start":346,"end":457},{"cath_id":"3.90.190.10","chopping":"867-1104","consensus_level":"high","plddt":93.6653,"start":867,"end":1104},{"cath_id":"3.90.190.10","chopping":"1133-1417","consensus_level":"medium","plddt":90.5399,"start":1133,"end":1417}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23470","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23470-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23470-F1-predicted_aligned_error_v6.png","plddt_mean":71.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRG","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRG"},"sequence":{"accession":"P23470","fasta_url":"https://rest.uniprot.org/uniprotkb/P23470.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23470/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23470"}},"corpus_meta":[{"pmid":"15897551","id":"PMC_15897551","title":"Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73.","date":"2005","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15897551","citation_count":187,"is_preprint":false},{"pmid":"20133774","id":"PMC_20133774","title":"The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20133774","citation_count":108,"is_preprint":false},{"pmid":"26830138","id":"PMC_26830138","title":"Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.","date":"2016","source":"Molecular 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oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35433461","citation_count":10,"is_preprint":false},{"pmid":"34767727","id":"PMC_34767727","title":"Long Noncoding RNAs PTPRG Antisense RNA 1 Targets Cyclin D1 to Facilitate Cell Proliferation in Lung Adenocarcinoma.","date":"2021","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/34767727","citation_count":9,"is_preprint":false},{"pmid":"32700424","id":"PMC_32700424","title":"Aberrant DNA methylation of PTPRG as one possible mechanism of its under-expression in CML patients in the State of Qatar.","date":"2020","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32700424","citation_count":9,"is_preprint":false},{"pmid":"23029056","id":"PMC_23029056","title":"Characterization of PTPRG in knockdown and phosphatase-inactive mutant mice and substrate trapping analysis of PTPRG in mammalian cells.","date":"2012","source":"PloS 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carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/41911437","citation_count":0,"is_preprint":false},{"pmid":"41993387","id":"PMC_41993387","title":"Cell-Type-Resolved Pseudobulk Classification Across Independent Cohorts Identifies Microglial PTPRG as a Transcriptional Hub in Alzheimer's Disease.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41993387","citation_count":0,"is_preprint":false},{"pmid":"35685905","id":"PMC_35685905","title":"Retraction: Long noncoding RNA PTPRG-AS1 regulates growth of glioma cells by sponging miR-185-5p.","date":"2021","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/35685905","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26537,"output_tokens":4404,"usd":0.072835,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12452,"output_tokens":4386,"usd":0.085955,"stage2_stop_reason":"end_turn"},"total_usd":0.15879,"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\": 2010,\n      \"finding\": \"Crystal structures of the carbonic anhydrase-like domains of PTPRG and PTPRZ revealed that PTPRG directly interacts with the second and third immunoglobulin repeats of contactins CNTN3, CNTN4, CNTN5, and CNTN6 (but not CNTN1, which is specific to PTPRZ). Crystal structure of mouse CNTN4 N-terminal Ig repeats in complex with the carbonic anhydrase-like domain of mouse PTPRG showed CNTN4 adopts a horseshoe-like conformation and contacts a discrete beta-hairpin loop region of PTPRG.\",\n      \"method\": \"X-ray crystallography; direct binding assay; structure of PTPRG carbonic anhydrase-like domain alone and in complex with CNTN4\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional validation of direct interaction, multiple contactin partners tested, rigorous structural data\",\n      \"pmids\": [\"20133774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Molecular modeling of human contactin 4, 5, and 6 interaction with PTPRG showed that interactive residues between contactin 4-6 and PTPRG are strictly conserved, and no differences in PTPRG binding were observed experimentally among contactin 5 and 6, suggesting differential neurite outgrowth effects of contactins do not result from distinct interactions with PTPRG.\",\n      \"method\": \"3D structural modeling; co-culture neuritogenesis assay; comparative binding analysis\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — computational modeling with functional assay, single lab, result is a negative finding (no differential PTPRG binding) supported by structural conservation analysis\",\n      \"pmids\": [\"23519440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRG interacts with and colocalizes with FGFR1 at the plasma membrane in osteosarcoma cells, and directly dephosphorylates activated FGFR1. Depletion of PTPRG increased FGFR1 activity, hypersensitized cells to FGF1 stimulation, elevated cell growth, and reduced efficacy of FGFR kinase inhibitors.\",\n      \"method\": \"Proximity-dependent biotin labeling (BioID) combined with label-free quantitative mass spectrometry; co-immunoprecipitation; colocalization imaging; PTPRG knockdown with phenotypic readouts; in vitro dephosphorylation assay\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct dephosphorylation shown in vitro, reciprocal interaction confirmed, multiple orthogonal methods (BioID-MS, Co-IP, KD with functional readout), single lab\",\n      \"pmids\": [\"29371290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRG, restricted to cholesterol-rich lipid domains, dephosphorylates the RTK AXL when AXL is recruited to lipid domains through its interaction with the GPI-anchored tumour suppressor OPCML (which binds activated AXL). This OPCML-PTPRG cooperation prevents AXL-mediated transactivation of cMET and EGFR, inhibits sustained phospho-ERK signalling, reduces EMT transcription factor Slug induction, and suppresses cell migration and invasion in ovarian cancer.\",\n      \"method\": \"Co-immunoprecipitation; lipid domain fractionation; phosphatase activity assay; OPCML/PTPRG functional knockdown; in vitro and in vivo tumor models\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct dephosphorylation demonstrated, mechanism defined through lipid domain co-localization and epistasis, multiple orthogonal methods, in vitro and in vivo validation\",\n      \"pmids\": [\"29907679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTPRG dephosphorylates EGFR at Y1068 and Y1086 in nasopharyngeal carcinoma (NPC) cells, inactivating the PI3K/Akt signaling cascade and downregulating pro-angiogenic and pro-invasive proteins VEGF, IL6, and IL8, thereby suppressing tumor cell proliferation, angiogenesis, and invasion in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (PTPRG-EGFR interaction); phospho-specific western blot; PTPRG overexpression and Akt knockdown; in vitro and in vivo tumor models\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, phospho-site specific readout, epistasis via Akt KD, in vivo validation, single lab\",\n      \"pmids\": [\"25970784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of PTPRG in MCF-7 breast cancer cells inhibited tumor formation in vivo (athymic mouse model), upregulated p21(cip) and p27(kip) cell cycle inhibitors, delayed cell cycle re-entry after serum starvation, and reduced ERK1/2 phosphorylation, indicating PTPRG acts as a tumor suppressor through the ERK1/2 pathway.\",\n      \"method\": \"Xenograft tumor model; western blot for cell cycle regulators; ERK1/2 phosphorylation assay; cell cycle re-entry assay; methylation assay\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo tumor suppression confirmed, multiple mechanistic readouts (ERK1/2, p21, p27), single lab with orthogonal methods\",\n      \"pmids\": [\"20651337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTPRG (RPTPγ) exhibits tyrosine phosphatase activity in vitro; a C1060S catalytic mutant is completely inactive. PTPRG auto-dephosphorylates at Y1307 in its D2 domain, as demonstrated by substrate trapping mutant analysis (C1060S, D1028A) and in vitro dephosphorylation experiments. Loss of PTPRG phosphatase activity (knockdown or catalytically inactive knock-in mice) produces antidepressive-like behavior in mice.\",\n      \"method\": \"In vitro phosphatase activity assay; active-site mutagenesis (C1060S, D1028A); substrate trapping; truncation and mutagenesis mapping; knock-in and knockdown mouse models; behavioral assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis, auto-dephosphorylation site mapped by mutagenesis, validated in mouse models, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23029056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In 293 cells, PTPRG expression induces dephosphorylation of ERK, a downstream RAS target, implicating PTPRG as a direct negative regulator of RAS/ERK signaling. DNA methylation of the PTPRG promoter silences PTPRG expression and cooperates with RAS mutations in childhood ALL oncogenesis; the PTPRG promoter contains a binding site for the RAS-responsive transcription factor RREB1.\",\n      \"method\": \"PTPRG expression in 293 cells with ERK phosphorylation readout; genome-wide methylation profiling; ChIP for RREB1 at PTPRG promoter; correlation of methylation with gene expression\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ERK dephosphorylation shown in cell assay, ChIP for RREB1, methylation-expression correlation, single lab\",\n      \"pmids\": [\"24496747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RPTPγ (encoded by PTPRG) functions as an HCO3−-sensor in endothelial cells of resistance arteries. Its presence enhances endothelial intracellular Ca2+ responses and facilitates endothelium-dependent vasorelaxation only when CO2/HCO3− is present. RPTPγ limits increases in cerebral perfusion during neuronal activity, amplifies decreases during hyperventilation, and augments hyperventilation-induced blood pressure elevations, without affecting resting blood pressure.\",\n      \"method\": \"Transgenic (knockout) mouse model; Ca2+ imaging in resistance artery endothelial cells; myography for vasorelaxation; cerebral perfusion measurement; blood pressure recording\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with multiple orthogonal functional readouts (Ca2+, vascular tone, perfusion, blood pressure), mechanistic role as HCO3- sensor established\",\n      \"pmids\": [\"32955439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRG expression positively modulates nilotinib response in CML cells and negatively affects BCR-ABL1-dependent transformation. PTPRG knockout by CRISPR/Cas9 in CML cell lines revealed that loss of PTPRG increases BCR-ABL1 signaling events, while overexpression reduces them.\",\n      \"method\": \"CRISPR/Cas9 gene knockout; PTPRG overexpression in CML cell lines; BCR-ABL1 signaling readout; functional nilotinib response assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with functional signaling readout and drug response phenotype, single lab\",\n      \"pmids\": [\"29507701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Within neurons, PTPRG physically binds and upregulates the m6A methyltransferase VIRMA, which inhibits translation of PRKN mRNA, thereby suppressing mitophagy and leading to neuronal death in Alzheimer's disease. This interaction was validated by co-immunoprecipitation in mouse brains.\",\n      \"method\": \"Single-cell RNA sequencing; spatial transcriptomics; co-immunoprecipitation in mouse brain; western blot; 5xFAD mouse model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP in mouse brain confirms physical interaction, but mechanistic chain (VIRMA upregulation → PRKN translation suppression → mitophagy inhibition) relies primarily on sequencing/computational data with limited direct experimental validation in the abstract\",\n      \"pmids\": [\"38325728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-19b directly suppresses PTPRG expression by binding two specific sites in the 3'-UTR of PTPRG, leading to increased cell proliferation, stimulated migration, and reduced apoptosis in breast cancer cells.\",\n      \"method\": \"miR-19b overexpression and knockdown in MCF-7 and MDA-231 cells; western blot for PTPRG protein; 3'-UTR luciferase reporter assay; proliferation, migration, and apoptosis assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validated by 3'-UTR reporter assay and western blot in two cell lines, loss/gain of function with phenotypic readout, single lab\",\n      \"pmids\": [\"27602768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Mouse L-cells (a sarcoma-producing cell line) exhibit homozygous intragenic deletion of the Ptprg gene within the carbonic anhydrase-like domain (exons 2-4 deleted), resulting in a mutant transcript 400 bp shorter than wild type, and loss of one allele—consistent with biallelic inactivation of a tumor suppressor locus.\",\n      \"method\": \"RT-PCR on L-cell mRNA; PCR on genomic DNA; interspecific backcross mapping; sequencing of deletion boundaries\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic and transcript analysis demonstrating biallelic deletion, clear molecular characterization, single lab\",\n      \"pmids\": [\"8453613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"siRNA-mediated knockdown of PTPRG in cultured dorsal root ganglion (DRG) neurons and explants increased neurite outgrowth and enhanced sensory axonal regeneration. RNA sequencing after PTPRG knockdown revealed activation of metabolism-related pathways and altered expression of the transcription factor PROX1, identifying PTPRG as a negative regulator of axonal regeneration.\",\n      \"method\": \"siRNA knockdown; neurite outgrowth and axonal regeneration assays in DRG neurons and explants; RNA sequencing\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct KD with specific phenotypic readout (neurite outgrowth), transcriptomic pathway analysis, single lab, single method for mechanistic follow-up\",\n      \"pmids\": [\"41323734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Methylation of PTPRG intron 1 in colorectal cancer is associated with loss of binding of the insulator protein CTCF to the methylated region, as demonstrated by chromatin immunoprecipitation (ChIP). This methylation does not directly affect PTPRG expression levels but may affect tumor gene expression through CTCF-dependent enhancer blocking or chromosome loop formation.\",\n      \"method\": \"CpG island microarray; bisulfite sequencing; ChIP for CTCF binding\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly demonstrates loss of CTCF binding at methylated locus, two orthogonal methods (methylation profiling and ChIP), single lab\",\n      \"pmids\": [\"21150880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In multiple myeloma cell lines (U266 and NCI-H929), siRNA-mediated knockdown of PTPRG reduced cell viability and increased apoptosis, identifying PTPRG as a positive regulator of survival/stemness in malignant plasma cells (in contrast to its tumor suppressor role in solid tumors).\",\n      \"method\": \"siRNA knockdown in MM cell lines; cell viability assay; apoptosis assay; single-cell RNA sequencing for context\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional KD experiment in cell lines with viability/apoptosis readout, limited mechanistic detail in abstract, single lab\",\n      \"pmids\": [\"41050668\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRG is a receptor-type protein tyrosine phosphatase that directly dephosphorylates multiple receptor tyrosine kinases (including FGFR1, EGFR, and AXL) at the plasma membrane or in lipid domains to suppress PI3K/Akt and ERK/MAPK signaling; it binds contactins CNTN3-6 via its carbonic anhydrase-like domain (structurally defined by X-ray crystallography); it acts as an HCO3−-sensor in endothelial cells to regulate vasorelaxation and tissue perfusion; it auto-dephosphorylates at Y1307 in its D2 domain; it physically interacts with the m6A methyltransferase VIRMA in neurons; and it functions as a tumor suppressor in most cancers but paradoxically promotes survival in multiple myeloma plasma cells, with its expression regulated by promoter CpG methylation in multiple cancer types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPRG is a receptor-type protein tyrosine phosphatase that functions broadly as a negative regulator of receptor tyrosine kinase signaling and, in most contexts, as a tumor suppressor [#5, #12]. Its catalytic activity resides in a phosphatase domain whose C1060 active-site cysteine is essential, and it auto-dephosphorylates at Y1307 within its D2 domain [#6]. At the plasma membrane and within cholesterol-rich lipid domains it directly dephosphorylates activated receptor tyrosine kinases, including FGFR1 in osteosarcoma [#2], EGFR at Y1068/Y1086 in nasopharyngeal carcinoma [#4], and AXL when AXL is recruited to lipid domains through the GPI-anchored partner OPCML [#3]; through these substrates it suppresses PI3K/Akt and RAS/ERK signaling, restraining proliferation, angiogenesis, migration, and invasion [#3, #4, #5, #7]. PTPRG also dampens BCR-ABL1 signaling and modulates nilotinib response in CML [#9]. Its extracellular carbonic anhydrase-like domain mediates direct, structurally defined binding to contactins CNTN3-6 via their N-terminal Ig repeats [#0, #1], and in endothelial cells of resistance arteries the protein acts as an HCO3\\u2212-sensor that couples bicarbonate sensing to endothelium-dependent vasorelaxation, cerebral perfusion, and blood pressure control [#8]. PTPRG expression is silenced or attenuated through promoter and intronic CpG methylation and by miR-19b targeting of its 3'-UTR [#7, #11, #14]. In contrast to its solid-tumor suppressor role, PTPRG supports survival of malignant plasma cells in multiple myeloma [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established PTPRG as a candidate tumor suppressor by showing biallelic inactivation of the locus in a transformed cell line.\",\n      \"evidence\": \"RT-PCR, genomic PCR, and deletion-boundary sequencing in mouse L-cells\",\n      \"pmids\": [\"8453613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the phosphatase substrates or signaling pathways PTPRG restrains\", \"Deletion within the carbonic anhydrase-like domain; functional consequence for catalysis not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the structural basis of PTPRG's extracellular adhesion function, showing its carbonic anhydrase-like domain selectively binds contactins CNTN3-6.\",\n      \"evidence\": \"X-ray crystallography of PTPRG CA-like domain alone and in complex with CNTN4, plus direct binding assays\",\n      \"pmids\": [\"20133774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional downstream consequence of contactin binding not resolved\", \"Did not connect adhesion to phosphatase signaling output\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked PTPRG re-expression to tumor suppression through cell-cycle arrest and ERK pathway attenuation.\",\n      \"evidence\": \"PTPRG overexpression in MCF-7 breast cancer cells, xenografts, and western blots for p21/p27 and ERK1/2\",\n      \"pmids\": [\"20651337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the direct RTK substrate upstream of ERK in this system\", \"Mechanism by which PTPRG raises p21/p27 unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated PTPRG is an active tyrosine phosphatase and mapped an intramolecular auto-dephosphorylation event, providing the catalytic ground truth for its signaling roles.\",\n      \"evidence\": \"In vitro phosphatase assays, active-site (C1060S) and substrate-trapping (D1028A) mutagenesis, and knock-in/knockdown mouse behavioral models\",\n      \"pmids\": [\"23029056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates dephosphorylated in neurons not identified\", \"Functional role of Y1307 auto-dephosphorylation in vivo unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that PTPRG intronic methylation acts non-canonically by displacing the CTCF insulator rather than simply silencing expression.\",\n      \"evidence\": \"CpG island microarray, bisulfite sequencing, and CTCF ChIP in colorectal cancer\",\n      \"pmids\": [\"21150880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream genes affected by altered CTCF looping not defined\", \"Did not link to PTPRG phosphatase activity\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Positioned PTPRG as a direct negative regulator of RAS/ERK and explained its silencing through RREB1/methylation-controlled transcription in leukemia.\",\n      \"evidence\": \"ERK dephosphorylation in 293 cells, genome-wide methylation profiling, and RREB1 ChIP at the PTPRG promoter in childhood ALL\",\n      \"pmids\": [\"24496747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RTK substrate upstream of RAS/ERK not identified\", \"Cooperation with RAS mutations correlative\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified EGFR as a direct PTPRG substrate and connected dephosphorylation to suppression of pro-angiogenic/pro-invasive output.\",\n      \"evidence\": \"Co-IP, phospho-site-specific western blot, Akt knockdown, and in vitro/in vivo tumor models in nasopharyngeal carcinoma\",\n      \"pmids\": [\"25970784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP for interaction\", \"Whether EGFR dephosphorylation occurs directly or via an intermediate not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established post-transcriptional control of PTPRG by miR-19b, adding a regulatory layer to its loss in cancer.\",\n      \"evidence\": \"miR-19b gain/loss of function, 3'-UTR luciferase reporter, and phenotypic assays in breast cancer lines\",\n      \"pmids\": [\"27602768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of the miR-19b\\u2013PTPRG axis not tested\", \"Downstream signaling not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated direct dephosphorylation of FGFR1 by PTPRG at the membrane, showing its loss confers RTK inhibitor resistance.\",\n      \"evidence\": \"BioID-MS, Co-IP, colocalization, in vitro dephosphorylation, and knockdown phenotypes in osteosarcoma cells\",\n      \"pmids\": [\"29371290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site-specific FGFR1 residues dephosphorylated not detailed\", \"Generality across FGFR family members untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a lipid-domain-restricted mechanism whereby OPCML recruits AXL to PTPRG for dephosphorylation, blocking RTK transactivation and EMT.\",\n      \"evidence\": \"Co-IP, lipid domain fractionation, phosphatase assays, OPCML/PTPRG knockdown, and in vitro/in vivo ovarian cancer models\",\n      \"pmids\": [\"29907679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of the OPCML-AXL-PTPRG assembly not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended PTPRG's RTK-suppressor role to oncogenic fusion kinase signaling and drug sensitivity in CML.\",\n      \"evidence\": \"CRISPR/Cas9 knockout and overexpression with BCR-ABL1 signaling and nilotinib response readouts in CML lines\",\n      \"pmids\": [\"29507701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PTPRG dephosphorylates BCR-ABL1 directly not established\", \"Clinical correlation absent\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a non-tumor physiological function: PTPRG acts as an endothelial HCO3\\u2212-sensor controlling vascular tone and perfusion.\",\n      \"evidence\": \"Knockout mice with Ca2+ imaging, myography, cerebral perfusion, and blood pressure measurements in resistance arteries\",\n      \"pmids\": [\"32955439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between HCO3\\u2212 sensing and phosphatase activity not defined\", \"Substrate dephosphorylated during bicarbonate sensing unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated PTPRG in neurodegeneration by linking it to VIRMA-dependent m6A control of mitophagy.\",\n      \"evidence\": \"scRNA-seq, spatial transcriptomics, Co-IP in mouse brain, and 5xFAD model\",\n      \"pmids\": [\"38325728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"VIRMA \\u2192 PRKN \\u2192 mitophagy chain relies largely on sequencing/computational inference\", \"Whether PTPRG phosphatase activity is required for VIRMA regulation untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified PTPRG as a negative regulator of sensory axonal regeneration.\",\n      \"evidence\": \"siRNA knockdown with neurite outgrowth/regeneration assays and RNA-seq in DRG neurons and explants\",\n      \"pmids\": [\"41323734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate and signaling pathway mediating outgrowth suppression not defined\", \"PROX1 link correlative\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Documented a context-dependent reversal of PTPRG function, supporting survival of malignant plasma cells in multiple myeloma.\",\n      \"evidence\": \"siRNA knockdown with viability/apoptosis readouts and scRNA-seq context in MM cell lines\",\n      \"pmids\": [\"41050668\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single functional KD experiment without mechanistic detail\", \"Molecular basis for the pro-survival switch unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTPRG's catalytic activity is mechanistically coupled to its diverse roles \\u2014 contactin adhesion, bicarbonate sensing, and context-dependent tumor suppression versus plasma-cell survival \\u2014 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model linking extracellular ligand/sensor inputs to substrate selection\", \"Basis of the myeloma-specific pro-survival role uncharacterized in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 4, 6, 7]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4, 5, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 12, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CNTN4\", \"CNTN3\", \"CNTN5\", \"CNTN6\", \"FGFR1\", \"EGFR\", \"AXL\", \"VIRMA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}