{"gene":"PTPRG","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2010,"finding":"PTPRG and PTPRZ bind distinct members of the contactin family: PTPRZ binds only CNTN1, whereas PTPRG interacts with CNTN3, 4, 5, and 6. Crystal structures of the carbonic anhydrase-like (CAH) domain of PTPRG and its complex with the N-terminal immunoglobulin repeats of CNTN4 reveal that the CAH domain contacts a binding site formed by the horseshoe-like Ig2-Ig3 conformation of CNTNs, mediated by an extended beta-hairpin loop on PTPRG.","method":"Crystal structure determination, direct binding assay, structural mutagenesis inference","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structures of free domains and a co-complex with functional validation of binding specificity","pmids":["20133774"],"is_preprint":false},{"year":2015,"finding":"PTPRG dephosphorylates EGFR at Y1068 and Y1086, inactivating the PI3K/Akt signaling cascade and downstream pro-angiogenic/invasive proteins (VEGF, IL-6, IL-8), thereby suppressing NPC tumor cell proliferation, angiogenesis, and invasion in vitro and in vivo.","method":"Co-immunoprecipitation (PTPRG-EGFR interaction), phospho-site-specific western blot, Akt knockdown rescue, in vivo xenograft","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP, phospho-site mapping, in vivo confirmation; single lab","pmids":["25970784"],"is_preprint":false},{"year":2018,"finding":"PTPRG directly interacts with and dephosphorylates activated FGFR1 at the plasma membrane in osteosarcoma cells; PTPRG depletion increases FGFR1 phosphorylation, elevates FGF1-stimulated cell growth, and reduces efficacy of FGFR kinase inhibitors.","method":"Proximity-dependent biotin labeling (BioID) + quantitative MS, co-localization by fluorescence microscopy, phospho-western blot after KD, cell growth assay","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1–2 — proximity labeling + MS identification, co-localization, biochemical dephosphorylation, functional KD phenotype; multiple orthogonal methods","pmids":["29371290"],"is_preprint":false},{"year":2018,"finding":"PTPRG localizes to cholesterol-rich lipid domains and dephosphorylates the RTK AXL, which is recruited to these domains by the GPI-anchored tumor suppressor OPCML upon Gas6-mediated AXL activation. PTPRG-mediated AXL de-phosphorylation prevents AXL-dependent transactivation of cMET and EGFR, inhibits sustained phospho-ERK signaling, Slug induction, and EMT-associated cell migration and invasion.","method":"Co-immunoprecipitation (AXL-OPCML), lipid domain fractionation, phospho-western blot (AXL, ERK), migration/invasion assays, in vitro and in vivo AXL inhibitor combination","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, lipid domain biochemistry, phospho-site readout, in vivo validation; multiple orthogonal methods in single study","pmids":["29907679"],"is_preprint":false},{"year":2012,"finding":"PTPRG has intrinsic tyrosine phosphatase activity; catalytic-site mutants C1060S and D1028A are completely inactive. Wild-type PTPRG auto-dephosphorylates at Y1307 in its D2 domain, as mapped by truncation and mutagenesis studies and confirmed by in vitro dephosphorylation assay. Substrate-trapping mutants (C1060S, D1028A) retain a phosphorylated tyrosine that wild-type PTPRG removes, confirming the catalytic mechanism.","method":"In vitro phosphatase assay with purified protein, active-site mutagenesis (C1060S, D1028A), truncation mapping, knock-in mouse (KI C1060S), behavioral phenotyping","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of phosphatase activity, mutagenesis of catalytic residue, auto-dephosphorylation site mapped by truncation + mutagenesis","pmids":["23029056"],"is_preprint":false},{"year":2020,"finding":"Endothelial cells express PTPRG (RPTPγ), which senses HCO3- and enhances intracellular Ca2+ responses in resistance arteries, facilitating endothelium-dependent vasorelaxation only when CO2/HCO3- is present. RPTPγ limits cerebral perfusion increases during neuronal activity, amplifies hyperventilation-induced blood pressure elevations, and loss-of-function PTPRG variants associate with increased risk of cerebral infarction and heart attack.","method":"Transgenic mouse experiments (RPTPγ knockout), Ca2+ imaging in resistance artery endothelial cells, vascular tension assays, cerebral perfusion measurement, human genetic association","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — transgenic animal model with direct functional readouts (Ca2+, vascular tone, perfusion), replicated in human cohort; multiple orthogonal methods","pmids":["32955439"],"is_preprint":false},{"year":2010,"finding":"Overexpression of PTPRG in breast cancer cells (MCF-7) inhibits tumor formation in vivo, upregulates p21(cip) and p27(kip) proteins, delays cell cycle re-entry after serum starvation, and reduces ERK1/2 phosphorylation, indicating that PTPRG suppresses proliferation through the ERK1/2 pathway.","method":"Athymic nude mouse xenograft, western blot for p21/p27 and phospho-ERK1/2, cell cycle re-entry assay, PTPRG overexpression","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo tumor suppression plus defined biochemical pathway readout; single lab with multiple orthogonal assays","pmids":["20651337"],"is_preprint":false},{"year":2014,"finding":"PTPRG expression induces dephosphorylation of ERK (a downstream RAS target) in 293 cells, and PTPRG expression is upregulated by RAS activation under DNA hypomethylating conditions via binding of the RAS-responsive transcription factor RREB1 to an element within the PTPRG promoter.","method":"PTPRG expression in 293 cells with phospho-ERK western blot, chromatin immunoprecipitation (ChIP) for RREB1 at PTPRG promoter, methylation profiling","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for transcription factor binding + phospho-ERK functional readout; single lab","pmids":["24496747"],"is_preprint":false},{"year":2018,"finding":"PTPRG positively modulates nilotinib response in chronic myeloid leukemia (CML): CRISPR/Cas9 knockout of PTPRG reduces nilotinib sensitivity and enhances BCR-ABL1-dependent transformation, while PTPRG overexpression has the opposite effect, indicating PTPRG antagonizes BCR-ABL1 kinase signaling.","method":"CRISPR/Cas9 gene knockout, PTPRG overexpression in CML cell lines, nilotinib sensitivity assay, transformation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — clean CRISPR KO and overexpression with defined drug-sensitivity and transformation phenotypes; single lab","pmids":["29507701"],"is_preprint":false},{"year":2013,"finding":"PTPRG binds contactins 4, 5, and 6 through conserved interactive residues in the Ig2 and Ig3 domains of the contactins (despite conformational differences in omega loops); contactins 4 and 6 increase neurite length while contactin 5 increases neurite branching in rat cortical neurons, but these differential effects are not due to distinct PTPRG binding.","method":"3D structural modeling of CNTN-PTPRG complexes, co-culture neurite outgrowth assay (rat cortical neurons + HEK293 cells secreting contactins), quantitative image analysis","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 3 — computational structural modeling + functional neurite assay; binding specificity not confirmed by in vitro biochemistry","pmids":["23519440"],"is_preprint":false},{"year":2013,"finding":"PTPRG isoforms are expressed in adult mouse brain neurons and some astrocytes; at least two distinct isoforms co-exist in different compartments of the same neuron (N-terminal domain positivity in soma without C-terminal counterpart, both in neuropil). Astrocytic PTPRG expression (and putative ~120 and ~80 kDa processing isoforms) increases during neuroinflammation (LPS treatment and Alzheimer's disease mouse model).","method":"Immunofluorescence with domain-specific antibodies, western blot of brain fractions, LPS neuroinflammation model, 5xFAD Alzheimer's mouse model","journal":"Brain structure & function","confidence":"Medium","confidence_rationale":"Tier 3 — direct immunological localization with functional disease-model context; replicated across two models","pmids":["23536318"],"is_preprint":false},{"year":2024,"finding":"In neurons, PTPRG physically interacts with the m6A methyltransferase VIRMA, upregulating it, which inhibits translation of PRKN mRNA (encoding Parkin), thereby suppressing mitophagy and contributing to neuronal death in Alzheimer's disease. This PTPRG-VIRMA-PRKN pathway was validated by co-immunoprecipitation in mouse brain tissue.","method":"Single-cell and spatial transcriptomics, co-immunoprecipitation in mouse brain (5xFAD), in vivo validation in 5xFAD mice, western blot","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP in native tissue confirming physical interaction, in vivo validation; single lab with omics + biochemical follow-up","pmids":["38325728"],"is_preprint":false},{"year":2014,"finding":"A heterozygous loss-of-function mutation in PTPRG, combined with a PDGFRB activating mutation, results in full penetrance of infantile myofibromatosis, suggesting PTPRG dephosphorylates PDGFRB and its partial loss removes a brake on PDGFRB-driven tumor growth.","method":"Exome sequencing, family-based genetic analysis, functional inference from known PTPRG-PDGFRB phosphatase relationship","journal":"Genetics and molecular research : GMR","confidence":"Low","confidence_rationale":"Tier 3 — genetic epistasis by family analysis; direct dephosphorylation of PDGFRB by PTPRG not biochemically demonstrated in this paper","pmids":["25158255"],"is_preprint":false},{"year":2016,"finding":"miR-19b directly suppresses PTPRG protein expression by binding two sites in the 3'-UTR of PTPRG mRNA, and this inhibition of PTPRG promotes breast cancer cell proliferation, migration, and reduces apoptosis.","method":"miR-19b overexpression/knockdown in MCF-7 and MDA-231 cells, western blot for PTPRG, luciferase 3'-UTR reporter assay, proliferation and migration assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — 3'-UTR luciferase reporter confirming direct miRNA-target interaction, functional rescue experiments; single lab","pmids":["27602768"],"is_preprint":false},{"year":2025,"finding":"siRNA-mediated knockdown of PTPRG in cultured dorsal root ganglion (DRG) neurons and explants enhances neurite outgrowth and axonal regeneration, associated with 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 in rat DRG neurons and explants, neurite outgrowth assay, RNA sequencing for pathway analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean siRNA KD with defined cellular phenotype (neurite outgrowth) and transcriptomic pathway identification; single lab","pmids":["41323734"],"is_preprint":false},{"year":2010,"finding":"Methylation of PTPRG intron 1 is associated with absence of CTCF insulator protein binding at that locus (demonstrated by ChIP), suggesting that PTPRG intron 1 methylation disrupts CTCF-mediated chromatin insulation rather than directly silencing PTPRG transcription.","method":"CpG island microarray, bisulfite sequencing, chromatin immunoprecipitation (ChIP) for CTCF","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP directly links methylation to loss of CTCF occupancy at defined genomic locus; single lab","pmids":["21150880"],"is_preprint":false}],"current_model":"PTPRG is a receptor-type protein tyrosine phosphatase whose carbonic anhydrase-like extracellular domain binds contactins 3–6 and acts as an HCO3- sensor in endothelial cells; its intracellular phosphatase domain (catalytic Cys1060) directly dephosphorylates multiple RTKs including EGFR (Y1068/Y1086), FGFR1, and AXL—the last facilitated by OPCML-mediated lipid-domain recruitment—thereby suppressing PI3K/Akt and ERK signaling, cell proliferation, migration, and invasion, while also auto-dephosphorylating at Y1307 in its D2 domain; in the CNS it interacts with VIRMA to modulate m6A-dependent PRKN translation and mitophagy, and its loss-of-function (via deletion, methylation-mediated silencing, or microRNA-mediated suppression) contributes to tumorigenesis across multiple cancer types and to ischemic vascular disease."},"narrative":{"teleology":[{"year":2010,"claim":"Determining how PTPRG's extracellular domain engages ligands established that the carbonic anhydrase-like domain binds contactins 3–6 (but not CNTN1/2) through a beta-hairpin loop contacting the Ig2–Ig3 horseshoe, distinguishing PTPRG from the related phosphatase PTPRZ.","evidence":"Crystal structures of PTPRG CAH domain alone and in complex with CNTN4 Ig repeats, plus direct binding assays","pmids":["20133774"],"confidence":"High","gaps":["Functional consequence of contactin binding on PTPRG phosphatase activity not determined","No structural data for CNTN3/5/6 complexes","Trans vs. cis signaling mode unresolved"]},{"year":2010,"claim":"Demonstrating that PTPRG overexpression suppresses tumor growth in vivo and reduces ERK1/2 phosphorylation while upregulating p21/p27 established PTPRG as a proliferation-suppressive phosphatase acting through the MAPK/ERK pathway.","evidence":"PTPRG overexpression in MCF-7 cells, athymic nude mouse xenograft, phospho-ERK and p21/p27 western blot","pmids":["20651337"],"confidence":"Medium","gaps":["Direct ERK dephosphorylation vs. indirect effect through upstream RTKs not distinguished","Only tested in one breast cancer cell line"]},{"year":2012,"claim":"Mapping the catalytic mechanism showed that Cys1060 and Asp1028 are essential for phosphatase activity and that PTPRG auto-dephosphorylates at Y1307 in its D2 domain, revealing an intrinsic regulatory mechanism.","evidence":"In vitro phosphatase assay with purified protein, C1060S/D1028A mutagenesis, truncation mapping of Y1307, knock-in mouse","pmids":["23029056"],"confidence":"High","gaps":["Functional significance of Y1307 auto-dephosphorylation for downstream signaling unknown","No structural basis for D2-domain regulation"]},{"year":2014,"claim":"Identifying RREB1 as a RAS-responsive transcription factor that binds the PTPRG promoter under demethylating conditions, while PTPRG expression reduces phospho-ERK, established a negative feedback loop between RAS/ERK signaling and PTPRG expression.","evidence":"ChIP for RREB1 at PTPRG promoter, phospho-ERK western blot in 293 cells, methylation profiling","pmids":["24496747"],"confidence":"Medium","gaps":["Feedback loop not demonstrated in a single endogenous system","Quantitative impact on RAS signaling dynamics unclear"]},{"year":2015,"claim":"Showing that PTPRG directly dephosphorylates EGFR at Y1068 and Y1086 to inactivate PI3K/Akt and suppress VEGF/IL-6/IL-8 identified specific substrate sites and linked PTPRG to anti-angiogenic tumor suppression.","evidence":"Co-IP of PTPRG–EGFR, phospho-site-specific western blot, in vivo xenograft in NPC cells","pmids":["25970784"],"confidence":"Medium","gaps":["Direct in vitro dephosphorylation with purified proteins not shown","Selectivity among EGFR phosphosites not comprehensively profiled"]},{"year":2018,"claim":"Proximity labeling identified FGFR1 as a direct PTPRG substrate at the plasma membrane, and PTPRG depletion increased FGFR1 phosphorylation and reduced FGFR inhibitor efficacy, broadening the RTK substrate repertoire and revealing pharmacological relevance.","evidence":"BioID + quantitative MS, co-localization, phospho-western after KD, cell growth assay in osteosarcoma cells","pmids":["29371290"],"confidence":"High","gaps":["Specific FGFR1 phospho-sites dephosphorylated not mapped","Whether PTPRG also dephosphorylates FGFR2/3/4 untested"]},{"year":2018,"claim":"Demonstrating that OPCML recruits AXL to cholesterol-rich lipid domains where PTPRG resides, enabling AXL dephosphorylation that blocks cMET/EGFR transactivation and EMT, revealed a lipid-domain-dependent substrate access mechanism.","evidence":"Lipid domain fractionation, co-IP of AXL–OPCML, phospho-AXL/ERK western blot, migration/invasion assays, in vivo combination with AXL inhibitor","pmids":["29907679"],"confidence":"High","gaps":["Whether PTPRG is constitutively in lipid rafts or dynamically recruited is unresolved","Structural basis for PTPRG–AXL recognition unknown"]},{"year":2018,"claim":"CRISPR knockout of PTPRG in CML cells reduced nilotinib sensitivity and enhanced BCR-ABL1-dependent transformation, establishing PTPRG as a modifier of tyrosine kinase inhibitor response in leukemia.","evidence":"CRISPR/Cas9 KO and overexpression in CML cell lines, nilotinib dose–response, transformation assay","pmids":["29507701"],"confidence":"Medium","gaps":["Direct dephosphorylation of BCR-ABL1 by PTPRG not biochemically demonstrated","Clinical relevance of PTPRG expression level for TKI response not validated in patient cohorts"]},{"year":2020,"claim":"Knockout mouse studies established that PTPRG functions as an endothelial HCO₃⁻ sensor that enhances Ca²⁺ signaling and vasorelaxation, linking PTPRG to cardiovascular physiology and ischemic disease risk in humans.","evidence":"PTPRG KO mice, Ca²⁺ imaging in resistance artery endothelium, vascular tension assays, cerebral perfusion measurements, human genetic association study","pmids":["32955439"],"confidence":"High","gaps":["Molecular mechanism of HCO₃⁻ sensing by the extracellular domain not resolved","Whether phosphatase activity is required for vascular function not tested"]},{"year":2024,"claim":"Discovery that PTPRG physically binds and upregulates the m6A writer VIRMA, leading to reduced PRKN translation and suppressed mitophagy in Alzheimer's disease neurons, revealed a non-canonical PTPRG function in RNA modification.","evidence":"Co-IP in 5xFAD mouse brain tissue, single-cell and spatial transcriptomics, in vivo validation","pmids":["38325728"],"confidence":"Medium","gaps":["Whether PTPRG phosphatase activity is required for VIRMA interaction and stabilization unknown","Mechanism by which PTPRG upregulates VIRMA not defined","Not replicated in human tissue"]},{"year":2025,"claim":"siRNA knockdown of PTPRG in DRG neurons enhanced neurite outgrowth and axonal regeneration, identifying PTPRG as a negative regulator of peripheral nerve regeneration and linking it to metabolic pathway remodeling and PROX1 expression.","evidence":"siRNA KD in rat DRG neurons and explants, neurite outgrowth quantification, RNA-seq pathway analysis","pmids":["41323734"],"confidence":"Medium","gaps":["Direct PTPRG substrates mediating regeneration suppression not identified","In vivo nerve injury model not performed","Whether catalytic activity or extracellular contactin binding mediates the effect is unknown"]},{"year":null,"claim":"Key open questions include the molecular mechanism of HCO₃⁻ sensing by the extracellular domain, the structural basis for RTK substrate selectivity, whether phosphatase activity is required for the VIRMA interaction and vascular functions, and the physiological role of Y1307 auto-dephosphorylation.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the full-length receptor or its orientation in the membrane","Comprehensive phosphoproteomics to define the full substrate spectrum not performed","Relationship between contactin binding and intracellular catalytic regulation unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,3,4,8]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3,5,6,7,8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[9,10,11,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,6,8,13]}],"complexes":[],"partners":["CNTN3","CNTN4","CNTN5","CNTN6","EGFR","FGFR1","AXL","VIRMA"],"other_free_text":[]},"mechanistic_narrative":"PTPRG is a receptor-type protein tyrosine phosphatase that functions as a broad-specificity negative regulator of receptor tyrosine kinase signaling, with roles spanning vascular physiology, neuronal development, and tumor suppression. Its extracellular carbonic anhydrase-like domain binds contactins 3–6 via a beta-hairpin loop contacting the Ig2–Ig3 horseshoe of the contactin and senses extracellular HCO₃⁻ in endothelial cells to modulate Ca²⁺-dependent vasorelaxation [PMID:20133774, PMID:32955439]. The intracellular catalytic domain (catalytic residue Cys1060) directly dephosphorylates multiple RTKs—EGFR at Y1068/Y1086, FGFR1, and AXL (the last facilitated by OPCML-mediated lipid-domain recruitment)—thereby suppressing PI3K/Akt and ERK signaling, proliferation, migration, and invasion, while also auto-dephosphorylating at Y1307 in its D2 domain [PMID:23029056, PMID:25970784, PMID:29371290, PMID:29907679]. In neurons, PTPRG interacts with the m6A methyltransferase VIRMA to inhibit PRKN translation and mitophagy, and acts as a negative regulator of axonal regeneration; loss-of-function PTPRG variants associate with increased risk of ischemic cerebrovascular and cardiac events [PMID:38325728, PMID:41323734, PMID:32955439]."},"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":186,"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":106,"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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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":"35433461","id":"PMC_35433461","title":"Integrated Multi-Omics Analysis Identified PTPRG and CHL1 as Key Regulators of Immunophenotypes in Clear Cell Renal Cell Carcinoma(ccRCC).","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35433461","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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25773,"output_tokens":4242,"usd":0.070474},"stage2":{"model":"claude-opus-4-6","input_tokens":7682,"output_tokens":3109,"usd":0.174203},"total_usd":0.244677,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"PTPRG and PTPRZ bind distinct members of the contactin family: PTPRZ binds only CNTN1, whereas PTPRG interacts with CNTN3, 4, 5, and 6. Crystal structures of the carbonic anhydrase-like (CAH) domain of PTPRG and its complex with the N-terminal immunoglobulin repeats of CNTN4 reveal that the CAH domain contacts a binding site formed by the horseshoe-like Ig2-Ig3 conformation of CNTNs, mediated by an extended beta-hairpin loop on PTPRG.\",\n      \"method\": \"Crystal structure determination, direct binding assay, structural mutagenesis inference\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures of free domains and a co-complex with functional validation of binding specificity\",\n      \"pmids\": [\"20133774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTPRG dephosphorylates EGFR at Y1068 and Y1086, inactivating the PI3K/Akt signaling cascade and downstream pro-angiogenic/invasive proteins (VEGF, IL-6, IL-8), thereby suppressing NPC tumor cell proliferation, angiogenesis, and invasion in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (PTPRG-EGFR interaction), phospho-site-specific western blot, Akt knockdown rescue, in vivo xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, phospho-site mapping, in vivo confirmation; single lab\",\n      \"pmids\": [\"25970784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRG directly interacts with and dephosphorylates activated FGFR1 at the plasma membrane in osteosarcoma cells; PTPRG depletion increases FGFR1 phosphorylation, elevates FGF1-stimulated cell growth, and reduces efficacy of FGFR kinase inhibitors.\",\n      \"method\": \"Proximity-dependent biotin labeling (BioID) + quantitative MS, co-localization by fluorescence microscopy, phospho-western blot after KD, cell growth assay\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — proximity labeling + MS identification, co-localization, biochemical dephosphorylation, functional KD phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"29371290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRG localizes to cholesterol-rich lipid domains and dephosphorylates the RTK AXL, which is recruited to these domains by the GPI-anchored tumor suppressor OPCML upon Gas6-mediated AXL activation. PTPRG-mediated AXL de-phosphorylation prevents AXL-dependent transactivation of cMET and EGFR, inhibits sustained phospho-ERK signaling, Slug induction, and EMT-associated cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation (AXL-OPCML), lipid domain fractionation, phospho-western blot (AXL, ERK), migration/invasion assays, in vitro and in vivo AXL inhibitor combination\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, lipid domain biochemistry, phospho-site readout, in vivo validation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"29907679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTPRG has intrinsic tyrosine phosphatase activity; catalytic-site mutants C1060S and D1028A are completely inactive. Wild-type PTPRG auto-dephosphorylates at Y1307 in its D2 domain, as mapped by truncation and mutagenesis studies and confirmed by in vitro dephosphorylation assay. Substrate-trapping mutants (C1060S, D1028A) retain a phosphorylated tyrosine that wild-type PTPRG removes, confirming the catalytic mechanism.\",\n      \"method\": \"In vitro phosphatase assay with purified protein, active-site mutagenesis (C1060S, D1028A), truncation mapping, knock-in mouse (KI C1060S), behavioral phenotyping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of phosphatase activity, mutagenesis of catalytic residue, auto-dephosphorylation site mapped by truncation + mutagenesis\",\n      \"pmids\": [\"23029056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Endothelial cells express PTPRG (RPTPγ), which senses HCO3- and enhances intracellular Ca2+ responses in resistance arteries, facilitating endothelium-dependent vasorelaxation only when CO2/HCO3- is present. RPTPγ limits cerebral perfusion increases during neuronal activity, amplifies hyperventilation-induced blood pressure elevations, and loss-of-function PTPRG variants associate with increased risk of cerebral infarction and heart attack.\",\n      \"method\": \"Transgenic mouse experiments (RPTPγ knockout), Ca2+ imaging in resistance artery endothelial cells, vascular tension assays, cerebral perfusion measurement, human genetic association\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transgenic animal model with direct functional readouts (Ca2+, vascular tone, perfusion), replicated in human cohort; multiple orthogonal methods\",\n      \"pmids\": [\"32955439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of PTPRG in breast cancer cells (MCF-7) inhibits tumor formation in vivo, upregulates p21(cip) and p27(kip) proteins, delays cell cycle re-entry after serum starvation, and reduces ERK1/2 phosphorylation, indicating that PTPRG suppresses proliferation through the ERK1/2 pathway.\",\n      \"method\": \"Athymic nude mouse xenograft, western blot for p21/p27 and phospho-ERK1/2, cell cycle re-entry assay, PTPRG overexpression\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo tumor suppression plus defined biochemical pathway readout; single lab with multiple orthogonal assays\",\n      \"pmids\": [\"20651337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTPRG expression induces dephosphorylation of ERK (a downstream RAS target) in 293 cells, and PTPRG expression is upregulated by RAS activation under DNA hypomethylating conditions via binding of the RAS-responsive transcription factor RREB1 to an element within the PTPRG promoter.\",\n      \"method\": \"PTPRG expression in 293 cells with phospho-ERK western blot, chromatin immunoprecipitation (ChIP) for RREB1 at PTPRG promoter, methylation profiling\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for transcription factor binding + phospho-ERK functional readout; single lab\",\n      \"pmids\": [\"24496747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRG positively modulates nilotinib response in chronic myeloid leukemia (CML): CRISPR/Cas9 knockout of PTPRG reduces nilotinib sensitivity and enhances BCR-ABL1-dependent transformation, while PTPRG overexpression has the opposite effect, indicating PTPRG antagonizes BCR-ABL1 kinase signaling.\",\n      \"method\": \"CRISPR/Cas9 gene knockout, PTPRG overexpression in CML cell lines, nilotinib sensitivity assay, transformation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean CRISPR KO and overexpression with defined drug-sensitivity and transformation phenotypes; single lab\",\n      \"pmids\": [\"29507701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTPRG binds contactins 4, 5, and 6 through conserved interactive residues in the Ig2 and Ig3 domains of the contactins (despite conformational differences in omega loops); contactins 4 and 6 increase neurite length while contactin 5 increases neurite branching in rat cortical neurons, but these differential effects are not due to distinct PTPRG binding.\",\n      \"method\": \"3D structural modeling of CNTN-PTPRG complexes, co-culture neurite outgrowth assay (rat cortical neurons + HEK293 cells secreting contactins), quantitative image analysis\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — computational structural modeling + functional neurite assay; binding specificity not confirmed by in vitro biochemistry\",\n      \"pmids\": [\"23519440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTPRG isoforms are expressed in adult mouse brain neurons and some astrocytes; at least two distinct isoforms co-exist in different compartments of the same neuron (N-terminal domain positivity in soma without C-terminal counterpart, both in neuropil). Astrocytic PTPRG expression (and putative ~120 and ~80 kDa processing isoforms) increases during neuroinflammation (LPS treatment and Alzheimer's disease mouse model).\",\n      \"method\": \"Immunofluorescence with domain-specific antibodies, western blot of brain fractions, LPS neuroinflammation model, 5xFAD Alzheimer's mouse model\",\n      \"journal\": \"Brain structure & function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct immunological localization with functional disease-model context; replicated across two models\",\n      \"pmids\": [\"23536318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In neurons, PTPRG physically interacts with the m6A methyltransferase VIRMA, upregulating it, which inhibits translation of PRKN mRNA (encoding Parkin), thereby suppressing mitophagy and contributing to neuronal death in Alzheimer's disease. This PTPRG-VIRMA-PRKN pathway was validated by co-immunoprecipitation in mouse brain tissue.\",\n      \"method\": \"Single-cell and spatial transcriptomics, co-immunoprecipitation in mouse brain (5xFAD), in vivo validation in 5xFAD mice, western blot\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP in native tissue confirming physical interaction, in vivo validation; single lab with omics + biochemical follow-up\",\n      \"pmids\": [\"38325728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A heterozygous loss-of-function mutation in PTPRG, combined with a PDGFRB activating mutation, results in full penetrance of infantile myofibromatosis, suggesting PTPRG dephosphorylates PDGFRB and its partial loss removes a brake on PDGFRB-driven tumor growth.\",\n      \"method\": \"Exome sequencing, family-based genetic analysis, functional inference from known PTPRG-PDGFRB phosphatase relationship\",\n      \"journal\": \"Genetics and molecular research : GMR\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic epistasis by family analysis; direct dephosphorylation of PDGFRB by PTPRG not biochemically demonstrated in this paper\",\n      \"pmids\": [\"25158255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-19b directly suppresses PTPRG protein expression by binding two sites in the 3'-UTR of PTPRG mRNA, and this inhibition of PTPRG promotes breast cancer cell proliferation, migration, and reduces apoptosis.\",\n      \"method\": \"miR-19b overexpression/knockdown in MCF-7 and MDA-231 cells, western blot for PTPRG, luciferase 3'-UTR reporter assay, proliferation and migration assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — 3'-UTR luciferase reporter confirming direct miRNA-target interaction, functional rescue experiments; single lab\",\n      \"pmids\": [\"27602768\"],\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 enhances neurite outgrowth and axonal regeneration, associated with 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 in rat DRG neurons and explants, neurite outgrowth assay, RNA sequencing for pathway analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean siRNA KD with defined cellular phenotype (neurite outgrowth) and transcriptomic pathway identification; single lab\",\n      \"pmids\": [\"41323734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Methylation of PTPRG intron 1 is associated with absence of CTCF insulator protein binding at that locus (demonstrated by ChIP), suggesting that PTPRG intron 1 methylation disrupts CTCF-mediated chromatin insulation rather than directly silencing PTPRG transcription.\",\n      \"method\": \"CpG island microarray, bisulfite sequencing, chromatin immunoprecipitation (ChIP) for CTCF\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP directly links methylation to loss of CTCF occupancy at defined genomic locus; single lab\",\n      \"pmids\": [\"21150880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRG is a receptor-type protein tyrosine phosphatase whose carbonic anhydrase-like extracellular domain binds contactins 3–6 and acts as an HCO3- sensor in endothelial cells; its intracellular phosphatase domain (catalytic Cys1060) directly dephosphorylates multiple RTKs including EGFR (Y1068/Y1086), FGFR1, and AXL—the last facilitated by OPCML-mediated lipid-domain recruitment—thereby suppressing PI3K/Akt and ERK signaling, cell proliferation, migration, and invasion, while also auto-dephosphorylating at Y1307 in its D2 domain; in the CNS it interacts with VIRMA to modulate m6A-dependent PRKN translation and mitophagy, and its loss-of-function (via deletion, methylation-mediated silencing, or microRNA-mediated suppression) contributes to tumorigenesis across multiple cancer types and to ischemic vascular disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PTPRG is a receptor-type protein tyrosine phosphatase that functions as a broad-specificity negative regulator of receptor tyrosine kinase signaling, with roles spanning vascular physiology, neuronal development, and tumor suppression. Its extracellular carbonic anhydrase-like domain binds contactins 3–6 via a beta-hairpin loop contacting the Ig2–Ig3 horseshoe of the contactin and senses extracellular HCO₃⁻ in endothelial cells to modulate Ca²⁺-dependent vasorelaxation [PMID:20133774, PMID:32955439]. The intracellular catalytic domain (catalytic residue Cys1060) directly dephosphorylates multiple RTKs—EGFR at Y1068/Y1086, FGFR1, and AXL (the last facilitated by OPCML-mediated lipid-domain recruitment)—thereby suppressing PI3K/Akt and ERK signaling, proliferation, migration, and invasion, while also auto-dephosphorylating at Y1307 in its D2 domain [PMID:23029056, PMID:25970784, PMID:29371290, PMID:29907679]. In neurons, PTPRG interacts with the m6A methyltransferase VIRMA to inhibit PRKN translation and mitophagy, and acts as a negative regulator of axonal regeneration; loss-of-function PTPRG variants associate with increased risk of ischemic cerebrovascular and cardiac events [PMID:38325728, PMID:41323734, PMID:32955439].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Determining how PTPRG's extracellular domain engages ligands established that the carbonic anhydrase-like domain binds contactins 3–6 (but not CNTN1/2) through a beta-hairpin loop contacting the Ig2–Ig3 horseshoe, distinguishing PTPRG from the related phosphatase PTPRZ.\",\n      \"evidence\": \"Crystal structures of PTPRG CAH domain alone and in complex with CNTN4 Ig repeats, plus direct binding assays\",\n      \"pmids\": [\"20133774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of contactin binding on PTPRG phosphatase activity not determined\", \"No structural data for CNTN3/5/6 complexes\", \"Trans vs. cis signaling mode unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that PTPRG overexpression suppresses tumor growth in vivo and reduces ERK1/2 phosphorylation while upregulating p21/p27 established PTPRG as a proliferation-suppressive phosphatase acting through the MAPK/ERK pathway.\",\n      \"evidence\": \"PTPRG overexpression in MCF-7 cells, athymic nude mouse xenograft, phospho-ERK and p21/p27 western blot\",\n      \"pmids\": [\"20651337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ERK dephosphorylation vs. indirect effect through upstream RTKs not distinguished\", \"Only tested in one breast cancer cell line\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapping the catalytic mechanism showed that Cys1060 and Asp1028 are essential for phosphatase activity and that PTPRG auto-dephosphorylates at Y1307 in its D2 domain, revealing an intrinsic regulatory mechanism.\",\n      \"evidence\": \"In vitro phosphatase assay with purified protein, C1060S/D1028A mutagenesis, truncation mapping of Y1307, knock-in mouse\",\n      \"pmids\": [\"23029056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of Y1307 auto-dephosphorylation for downstream signaling unknown\", \"No structural basis for D2-domain regulation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying RREB1 as a RAS-responsive transcription factor that binds the PTPRG promoter under demethylating conditions, while PTPRG expression reduces phospho-ERK, established a negative feedback loop between RAS/ERK signaling and PTPRG expression.\",\n      \"evidence\": \"ChIP for RREB1 at PTPRG promoter, phospho-ERK western blot in 293 cells, methylation profiling\",\n      \"pmids\": [\"24496747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Feedback loop not demonstrated in a single endogenous system\", \"Quantitative impact on RAS signaling dynamics unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that PTPRG directly dephosphorylates EGFR at Y1068 and Y1086 to inactivate PI3K/Akt and suppress VEGF/IL-6/IL-8 identified specific substrate sites and linked PTPRG to anti-angiogenic tumor suppression.\",\n      \"evidence\": \"Co-IP of PTPRG–EGFR, phospho-site-specific western blot, in vivo xenograft in NPC cells\",\n      \"pmids\": [\"25970784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro dephosphorylation with purified proteins not shown\", \"Selectivity among EGFR phosphosites not comprehensively profiled\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Proximity labeling identified FGFR1 as a direct PTPRG substrate at the plasma membrane, and PTPRG depletion increased FGFR1 phosphorylation and reduced FGFR inhibitor efficacy, broadening the RTK substrate repertoire and revealing pharmacological relevance.\",\n      \"evidence\": \"BioID + quantitative MS, co-localization, phospho-western after KD, cell growth assay in osteosarcoma cells\",\n      \"pmids\": [\"29371290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific FGFR1 phospho-sites dephosphorylated not mapped\", \"Whether PTPRG also dephosphorylates FGFR2/3/4 untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that OPCML recruits AXL to cholesterol-rich lipid domains where PTPRG resides, enabling AXL dephosphorylation that blocks cMET/EGFR transactivation and EMT, revealed a lipid-domain-dependent substrate access mechanism.\",\n      \"evidence\": \"Lipid domain fractionation, co-IP of AXL–OPCML, phospho-AXL/ERK western blot, migration/invasion assays, in vivo combination with AXL inhibitor\",\n      \"pmids\": [\"29907679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PTPRG is constitutively in lipid rafts or dynamically recruited is unresolved\", \"Structural basis for PTPRG–AXL recognition unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CRISPR knockout of PTPRG in CML cells reduced nilotinib sensitivity and enhanced BCR-ABL1-dependent transformation, establishing PTPRG as a modifier of tyrosine kinase inhibitor response in leukemia.\",\n      \"evidence\": \"CRISPR/Cas9 KO and overexpression in CML cell lines, nilotinib dose–response, transformation assay\",\n      \"pmids\": [\"29507701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation of BCR-ABL1 by PTPRG not biochemically demonstrated\", \"Clinical relevance of PTPRG expression level for TKI response not validated in patient cohorts\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Knockout mouse studies established that PTPRG functions as an endothelial HCO₃⁻ sensor that enhances Ca²⁺ signaling and vasorelaxation, linking PTPRG to cardiovascular physiology and ischemic disease risk in humans.\",\n      \"evidence\": \"PTPRG KO mice, Ca²⁺ imaging in resistance artery endothelium, vascular tension assays, cerebral perfusion measurements, human genetic association study\",\n      \"pmids\": [\"32955439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of HCO₃⁻ sensing by the extracellular domain not resolved\", \"Whether phosphatase activity is required for vascular function not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that PTPRG physically binds and upregulates the m6A writer VIRMA, leading to reduced PRKN translation and suppressed mitophagy in Alzheimer's disease neurons, revealed a non-canonical PTPRG function in RNA modification.\",\n      \"evidence\": \"Co-IP in 5xFAD mouse brain tissue, single-cell and spatial transcriptomics, in vivo validation\",\n      \"pmids\": [\"38325728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PTPRG phosphatase activity is required for VIRMA interaction and stabilization unknown\", \"Mechanism by which PTPRG upregulates VIRMA not defined\", \"Not replicated in human tissue\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"siRNA knockdown of PTPRG in DRG neurons enhanced neurite outgrowth and axonal regeneration, identifying PTPRG as a negative regulator of peripheral nerve regeneration and linking it to metabolic pathway remodeling and PROX1 expression.\",\n      \"evidence\": \"siRNA KD in rat DRG neurons and explants, neurite outgrowth quantification, RNA-seq pathway analysis\",\n      \"pmids\": [\"41323734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PTPRG substrates mediating regeneration suppression not identified\", \"In vivo nerve injury model not performed\", \"Whether catalytic activity or extracellular contactin binding mediates the effect is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the molecular mechanism of HCO₃⁻ sensing by the extracellular domain, the structural basis for RTK substrate selectivity, whether phosphatase activity is required for the VIRMA interaction and vascular functions, and the physiological role of Y1307 auto-dephosphorylation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the full-length receptor or its orientation in the membrane\", \"Comprehensive phosphoproteomics to define the full substrate spectrum not performed\", \"Relationship between contactin binding and intracellular catalytic regulation unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3, 4, 8]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3, 5, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [9, 10, 11, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 6, 8, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CNTN3\",\n      \"CNTN4\",\n      \"CNTN5\",\n      \"CNTN6\",\n      \"EGFR\",\n      \"FGFR1\",\n      \"AXL\",\n      \"VIRMA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}