{"gene":"PTPRA","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2020,"finding":"PTPRA directly interacts with the RET receptor tyrosine kinase and acts as a direct dephosphorylation phosphatase for RET both in vivo and in vitro. The first phosphatase domain (domain-1) of PTPRA is indispensable for its inhibitory role on RET activity and downstream Ras-MAPK signaling, while domain-2 has only minor effect. PTPRA also regulates the RET oncogenic mutant MEN2A activity and invasion capacity, but the MEN2B mutant is insensitive to PTPRA.","method":"Comprehensive interactome mapping (phosphatome interactome analysis), co-immunoprecipitation, phosphoproteomic approach (in vivo and in vitro dephosphorylation assays), domain deletion/mutagenesis, invasion assays","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro and in vivo dephosphorylation assays combined with domain mutagenesis and interactome mapping in a single focused study","pmids":["32062451"],"is_preprint":false},{"year":2019,"finding":"miR-146a-5p inhibits PTPRA expression by binding to its 3'-UTR, and PTPRA positively regulates SRC activation (PTPRA-SRC signaling axis). Restoration of miR-146a-5p suppressed α-SMA and collagen 1 expression in irradiated and TGF-β1-treated hepatic stellate cells, and enhancement of PTPRA partially reversed this suppressive effect.","method":"Dual-luciferase reporter assay (miR-146a-5p targeting of PTPRA 3'-UTR), western blot (SRC phosphorylation), miR-146a-5p overexpression and PTPRA rescue experiments in LX2 cells","journal":"Radiation research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — luciferase validation of miR-146a-5p/PTPRA interaction and PTPRA rescue experiments in a single lab, two orthogonal methods","pmids":["31560641"],"is_preprint":false},{"year":2023,"finding":"miR-146a-5p agomir treatment in irradiated mice reduced PTPRA protein levels and phosphorylated SRC in liver tissue, confirming the PTPRA-SRC signaling axis in vivo in radiation-induced liver fibrosis.","method":"In vivo mouse model (fractionated liver irradiation), miR-146a-5p agomir treatment, western blot for PTPRA and phospho-SRC, histopathological analysis","journal":"Radiation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo corroboration of PTPRA-SRC axis with agomir treatment and protein-level readouts, single lab replicating prior in vitro findings","pmids":["38014555"],"is_preprint":false},{"year":2020,"finding":"PTPRA overexpression promotes NF-κB transcriptional activity in a dose-dependent manner and enhances TNF-α-mediated NF-κB signaling in MCF-7 breast cancer cells; PTPRA knockdown attenuates TNF-α-induced NF-κB activity, cell proliferation, and migration.","method":"Luciferase reporter assay (NF-κB pathway activation by PTPRA in HEK293T cells), growth curve, colony formation, Transwell assay, PTPRA knockdown and overexpression in MCF-7 cells","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase reporter and cell-based assays in a single lab without biochemical reconstitution of the PTPRA-NF-κB connection","pmids":["32934700"],"is_preprint":false},{"year":2022,"finding":"The PTPRA p.R223W missense mutation does not impair RPTPα expression or plasma membrane trafficking in HEK293T cells, but alters proteolytic processing of RPTPα (accumulation of a cleavage product) and results in decreased activation of Src family kinases.","method":"Overexpression of wild-type and R223W mutant RPTPα in HEK293T cells, western blot for expression and cleavage products, plasma membrane trafficking assay, Src family kinase activation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct comparison of WT vs. mutant protein in cellular system with multiple functional readouts (trafficking, proteolytic processing, kinase activation), single lab","pmids":["35900966"],"is_preprint":false},{"year":1995,"finding":"The Ptpra gene (encoding receptor-like protein tyrosine phosphatase PTPα/LRP) was mapped to rat chromosome 3q36 and mouse chromosome 2G by fluorescence in situ hybridization, establishing conserved synteny with human 20p13.","method":"Fluorescence in situ hybridization (FISH) in rat and mouse","journal":"Idengaku zasshi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single mapping study, no functional mechanism established beyond chromosomal localization","pmids":["8790445"],"is_preprint":false}],"current_model":"PTPRA (RPTPα) is a receptor-type protein tyrosine phosphatase whose first catalytic domain directly dephosphorylates the RET receptor tyrosine kinase to suppress Ras-MAPK signaling; it also activates Src family kinases (a function impaired by the R223W mutation that alters proteolytic processing), positively regulates NF-κB transcriptional activity downstream of TNF-α in breast cancer cells, and is subject to negative regulation by miR-146a-5p targeting its 3'-UTR, which suppresses the PTPRA-SRC signaling axis in hepatic stellate cells."},"narrative":{"mechanistic_narrative":"PTPRA (RPTPα) is a receptor-type protein tyrosine phosphatase that controls tyrosine kinase signaling output in opposing ways depending on substrate context [PMID:32062451, PMID:35900966]. It binds the RET receptor tyrosine kinase and directly dephosphorylates it, with its membrane-proximal first phosphatase domain (domain-1) being indispensable for suppressing RET activity and downstream Ras-MAPK signaling; PTPRA restrains the oncogenic MEN2A RET mutant and its invasion phenotype, whereas the MEN2B mutant is insensitive to it [PMID:32062451]. In contrast to its inhibitory action on RET, PTPRA positively drives Src family kinase activation, and the p.R223W missense mutation that alters RPTPα proteolytic processing leads to decreased Src family kinase activation [PMID:35900966]. This PTPRA-SRC axis is held in check by miR-146a-5p, which binds the PTPRA 3'-UTR to repress its expression; loss of this repression elevates phospho-SRC and promotes a fibrotic phenotype in hepatic stellate cells and irradiated liver [PMID:31560641, PMID:38014555]. Beyond these signaling roles, no broader cellular or structural mechanism for PTPRA has been characterized in the available corpus.","teleology":[{"year":1995,"claim":"Before functional studies, the genomic position of Ptpra was unknown; mapping placed the gene on rat chromosome 3q36 and mouse chromosome 2G, establishing conserved synteny with human 20p13 and a basis for cross-species study.","evidence":"Fluorescence in situ hybridization in rat and mouse","pmids":["8790445"],"confidence":"Low","gaps":["Single mapping study with no functional mechanism established","No link to protein activity or substrates"]},{"year":2019,"claim":"It was unclear how PTPRA expression is post-transcriptionally controlled and what kinase it regulates; miR-146a-5p was shown to bind the PTPRA 3'-UTR to repress it, defining a PTPRA-SRC signaling axis whose loss promotes fibrotic markers in hepatic stellate cells.","evidence":"Dual-luciferase 3'-UTR reporter, western blot for SRC phosphorylation, and miR-146a-5p overexpression with PTPRA rescue in LX2 cells","pmids":["31560641"],"confidence":"Medium","gaps":["Whether PTPRA dephosphorylates an inhibitory SRC site directly was not biochemically reconstituted","Single-lab in vitro evidence"]},{"year":2020,"claim":"The direct substrate of PTPRA in receptor tyrosine kinase signaling was undefined; interactome and dephosphorylation assays identified RET as a direct substrate and showed domain-1 is required for suppressing RET-driven Ras-MAPK signaling and invasion, with differential effects on MEN2A versus MEN2B mutants.","evidence":"Phosphatome interactome mapping, co-IP, in vivo and in vitro dephosphorylation assays, domain deletion/mutagenesis, invasion assays","pmids":["32062451"],"confidence":"High","gaps":["Why the MEN2B mutant is insensitive to PTPRA is not mechanistically explained","Cell-type breadth of the PTPRA-RET relationship not established"]},{"year":2020,"claim":"Whether PTPRA influences inflammatory transcription was untested; reporter and cell-based assays indicated PTPRA promotes TNF-α-mediated NF-κB activity, proliferation, and migration in MCF-7 breast cancer cells.","evidence":"NF-κB luciferase reporter in HEK293T, growth/colony/Transwell assays with PTPRA knockdown and overexpression in MCF-7 cells","pmids":["32934700"],"confidence":"Low","gaps":["No biochemical reconstitution of how PTPRA connects to NF-κB","Single-lab cell-based evidence only","Direct phosphatase substrate in this pathway not identified"]},{"year":2022,"claim":"The consequence of the PTPRA p.R223W variant was unknown; comparison of WT and mutant protein showed normal expression and membrane trafficking but altered proteolytic processing and decreased Src family kinase activation, linking proteolytic processing to RPTPα signaling output.","evidence":"WT vs R223W overexpression in HEK293T, western blot for cleavage products, membrane trafficking assay, Src family kinase activation assay","pmids":["35900966"],"confidence":"Medium","gaps":["The protease responsible for the altered cleavage is not identified","Physiological/disease context of R223W not established in patients","Single-lab cellular system"]},{"year":2023,"claim":"It was unclear whether the miR-146a-5p/PTPRA-SRC axis operates in vivo; agomir treatment of irradiated mice reduced PTPRA and phospho-SRC in liver, confirming the axis in radiation-induced liver fibrosis.","evidence":"Fractionated liver irradiation mouse model with miR-146a-5p agomir, western blot for PTPRA and phospho-SRC, histopathology","pmids":["38014555"],"confidence":"Medium","gaps":["Direct demonstration that PTPRA acts on SRC enzymatically in this tissue is lacking","Other miR-146a-5p targets could contribute to the phenotype"]},{"year":null,"claim":"How PTPRA reconciles its opposing roles — inhibiting RET while activating Src family kinases — and what governs substrate selection, localization, and proteolytic regulation across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking domain-1/domain-2 architecture to substrate choice","Mechanism coupling proteolytic processing to SFK activation undefined","Physiological regulators of PTPRA expression beyond miR-146a-5p unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["RET","SRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P18433","full_name":"Receptor-type tyrosine-protein phosphatase alpha","aliases":[],"length_aa":802,"mass_kda":90.7,"function":"Tyrosine protein phosphatase which is involved in integrin-mediated focal adhesion formation (By similarity). Following integrin engagement, specifically recruits BCAR3, BCAR1 and CRK to focal adhesions thereby promoting SRC-mediated phosphorylation of BRAC1 and the subsequent activation of PAK and small GTPase RAC1 and CDC42 (By similarity)","subcellular_location":"Cell membrane; Cell junction, focal adhesion","url":"https://www.uniprot.org/uniprotkb/P18433/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRA","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GRB2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PTPRA","total_profiled":1310},"omim":[{"mim_id":"608712","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, T; PTPRT","url":"https://www.omim.org/entry/608712"},{"mim_id":"602853","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, R; PTPRR","url":"https://www.omim.org/entry/602853"},{"mim_id":"602545","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, KAPPA; PTPRK","url":"https://www.omim.org/entry/602545"},{"mim_id":"602510","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, H; PTPRH","url":"https://www.omim.org/entry/602510"},{"mim_id":"602454","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, U; PTPRU","url":"https://www.omim.org/entry/602454"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTPRA"},"hgnc":{"alias_symbol":["LRP","HLPR","HPTPA","RPTPA"],"prev_symbol":["PTPRL2","PTPA"]},"alphafold":{"accession":"P18433","domains":[{"cath_id":"3.90.190.10","chopping":"222-505","consensus_level":"medium","plddt":96.0738,"start":222,"end":505},{"cath_id":"3.90.190.10","chopping":"534-796","consensus_level":"medium","plddt":95.8502,"start":534,"end":796}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P18433","model_url":"https://alphafold.ebi.ac.uk/files/AF-P18433-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P18433-F1-predicted_aligned_error_v6.png","plddt_mean":81.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRA","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRA"},"sequence":{"accession":"P18433","fasta_url":"https://rest.uniprot.org/uniprotkb/P18433.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P18433/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P18433"}},"corpus_meta":[{"pmid":"33336764","id":"PMC_33336764","title":"CircRNA-PTPRA promoted the progression of atherosclerosis through sponging with miR-636 and upregulating the transcription factor SP1.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33336764","citation_count":41,"is_preprint":false},{"pmid":"35185285","id":"PMC_35185285","title":"Exosomal circ_PTPRA inhibits tumorigenesis and promotes radiosensitivity in colorectal cancer by enriching the level of SMAD4 via competitively binding to miR-671-5p.","date":"2022","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/35185285","citation_count":21,"is_preprint":false},{"pmid":"32062451","id":"PMC_32062451","title":"PTPRA Phosphatase Regulates GDNF-Dependent RET Signaling and Inhibits the RET Mutant MEN2A Oncogenic Potential.","date":"2020","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/32062451","citation_count":17,"is_preprint":false},{"pmid":"31560641","id":"PMC_31560641","title":"MicroRNA-146a-5p Attenuates Fibrosis-related Molecules in Irradiated and TGF-beta1-Treated Human Hepatic Stellate Cells by Regulating PTPRA-SRC Signaling.","date":"2019","source":"Radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/31560641","citation_count":16,"is_preprint":false},{"pmid":"35817886","id":"PMC_35817886","title":"CircRNA-PTPRA Knockdown Inhibits Atherosclerosis Progression by Repressing ox-LDL-Induced Endothelial Cell Injury via Sponging of miR-671-5p.","date":"2022","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35817886","citation_count":13,"is_preprint":false},{"pmid":"30594456","id":"PMC_30594456","title":"Rare variants in Protein tyrosine phosphatase, receptor type A (PTPRA) in schizophrenia: Evidence from a family based study.","date":"2018","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/30594456","citation_count":9,"is_preprint":false},{"pmid":"25393624","id":"PMC_25393624","title":"Resequencing and association analysis of PTPRA, a possible susceptibility gene for schizophrenia and autism spectrum disorders.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25393624","citation_count":7,"is_preprint":false},{"pmid":"34594413","id":"PMC_34594413","title":"circRNA_PTPRA functions as a sponge of miR-582-3p to regulate hepatocellular carcinoma cell proliferation, migration, invasion and apoptosis.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34594413","citation_count":6,"is_preprint":false},{"pmid":"32934700","id":"PMC_32934700","title":"PTPRA facilitates cancer growth and migration via the TNF-α-mediated PTPRA-NF-κB pathway in MCF-7 breast cancer cells.","date":"2020","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/32934700","citation_count":5,"is_preprint":false},{"pmid":"8790445","id":"PMC_8790445","title":"Regional localization of rat and mouse protein-tyrosine phosphatase PTP alpha/LRP gene (Ptpra) by fluorescence in situ hybridization.","date":"1995","source":"Idengaku zasshi","url":"https://pubmed.ncbi.nlm.nih.gov/8790445","citation_count":3,"is_preprint":false},{"pmid":"38014555","id":"PMC_38014555","title":"miR-146a-5p Alleviates Radiation-Induced Liver Fibrosis by Regulating PTPRA-SRC Signaling in Mice.","date":"2023","source":"Radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/38014555","citation_count":1,"is_preprint":false},{"pmid":"35900966","id":"PMC_35900966","title":"Does a rare mutation in PTPRA contribute to the development of Parkinson's disease in an Australian multi-incident family?","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/35900966","citation_count":0,"is_preprint":false},{"pmid":"41383245","id":"PMC_41383245","title":"[Retracted] circRNA_PTPRA functions as a sponge of miR-582-3p to regulate hepatocellular carcinoma cell proliferation, migration, invasion and apoptosis.","date":"2025","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41383245","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.18.638894","title":"A Genetic Analysis of Lipid Metabolism Regulation in Han Chinese Youth in Xinjiang via Extreme Phenotypic Strategies","date":"2025-02-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.18.638894","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9161,"output_tokens":1690,"usd":0.026416,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8496,"output_tokens":2468,"usd":0.05209,"stage2_stop_reason":"end_turn"},"total_usd":0.078506,"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\": 2020,\n      \"finding\": \"PTPRA directly interacts with the RET receptor tyrosine kinase and acts as a direct dephosphorylation phosphatase for RET both in vivo and in vitro. The first phosphatase domain (domain-1) of PTPRA is indispensable for its inhibitory role on RET activity and downstream Ras-MAPK signaling, while domain-2 has only minor effect. PTPRA also regulates the RET oncogenic mutant MEN2A activity and invasion capacity, but the MEN2B mutant is insensitive to PTPRA.\",\n      \"method\": \"Comprehensive interactome mapping (phosphatome interactome analysis), co-immunoprecipitation, phosphoproteomic approach (in vivo and in vitro dephosphorylation assays), domain deletion/mutagenesis, invasion assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro and in vivo dephosphorylation assays combined with domain mutagenesis and interactome mapping in a single focused study\",\n      \"pmids\": [\"32062451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-146a-5p inhibits PTPRA expression by binding to its 3'-UTR, and PTPRA positively regulates SRC activation (PTPRA-SRC signaling axis). Restoration of miR-146a-5p suppressed α-SMA and collagen 1 expression in irradiated and TGF-β1-treated hepatic stellate cells, and enhancement of PTPRA partially reversed this suppressive effect.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-146a-5p targeting of PTPRA 3'-UTR), western blot (SRC phosphorylation), miR-146a-5p overexpression and PTPRA rescue experiments in LX2 cells\",\n      \"journal\": \"Radiation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — luciferase validation of miR-146a-5p/PTPRA interaction and PTPRA rescue experiments in a single lab, two orthogonal methods\",\n      \"pmids\": [\"31560641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-146a-5p agomir treatment in irradiated mice reduced PTPRA protein levels and phosphorylated SRC in liver tissue, confirming the PTPRA-SRC signaling axis in vivo in radiation-induced liver fibrosis.\",\n      \"method\": \"In vivo mouse model (fractionated liver irradiation), miR-146a-5p agomir treatment, western blot for PTPRA and phospho-SRC, histopathological analysis\",\n      \"journal\": \"Radiation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo corroboration of PTPRA-SRC axis with agomir treatment and protein-level readouts, single lab replicating prior in vitro findings\",\n      \"pmids\": [\"38014555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPRA overexpression promotes NF-κB transcriptional activity in a dose-dependent manner and enhances TNF-α-mediated NF-κB signaling in MCF-7 breast cancer cells; PTPRA knockdown attenuates TNF-α-induced NF-κB activity, cell proliferation, and migration.\",\n      \"method\": \"Luciferase reporter assay (NF-κB pathway activation by PTPRA in HEK293T cells), growth curve, colony formation, Transwell assay, PTPRA knockdown and overexpression in MCF-7 cells\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter and cell-based assays in a single lab without biochemical reconstitution of the PTPRA-NF-κB connection\",\n      \"pmids\": [\"32934700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The PTPRA p.R223W missense mutation does not impair RPTPα expression or plasma membrane trafficking in HEK293T cells, but alters proteolytic processing of RPTPα (accumulation of a cleavage product) and results in decreased activation of Src family kinases.\",\n      \"method\": \"Overexpression of wild-type and R223W mutant RPTPα in HEK293T cells, western blot for expression and cleavage products, plasma membrane trafficking assay, Src family kinase activation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct comparison of WT vs. mutant protein in cellular system with multiple functional readouts (trafficking, proteolytic processing, kinase activation), single lab\",\n      \"pmids\": [\"35900966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The Ptpra gene (encoding receptor-like protein tyrosine phosphatase PTPα/LRP) was mapped to rat chromosome 3q36 and mouse chromosome 2G by fluorescence in situ hybridization, establishing conserved synteny with human 20p13.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) in rat and mouse\",\n      \"journal\": \"Idengaku zasshi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single mapping study, no functional mechanism established beyond chromosomal localization\",\n      \"pmids\": [\"8790445\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRA (RPTPα) is a receptor-type protein tyrosine phosphatase whose first catalytic domain directly dephosphorylates the RET receptor tyrosine kinase to suppress Ras-MAPK signaling; it also activates Src family kinases (a function impaired by the R223W mutation that alters proteolytic processing), positively regulates NF-κB transcriptional activity downstream of TNF-α in breast cancer cells, and is subject to negative regulation by miR-146a-5p targeting its 3'-UTR, which suppresses the PTPRA-SRC signaling axis in hepatic stellate cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPRA (RPTPα) is a receptor-type protein tyrosine phosphatase that controls tyrosine kinase signaling output in opposing ways depending on substrate context [#0, #4]. It binds the RET receptor tyrosine kinase and directly dephosphorylates it, with its membrane-proximal first phosphatase domain (domain-1) being indispensable for suppressing RET activity and downstream Ras-MAPK signaling; PTPRA restrains the oncogenic MEN2A RET mutant and its invasion phenotype, whereas the MEN2B mutant is insensitive to it [#0]. In contrast to its inhibitory action on RET, PTPRA positively drives Src family kinase activation, and the p.R223W missense mutation that alters RPTPα proteolytic processing leads to decreased Src family kinase activation [#4]. This PTPRA-SRC axis is held in check by miR-146a-5p, which binds the PTPRA 3'-UTR to repress its expression; loss of this repression elevates phospho-SRC and promotes a fibrotic phenotype in hepatic stellate cells and irradiated liver [#1, #2]. Beyond these signaling roles, no broader cellular or structural mechanism for PTPRA has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Before functional studies, the genomic position of Ptpra was unknown; mapping placed the gene on rat chromosome 3q36 and mouse chromosome 2G, establishing conserved synteny with human 20p13 and a basis for cross-species study.\",\n      \"evidence\": \"Fluorescence in situ hybridization in rat and mouse\",\n      \"pmids\": [\"8790445\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single mapping study with no functional mechanism established\", \"No link to protein activity or substrates\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"It was unclear how PTPRA expression is post-transcriptionally controlled and what kinase it regulates; miR-146a-5p was shown to bind the PTPRA 3'-UTR to repress it, defining a PTPRA-SRC signaling axis whose loss promotes fibrotic markers in hepatic stellate cells.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR reporter, western blot for SRC phosphorylation, and miR-146a-5p overexpression with PTPRA rescue in LX2 cells\",\n      \"pmids\": [\"31560641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PTPRA dephosphorylates an inhibitory SRC site directly was not biochemically reconstituted\", \"Single-lab in vitro evidence\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The direct substrate of PTPRA in receptor tyrosine kinase signaling was undefined; interactome and dephosphorylation assays identified RET as a direct substrate and showed domain-1 is required for suppressing RET-driven Ras-MAPK signaling and invasion, with differential effects on MEN2A versus MEN2B mutants.\",\n      \"evidence\": \"Phosphatome interactome mapping, co-IP, in vivo and in vitro dephosphorylation assays, domain deletion/mutagenesis, invasion assays\",\n      \"pmids\": [\"32062451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why the MEN2B mutant is insensitive to PTPRA is not mechanistically explained\", \"Cell-type breadth of the PTPRA-RET relationship not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether PTPRA influences inflammatory transcription was untested; reporter and cell-based assays indicated PTPRA promotes TNF-α-mediated NF-κB activity, proliferation, and migration in MCF-7 breast cancer cells.\",\n      \"evidence\": \"NF-κB luciferase reporter in HEK293T, growth/colony/Transwell assays with PTPRA knockdown and overexpression in MCF-7 cells\",\n      \"pmids\": [\"32934700\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No biochemical reconstitution of how PTPRA connects to NF-κB\", \"Single-lab cell-based evidence only\", \"Direct phosphatase substrate in this pathway not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The consequence of the PTPRA p.R223W variant was unknown; comparison of WT and mutant protein showed normal expression and membrane trafficking but altered proteolytic processing and decreased Src family kinase activation, linking proteolytic processing to RPTPα signaling output.\",\n      \"evidence\": \"WT vs R223W overexpression in HEK293T, western blot for cleavage products, membrane trafficking assay, Src family kinase activation assay\",\n      \"pmids\": [\"35900966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The protease responsible for the altered cleavage is not identified\", \"Physiological/disease context of R223W not established in patients\", \"Single-lab cellular system\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"It was unclear whether the miR-146a-5p/PTPRA-SRC axis operates in vivo; agomir treatment of irradiated mice reduced PTPRA and phospho-SRC in liver, confirming the axis in radiation-induced liver fibrosis.\",\n      \"evidence\": \"Fractionated liver irradiation mouse model with miR-146a-5p agomir, western blot for PTPRA and phospho-SRC, histopathology\",\n      \"pmids\": [\"38014555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that PTPRA acts on SRC enzymatically in this tissue is lacking\", \"Other miR-146a-5p targets could contribute to the phenotype\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTPRA reconciles its opposing roles — inhibiting RET while activating Src family kinases — and what governs substrate selection, localization, and proteolytic regulation across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model linking domain-1/domain-2 architecture to substrate choice\", \"Mechanism coupling proteolytic processing to SFK activation undefined\", \"Physiological regulators of PTPRA expression beyond miR-146a-5p unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RET\", \"SRC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}