{"gene":"PTPRB","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2014,"finding":"PTPRB harbors predominantly truncating (loss-of-function) somatic mutations in 26% of angiosarcomas (10/39 tumors), identifying it as a negative regulator of vascular growth factor tyrosine kinases and a recurrent driver in angiosarcoma.","method":"Whole-genome, whole-exome, and targeted sequencing of primary and secondary angiosarcoma tumors","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale sequencing across multiple tumor types with recurrent truncating mutations pointing to loss-of-function mechanism, single study","pmids":["24633157"],"is_preprint":false},{"year":2019,"finding":"Deletion of a single allele of Ptprb in Tek haploinsufficient mice elevated TEK phosphorylation, restored Schlemm's canal development, and prevented ocular hypertension and retinal ganglion cell loss, establishing PTPRB as a direct negative regulator of TEK (Tie2) receptor kinase signaling in the aqueous humor outflow pathway.","method":"Genetic epistasis in mice (Tek+/-;Ptprb+/- double haploinsufficiency), measurement of IOP, Schlemm's canal morphology, and RGC counts","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo genetic epistasis with multiple orthogonal phenotypic readouts (IOP, canal development, RGC survival, TEK phosphorylation), replicated in the context of glaucoma","pmids":["31621585"],"is_preprint":false},{"year":2018,"finding":"PTPRB is a direct downstream target of miR-665 in hepatocellular carcinoma; its restoration reverses miR-665-driven migration, invasion, and proliferation, and PTPRB mediates these effects through regulation of the Hippo signaling pathway.","method":"Luciferase reporter assay (direct target validation), Western blotting, gain/loss-of-function cell assays, in vitro and in vivo functional rescue experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus functional rescue, single lab, two orthogonal methods","pmids":["30237408"],"is_preprint":false},{"year":2019,"finding":"PTPRB is a direct downstream target of miR-624-5p in osteosarcoma; PTPRB restoration reverses miR-624-5p-driven migration and invasion, with the Hippo signaling pathway identified as the downstream effector of the miR-624-5p/PTPRB axis.","method":"Luciferase reporter assay, Western blotting, gain/loss-of-function cell and mouse tumorigenicity assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus functional rescue, single lab, two orthogonal methods","pmids":["31829261"],"is_preprint":false},{"year":2016,"finding":"PTPRB regulates Src phosphorylation in NSCLC cells; knockdown of PTPRB increased Src phosphorylation and cell invasion, effects reversed by the Src inhibitor PP2, placing PTPRB as a phosphatase upstream of Src in lung cancer signaling.","method":"Lentiviral overexpression/shRNA knockdown, phospho-Src Western blotting, pharmacological rescue with PP2, xenograft mouse model","journal":"Clinical and experimental pharmacology & physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue epistasis combined with KD/OE, single lab","pmids":["27314562"],"is_preprint":false},{"year":2017,"finding":"PTPRB negatively regulates branching morphogenesis in the mouse mammary epithelium by modulating FGFR signaling; Ptprb knockdown increased FGFR activation and ERK1/2 phosphorylation at baseline and after FGF2 stimulation, resulting in increased branching density in vivo and in organoids.","method":"In vivo shRNA knockdown in cleared mammary fat pad transplants, in vitro organoid assay, phospho-FGFR and phospho-ERK1/2 Western blotting","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro complementary experiments, biochemical readout of pathway activation, single lab","pmids":["28870991"],"is_preprint":false},{"year":2019,"finding":"PTPRB promotes epithelial-mesenchymal transition (EMT) and metastasis in colorectal cancer cells; PTPRB overexpression decreased vimentin and increased E-cadherin expression; hypoxia-induced EMT and invasion were eliminated by PTPRB knockdown; TWIST1 knockdown blocked migration even when PTPRB was overexpressed, placing PTPRB upstream of TWIST1-dependent EMT.","method":"shRNA knockdown and cDNA overexpression, wound-healing and invasion assays, in vivo metastasis model, Western blotting for EMT markers, epistasis with TWIST1 knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with TWIST1 plus complementary KD/OE with multiple EMT marker readouts, single lab","pmids":["31040266"],"is_preprint":false},{"year":2019,"finding":"PTPRB inhibits brown adipocyte differentiation through its phosphatase activity; ectopic PTPRB overexpression suppressed tyrosine phosphorylation of VEGFR2 and downregulated brown adipocyte genes (UCP-1, PGC-1α, PRDM16, PPARγ, CIDEA), while a catalytically inactive PTPRB mutant had no effect on differentiation or VEGFR2 phosphorylation.","method":"Overexpression of wild-type vs. catalytic-dead PTPRB mutant, phospho-VEGFR2 Western blotting, gene expression analysis of brown adipocyte markers","journal":"Journal of microbiology and biotechnology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis with substrate phosphorylation readout, single lab, single study","pmids":["30845793"],"is_preprint":false},{"year":1992,"finding":"The human PTPRB gene was localized to chromosome 12q15→q21 by in situ hybridization using a cDNA probe.","method":"In situ hybridization with cDNA probe","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cytogenetic localization, standard method for the era","pmids":["1486802"],"is_preprint":false},{"year":2022,"finding":"A rare homozygous splice-acceptor variant in PTPRB (c.56-2A>C) causes aberrant mRNA splicing with deletion of one amino acid (p.Glu19del) in the signal peptide of VE-PTP, associated with hypoplastic left heart syndrome, implicating PTPRB signal peptide integrity in cardiac development.","method":"Whole-genome sequencing, Sanger confirmation, minigene splicing assay, in silico structure prediction","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — minigene splicing assay confirms transcript defect but functional link to cardiac phenotype is inferential; single family","pmids":["36148623"],"is_preprint":false},{"year":2025,"finding":"Exosomal SPRY4 from adipogenic BMSCs directly interacts with PTPRB and enhances its phosphatase activity, causing inhibition of TIE2 receptor autophosphorylation and suppression of downstream PI3K/AKT signaling, thereby impairing angiogenesis in steroid-induced osteonecrosis of the femoral head.","method":"Co-immunoprecipitation and mass spectrometry (SPRY4-PTPRB interaction), Western blotting (TIE2 phosphorylation, PI3K/AKT), tube formation and migration assays, in vivo rat SONFH model with pharmacological modulation","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus mass spectrometry for interaction, biochemical pathway readout, in vivo validation, single lab","pmids":["40660390"],"is_preprint":false},{"year":2024,"finding":"Forsythoside A ameliorates pulmonary fibrosis partly via PTPRB; pharmacological inhibition of PTPRB attenuated the effect of forsythoside A on TGF-β1-induced endothelial-to-mesenchymal transition (EndMT) in HUVECs and fibroblast proliferation in HFL1 cells, placing PTPRB as a required mediator of the anti-fibrotic response.","method":"Pharmacological inhibition of PTPRB in TGF-β1-stimulated HUVECs and HFL1 cells, Western blotting for EMT/fibrosis markers, mouse BLM model","journal":"Phytomedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibitor used (not genetic KO/KD), single lab, mechanism inferred from rescue experiment","pmids":["38788399"],"is_preprint":false}],"current_model":"PTPRB (VE-PTP) is a transmembrane receptor-type protein tyrosine phosphatase that acts as a negative regulator of multiple receptor tyrosine kinases in vascular and epithelial contexts: it directly dephosphorylates and inactivates TEK/TIE2 (controlling Schlemm's canal formation and aqueous humor outflow), VEGFR2 (inhibiting brown adipogenesis), and FGFR (suppressing mammary branching morphogenesis), while also modulating Src phosphorylation in lung cancer cells and acting upstream of TWIST1-dependent EMT in colorectal cancer; its phosphatase catalytic activity is required for these functions, and it is recurrently inactivated by truncating mutations in angiosarcoma."},"narrative":{"mechanistic_narrative":"PTPRB (VE-PTP) is a receptor-type protein tyrosine phosphatase that acts as a negative regulator of receptor tyrosine kinase signaling in vascular and epithelial contexts, with its phosphatase catalytic activity required for these functions [PMID:30845793]. It directly restrains TEK/TIE2 receptor kinase signaling: genetic reduction of Ptprb in Tek-haploinsufficient mice elevated TEK phosphorylation, restored Schlemm's canal development, and prevented ocular hypertension and retinal ganglion cell loss [PMID:31621585]. PTPRB likewise dephosphorylates VEGFR2 to suppress brown adipocyte differentiation—an effect abolished by an active-site mutant [PMID:30845793]—and limits FGFR/ERK1/2 activation to constrain mammary branching morphogenesis [PMID:28870991]. In tumor settings PTPRB modulates Src phosphorylation and invasion in NSCLC [PMID:27314562] and acts upstream of TWIST1-dependent EMT in colorectal cancer [PMID:31040266]. Consistent with a tumor-suppressive role, recurrent truncating loss-of-function mutations occur in angiosarcoma [PMID:24633157]. Its phosphatase activity is amplified by physical interaction with exosomal SPRY4, which enhances TIE2 dephosphorylation and dampens downstream PI3K/AKT signaling [PMID:40660390].","teleology":[{"year":1992,"claim":"Established the chromosomal location of human PTPRB, providing the genomic anchor for later disease-association studies.","evidence":"In situ hybridization with a cDNA probe mapping to 12q15→q21","pmids":["1486802"],"confidence":"Medium","gaps":["No functional or mechanistic information","Does not address protein activity or substrates"]},{"year":2014,"claim":"Identified PTPRB as a recurrent loss-of-function driver in angiosarcoma, framing it as a negative regulator of vascular growth-factor tyrosine kinases.","evidence":"Whole-genome, whole-exome, and targeted sequencing of angiosarcoma tumors revealing truncating mutations in 26%","pmids":["24633157"],"confidence":"Medium","gaps":["Does not identify the specific kinase substrates dysregulated by truncation","No functional reconstitution of mutant alleles"]},{"year":2016,"claim":"Positioned PTPRB upstream of Src in lung cancer, linking its phosphatase function to invasion control.","evidence":"shRNA knockdown/overexpression with phospho-Src Western blotting and pharmacological rescue by PP2, plus xenograft","pmids":["27314562"],"confidence":"Medium","gaps":["Does not establish direct dephosphorylation of Src by PTPRB","Single lab"]},{"year":2017,"claim":"Demonstrated PTPRB restrains FGFR/ERK signaling to limit epithelial branching, extending its RTK-negative-regulator role to morphogenesis.","evidence":"In vivo shRNA knockdown in mammary fat pad transplants and organoids with phospho-FGFR and phospho-ERK1/2 readouts","pmids":["28870991"],"confidence":"Medium","gaps":["Direct FGFR dephosphorylation not shown biochemically","Single lab"]},{"year":2018,"claim":"Connected PTPRB to Hippo-pathway control as a miRNA-suppressed effector in hepatocellular carcinoma.","evidence":"Luciferase reporter validation of miR-665 targeting plus functional rescue in cell and in vivo assays","pmids":["30237408"],"confidence":"Medium","gaps":["Mechanism of Hippo pathway regulation by PTPRB unresolved","No phosphatase substrate identified in this context"]},{"year":2019,"claim":"Showed PTPRB phosphatase activity directly inactivates VEGFR2 to block brown adipogenesis, providing catalytic-dependence evidence via active-site mutagenesis.","evidence":"Overexpression of wild-type vs catalytic-dead PTPRB with phospho-VEGFR2 Western blot and adipocyte marker analysis","pmids":["30845793"],"confidence":"Medium","gaps":["Direct enzyme-substrate assay on VEGFR2 not reconstituted in vitro","Single study"]},{"year":2019,"claim":"Provided clean in vivo genetic proof that PTPRB directly antagonizes TEK/TIE2 signaling in Schlemm's canal development and IOP control.","evidence":"Tek+/-;Ptprb+/- double-haploinsufficiency mice with IOP, canal morphology, RGC counts, and TEK phosphorylation readouts","pmids":["31621585"],"confidence":"High","gaps":["Does not show direct biochemical dephosphorylation of TEK by PTPRB","Outflow-pathway specificity of other substrates unaddressed"]},{"year":2019,"claim":"Placed PTPRB upstream of TWIST1-dependent EMT and as a Hippo-linked miRNA target across additional cancers, broadening its tumor-modulating role.","evidence":"Epistasis with TWIST1 knockdown in colorectal cells and luciferase/rescue in osteosarcoma with miR-624-5p, plus in vivo models","pmids":["31040266","31829261"],"confidence":"Medium","gaps":["Direction of PTPRB effect differs between tumor types (suppressive vs EMT-promoting) without unifying mechanism","Substrates linking PTPRB to TWIST1 unidentified"]},{"year":2022,"claim":"Linked PTPRB signal-peptide integrity to cardiac development through a Mendelian variant.","evidence":"Whole-genome sequencing and minigene splicing assay of a homozygous splice-acceptor variant in a single family with hypoplastic left heart syndrome","pmids":["36148623"],"confidence":"Low","gaps":["Functional link to cardiac phenotype is inferential; single family","No functional protein assay of the p.Glu19del product"]},{"year":2025,"claim":"Identified a direct physical regulator of PTPRB, showing SPRY4 binding enhances its phosphatase activity against TIE2 and dampens PI3K/AKT-driven angiogenesis.","evidence":"Reciprocal Co-IP with mass spectrometry, phospho-TIE2 and PI3K/AKT Western blots, tube formation assays, and an in vivo rat SONFH model","pmids":["40660390"],"confidence":"Medium","gaps":["Structural basis of SPRY4-mediated activation not defined","Single lab"]},{"year":null,"claim":"How PTPRB substrate selectivity is determined and whether its opposing roles across tissues reflect distinct substrate repertoires remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vitro reconstituted phosphatase-substrate assays for TEK, VEGFR2, or FGFR","No structural model of substrate engagement","Mechanism reconciling tumor-suppressive vs EMT-promoting roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,7,5,10]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[7,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7,5,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0]}],"complexes":[],"partners":["TEK","VEGFR2","FGFR1","SRC","SPRY4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23467","full_name":"Receptor-type tyrosine-protein phosphatase beta","aliases":["Vascular endothelial protein tyrosine phosphatase","VE-PTP"],"length_aa":1997,"mass_kda":224.3,"function":"Plays an important role in blood vessel remodeling and angiogenesis. Not necessary for the initial formation of blood vessels, but is essential for their maintenance and remodeling. Can induce dephosphorylation of TEK/TIE2, CDH5/VE-cadherin and KDR/VEGFR-2. Regulates angiopoietin-TIE2 signaling in endothelial cells. Acts as a negative regulator of TIE2, and controls TIE2 driven endothelial cell proliferation, which in turn affects blood vessel remodeling during embryonic development and determines blood vessel size during perinatal growth. Essential for the maintenance of endothelial cell contact integrity and for the adhesive function of VE-cadherin in endothelial cells and this requires the presence of plakoglobin (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P23467/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRB","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTPRB","total_profiled":1310},"omim":[{"mim_id":"618608","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH NASAL SPEECH, DYSMORPHIC FACIES, AND VARIABLE SKELETAL ANOMALIES; IDNADFS","url":"https://www.omim.org/entry/618608"},{"mim_id":"602510","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, H; PTPRH","url":"https://www.omim.org/entry/602510"},{"mim_id":"176882","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, BETA; PTPRB","url":"https://www.omim.org/entry/176882"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTPRB"},"hgnc":{"alias_symbol":[],"prev_symbol":["PTPB"]},"alphafold":{"accession":"P23467","domains":[{"cath_id":"2.60.40.10","chopping":"32-110","consensus_level":"medium","plddt":70.5091,"start":32,"end":110},{"cath_id":"2.60.40.10","chopping":"115-203","consensus_level":"medium","plddt":78.0265,"start":115,"end":203},{"cath_id":"2.60.40.10","chopping":"204-287","consensus_level":"medium","plddt":81.0387,"start":204,"end":287},{"cath_id":"2.60.40.10","chopping":"294-375","consensus_level":"medium","plddt":83.8151,"start":294,"end":375},{"cath_id":"2.60.40.10","chopping":"385-465","consensus_level":"medium","plddt":81.5563,"start":385,"end":465},{"cath_id":"2.60.40.10","chopping":"468-554","consensus_level":"medium","plddt":79.6005,"start":468,"end":554},{"cath_id":"2.60.40.10","chopping":"559-641","consensus_level":"high","plddt":83.694,"start":559,"end":641},{"cath_id":"2.60.40.10","chopping":"648-729","consensus_level":"high","plddt":80.0805,"start":648,"end":729},{"cath_id":"2.60.40.10","chopping":"736-817","consensus_level":"high","plddt":78.3163,"start":736,"end":817},{"cath_id":"2.60.40.10","chopping":"824-905","consensus_level":"medium","plddt":80.6928,"start":824,"end":905},{"cath_id":"2.60.40.10","chopping":"1000-1023_1036-1083","consensus_level":"high","plddt":81.8486,"start":1000,"end":1083},{"cath_id":"2.60.40","chopping":"1090-1139_1153-1170","consensus_level":"medium","plddt":80.5453,"start":1090,"end":1170},{"cath_id":"2.60.40.10","chopping":"1181-1259","consensus_level":"high","plddt":84.1509,"start":1181,"end":1259},{"cath_id":"-","chopping":"1269-1342","consensus_level":"high","plddt":82.0577,"start":1269,"end":1342},{"cath_id":"2.60.40.10","chopping":"1360-1444","consensus_level":"high","plddt":83.6765,"start":1360,"end":1444},{"cath_id":"-","chopping":"1460-1615","consensus_level":"high","plddt":81.5183,"start":1460,"end":1615},{"cath_id":"3.90.190.10","chopping":"1684-1975","consensus_level":"high","plddt":88.4963,"start":1684,"end":1975}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23467","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23467-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23467-F1-predicted_aligned_error_v6.png","plddt_mean":80.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRB","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRB"},"sequence":{"accession":"P23467","fasta_url":"https://rest.uniprot.org/uniprotkb/P23467.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23467/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23467"}},"corpus_meta":[{"pmid":"24633157","id":"PMC_24633157","title":"Recurrent 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Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18361428","citation_count":14,"is_preprint":false},{"pmid":"38788399","id":"PMC_38788399","title":"Forsythoside A regulates pulmonary fibrosis by inhibiting endothelial-to-mesenchymal transition and lung fibroblast proliferation via the PTPRB signaling.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38788399","citation_count":13,"is_preprint":false},{"pmid":"18563235","id":"PMC_18563235","title":"Electrocatalytic mechanism and kinetics of SOMs oxidation on ordered PtPb and PtBi intermetallic compounds: DEMS and FTIRS study.","date":"2008","source":"Physical chemistry chemical physics : PCCP","url":"https://pubmed.ncbi.nlm.nih.gov/18563235","citation_count":13,"is_preprint":false},{"pmid":"21671000","id":"PMC_21671000","title":"Electrodeposition of chitosan-glucose oxidase biocomposite onto Pt-Pb nanoparticles modified stainless steel needle electrode for amperometric glucose biosensor.","date":"2011","source":"Journal of materials science. Materials in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21671000","citation_count":11,"is_preprint":false},{"pmid":"40319023","id":"PMC_40319023","title":"Rare genetic variation in PTPRB is associated with central serous chorioretinopathy, varicose veins and glaucoma.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40319023","citation_count":10,"is_preprint":false},{"pmid":"30845793","id":"PMC_30845793","title":"Protein Tyrosine Phosphatase, Receptor Type B (PTPRB) Inhibits Brown Adipocyte Differentiation through Regulation of VEGFR2 Phosphorylation.","date":"2019","source":"Journal of microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/30845793","citation_count":9,"is_preprint":false},{"pmid":"1486802","id":"PMC_1486802","title":"The gene for receptor-like protein tyrosine phosphatase (PTPRB) is assigned to chromosome 12q15-->q21.","date":"1992","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1486802","citation_count":8,"is_preprint":false},{"pmid":"36148623","id":"PMC_36148623","title":"Novel rare mutation in a conserved site of PTPRB causes human hypoplastic left heart syndrome.","date":"2022","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36148623","citation_count":7,"is_preprint":false},{"pmid":"40660390","id":"PMC_40660390","title":"Exosomal SPRY4 from adipogenic BMSCs impairs angiogenesis via the PTPRB/TIE2/PI3K axis in Steroid-induced osteonecrosis of the femoral head.","date":"2025","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40660390","citation_count":6,"is_preprint":false},{"pmid":"19747503","id":"PMC_19747503","title":"Analyzing the catalytic mechanism of protein tyrosine phosphatase PtpB from Staphylococcus aureus through site-directed mutagenesis.","date":"2009","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/19747503","citation_count":5,"is_preprint":false},{"pmid":"34069497","id":"PMC_34069497","title":"The Low-Molecular Weight Protein Arginine Phosphatase PtpB Affects Nuclease Production, Cell Wall Integrity, and Uptake Rates of Staphylococcus aureus by Polymorphonuclear Leukocytes.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34069497","citation_count":4,"is_preprint":false},{"pmid":"20820559","id":"PMC_20820559","title":"Fabrication and surface characterization of single crystal PtBi and PtPb (100) and (001) surfaces.","date":"2010","source":"Physical chemistry chemical physics : PCCP","url":"https://pubmed.ncbi.nlm.nih.gov/20820559","citation_count":4,"is_preprint":false},{"pmid":"40927927","id":"PMC_40927927","title":"Solvothermal synthesis of PtPb nanoparticles with efficient alcohol oxidation performance.","date":"2025","source":"Nanoscale","url":"https://pubmed.ncbi.nlm.nih.gov/40927927","citation_count":2,"is_preprint":false},{"pmid":"36397361","id":"PMC_36397361","title":"The variants in PTPRB, TRAF3IP3, and DISC1 genes were associated with Graves' disease in the Chinese population.","date":"2022","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36397361","citation_count":1,"is_preprint":false},{"pmid":"40935154","id":"PMC_40935154","title":"Mycobacterial Tyrosine Phosphatase PtpB Affects Host Cytokine Expression by Dephosphorylating ERK1/2 and STAT3.","date":"2025","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/40935154","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18948,"output_tokens":3231,"usd":0.052654,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10325,"output_tokens":3059,"usd":0.06405,"stage2_stop_reason":"end_turn"},"total_usd":0.116704,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to distinguish between:\n\n1. **PTPRB** (human/mammalian gene, also known as VE-PTP, vascular endothelial protein tyrosine phosphatase)\n2. **PtpB from Mycobacterium tuberculosis** — a completely different protein, just sharing a symbol\n3. **PtPb** — platinum-lead intermetallic materials (chemistry, not biology)\n4. **PtpB from Staphylococcus aureus** — another bacterial protein\n\nPapers 4, 7, 8, 9, 15, 20, 21, 31, 36 are about M. tuberculosis PtpB — different protein, EXCLUDE.\nPapers 2, 5, 6, 11, 16, 24, 25, 33, 34 are about PtPb chemical materials — EXCLUDE.\nPapers 32 is Staphylococcus aureus PtpB — EXCLUDE.\nPaper 13 is about PTP1B (a different phosphatase) interacting with insulin receptor — EXCLUDE (different gene).\n\nNow extracting from papers about human/mammalian PTPRB:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"PTPRB harbors predominantly truncating (loss-of-function) somatic mutations in 26% of angiosarcomas (10/39 tumors), identifying it as a negative regulator of vascular growth factor tyrosine kinases and a recurrent driver in angiosarcoma.\",\n      \"method\": \"Whole-genome, whole-exome, and targeted sequencing of primary and secondary angiosarcoma tumors\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale sequencing across multiple tumor types with recurrent truncating mutations pointing to loss-of-function mechanism, single study\",\n      \"pmids\": [\"24633157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Deletion of a single allele of Ptprb in Tek haploinsufficient mice elevated TEK phosphorylation, restored Schlemm's canal development, and prevented ocular hypertension and retinal ganglion cell loss, establishing PTPRB as a direct negative regulator of TEK (Tie2) receptor kinase signaling in the aqueous humor outflow pathway.\",\n      \"method\": \"Genetic epistasis in mice (Tek+/-;Ptprb+/- double haploinsufficiency), measurement of IOP, Schlemm's canal morphology, and RGC counts\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo genetic epistasis with multiple orthogonal phenotypic readouts (IOP, canal development, RGC survival, TEK phosphorylation), replicated in the context of glaucoma\",\n      \"pmids\": [\"31621585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRB is a direct downstream target of miR-665 in hepatocellular carcinoma; its restoration reverses miR-665-driven migration, invasion, and proliferation, and PTPRB mediates these effects through regulation of the Hippo signaling pathway.\",\n      \"method\": \"Luciferase reporter assay (direct target validation), Western blotting, gain/loss-of-function cell assays, in vitro and in vivo functional rescue experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus functional rescue, single lab, two orthogonal methods\",\n      \"pmids\": [\"30237408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTPRB is a direct downstream target of miR-624-5p in osteosarcoma; PTPRB restoration reverses miR-624-5p-driven migration and invasion, with the Hippo signaling pathway identified as the downstream effector of the miR-624-5p/PTPRB axis.\",\n      \"method\": \"Luciferase reporter assay, Western blotting, gain/loss-of-function cell and mouse tumorigenicity assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus functional rescue, single lab, two orthogonal methods\",\n      \"pmids\": [\"31829261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PTPRB regulates Src phosphorylation in NSCLC cells; knockdown of PTPRB increased Src phosphorylation and cell invasion, effects reversed by the Src inhibitor PP2, placing PTPRB as a phosphatase upstream of Src in lung cancer signaling.\",\n      \"method\": \"Lentiviral overexpression/shRNA knockdown, phospho-Src Western blotting, pharmacological rescue with PP2, xenograft mouse model\",\n      \"journal\": \"Clinical and experimental pharmacology & physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue epistasis combined with KD/OE, single lab\",\n      \"pmids\": [\"27314562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTPRB negatively regulates branching morphogenesis in the mouse mammary epithelium by modulating FGFR signaling; Ptprb knockdown increased FGFR activation and ERK1/2 phosphorylation at baseline and after FGF2 stimulation, resulting in increased branching density in vivo and in organoids.\",\n      \"method\": \"In vivo shRNA knockdown in cleared mammary fat pad transplants, in vitro organoid assay, phospho-FGFR and phospho-ERK1/2 Western blotting\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro complementary experiments, biochemical readout of pathway activation, single lab\",\n      \"pmids\": [\"28870991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTPRB promotes epithelial-mesenchymal transition (EMT) and metastasis in colorectal cancer cells; PTPRB overexpression decreased vimentin and increased E-cadherin expression; hypoxia-induced EMT and invasion were eliminated by PTPRB knockdown; TWIST1 knockdown blocked migration even when PTPRB was overexpressed, placing PTPRB upstream of TWIST1-dependent EMT.\",\n      \"method\": \"shRNA knockdown and cDNA overexpression, wound-healing and invasion assays, in vivo metastasis model, Western blotting for EMT markers, epistasis with TWIST1 knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with TWIST1 plus complementary KD/OE with multiple EMT marker readouts, single lab\",\n      \"pmids\": [\"31040266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTPRB inhibits brown adipocyte differentiation through its phosphatase activity; ectopic PTPRB overexpression suppressed tyrosine phosphorylation of VEGFR2 and downregulated brown adipocyte genes (UCP-1, PGC-1α, PRDM16, PPARγ, CIDEA), while a catalytically inactive PTPRB mutant had no effect on differentiation or VEGFR2 phosphorylation.\",\n      \"method\": \"Overexpression of wild-type vs. catalytic-dead PTPRB mutant, phospho-VEGFR2 Western blotting, gene expression analysis of brown adipocyte markers\",\n      \"journal\": \"Journal of microbiology and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis with substrate phosphorylation readout, single lab, single study\",\n      \"pmids\": [\"30845793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The human PTPRB gene was localized to chromosome 12q15→q21 by in situ hybridization using a cDNA probe.\",\n      \"method\": \"In situ hybridization with cDNA probe\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cytogenetic localization, standard method for the era\",\n      \"pmids\": [\"1486802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A rare homozygous splice-acceptor variant in PTPRB (c.56-2A>C) causes aberrant mRNA splicing with deletion of one amino acid (p.Glu19del) in the signal peptide of VE-PTP, associated with hypoplastic left heart syndrome, implicating PTPRB signal peptide integrity in cardiac development.\",\n      \"method\": \"Whole-genome sequencing, Sanger confirmation, minigene splicing assay, in silico structure prediction\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — minigene splicing assay confirms transcript defect but functional link to cardiac phenotype is inferential; single family\",\n      \"pmids\": [\"36148623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Exosomal SPRY4 from adipogenic BMSCs directly interacts with PTPRB and enhances its phosphatase activity, causing inhibition of TIE2 receptor autophosphorylation and suppression of downstream PI3K/AKT signaling, thereby impairing angiogenesis in steroid-induced osteonecrosis of the femoral head.\",\n      \"method\": \"Co-immunoprecipitation and mass spectrometry (SPRY4-PTPRB interaction), Western blotting (TIE2 phosphorylation, PI3K/AKT), tube formation and migration assays, in vivo rat SONFH model with pharmacological modulation\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus mass spectrometry for interaction, biochemical pathway readout, in vivo validation, single lab\",\n      \"pmids\": [\"40660390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Forsythoside A ameliorates pulmonary fibrosis partly via PTPRB; pharmacological inhibition of PTPRB attenuated the effect of forsythoside A on TGF-β1-induced endothelial-to-mesenchymal transition (EndMT) in HUVECs and fibroblast proliferation in HFL1 cells, placing PTPRB as a required mediator of the anti-fibrotic response.\",\n      \"method\": \"Pharmacological inhibition of PTPRB in TGF-β1-stimulated HUVECs and HFL1 cells, Western blotting for EMT/fibrosis markers, mouse BLM model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibitor used (not genetic KO/KD), single lab, mechanism inferred from rescue experiment\",\n      \"pmids\": [\"38788399\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRB (VE-PTP) is a transmembrane receptor-type protein tyrosine phosphatase that acts as a negative regulator of multiple receptor tyrosine kinases in vascular and epithelial contexts: it directly dephosphorylates and inactivates TEK/TIE2 (controlling Schlemm's canal formation and aqueous humor outflow), VEGFR2 (inhibiting brown adipogenesis), and FGFR (suppressing mammary branching morphogenesis), while also modulating Src phosphorylation in lung cancer cells and acting upstream of TWIST1-dependent EMT in colorectal cancer; its phosphatase catalytic activity is required for these functions, and it is recurrently inactivated by truncating mutations in angiosarcoma.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPRB (VE-PTP) is a receptor-type protein tyrosine phosphatase that acts as a negative regulator of receptor tyrosine kinase signaling in vascular and epithelial contexts, with its phosphatase catalytic activity required for these functions [#7]. It directly restrains TEK/TIE2 receptor kinase signaling: genetic reduction of Ptprb in Tek-haploinsufficient mice elevated TEK phosphorylation, restored Schlemm's canal development, and prevented ocular hypertension and retinal ganglion cell loss [#1]. PTPRB likewise dephosphorylates VEGFR2 to suppress brown adipocyte differentiation—an effect abolished by an active-site mutant [#7]—and limits FGFR/ERK1/2 activation to constrain mammary branching morphogenesis [#5]. In tumor settings PTPRB modulates Src phosphorylation and invasion in NSCLC [#4] and acts upstream of TWIST1-dependent EMT in colorectal cancer [#6]. Consistent with a tumor-suppressive role, recurrent truncating loss-of-function mutations occur in angiosarcoma [#0]. Its phosphatase activity is amplified by physical interaction with exosomal SPRY4, which enhances TIE2 dephosphorylation and dampens downstream PI3K/AKT signaling [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the chromosomal location of human PTPRB, providing the genomic anchor for later disease-association studies.\",\n      \"evidence\": \"In situ hybridization with a cDNA probe mapping to 12q15→q21\",\n      \"pmids\": [\"1486802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or mechanistic information\", \"Does not address protein activity or substrates\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified PTPRB as a recurrent loss-of-function driver in angiosarcoma, framing it as a negative regulator of vascular growth-factor tyrosine kinases.\",\n      \"evidence\": \"Whole-genome, whole-exome, and targeted sequencing of angiosarcoma tumors revealing truncating mutations in 26%\",\n      \"pmids\": [\"24633157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the specific kinase substrates dysregulated by truncation\", \"No functional reconstitution of mutant alleles\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Positioned PTPRB upstream of Src in lung cancer, linking its phosphatase function to invasion control.\",\n      \"evidence\": \"shRNA knockdown/overexpression with phospho-Src Western blotting and pharmacological rescue by PP2, plus xenograft\",\n      \"pmids\": [\"27314562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish direct dephosphorylation of Src by PTPRB\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated PTPRB restrains FGFR/ERK signaling to limit epithelial branching, extending its RTK-negative-regulator role to morphogenesis.\",\n      \"evidence\": \"In vivo shRNA knockdown in mammary fat pad transplants and organoids with phospho-FGFR and phospho-ERK1/2 readouts\",\n      \"pmids\": [\"28870991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct FGFR dephosphorylation not shown biochemically\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected PTPRB to Hippo-pathway control as a miRNA-suppressed effector in hepatocellular carcinoma.\",\n      \"evidence\": \"Luciferase reporter validation of miR-665 targeting plus functional rescue in cell and in vivo assays\",\n      \"pmids\": [\"30237408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Hippo pathway regulation by PTPRB unresolved\", \"No phosphatase substrate identified in this context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed PTPRB phosphatase activity directly inactivates VEGFR2 to block brown adipogenesis, providing catalytic-dependence evidence via active-site mutagenesis.\",\n      \"evidence\": \"Overexpression of wild-type vs catalytic-dead PTPRB with phospho-VEGFR2 Western blot and adipocyte marker analysis\",\n      \"pmids\": [\"30845793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzyme-substrate assay on VEGFR2 not reconstituted in vitro\", \"Single study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided clean in vivo genetic proof that PTPRB directly antagonizes TEK/TIE2 signaling in Schlemm's canal development and IOP control.\",\n      \"evidence\": \"Tek+/-;Ptprb+/- double-haploinsufficiency mice with IOP, canal morphology, RGC counts, and TEK phosphorylation readouts\",\n      \"pmids\": [\"31621585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not show direct biochemical dephosphorylation of TEK by PTPRB\", \"Outflow-pathway specificity of other substrates unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed PTPRB upstream of TWIST1-dependent EMT and as a Hippo-linked miRNA target across additional cancers, broadening its tumor-modulating role.\",\n      \"evidence\": \"Epistasis with TWIST1 knockdown in colorectal cells and luciferase/rescue in osteosarcoma with miR-624-5p, plus in vivo models\",\n      \"pmids\": [\"31040266\", \"31829261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of PTPRB effect differs between tumor types (suppressive vs EMT-promoting) without unifying mechanism\", \"Substrates linking PTPRB to TWIST1 unidentified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked PTPRB signal-peptide integrity to cardiac development through a Mendelian variant.\",\n      \"evidence\": \"Whole-genome sequencing and minigene splicing assay of a homozygous splice-acceptor variant in a single family with hypoplastic left heart syndrome\",\n      \"pmids\": [\"36148623\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional link to cardiac phenotype is inferential; single family\", \"No functional protein assay of the p.Glu19del product\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a direct physical regulator of PTPRB, showing SPRY4 binding enhances its phosphatase activity against TIE2 and dampens PI3K/AKT-driven angiogenesis.\",\n      \"evidence\": \"Reciprocal Co-IP with mass spectrometry, phospho-TIE2 and PI3K/AKT Western blots, tube formation assays, and an in vivo rat SONFH model\",\n      \"pmids\": [\"40660390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of SPRY4-mediated activation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTPRB substrate selectivity is determined and whether its opposing roles across tissues reflect distinct substrate repertoires remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vitro reconstituted phosphatase-substrate assays for TEK, VEGFR2, or FGFR\", \"No structural model of substrate engagement\", \"Mechanism reconciling tumor-suppressive vs EMT-promoting roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 7, 5, 10]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [7, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7, 5, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TEK\", \"VEGFR2\", \"FGFR1\", \"SRC\", \"SPRY4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}